The DOI matches its Crossref record; 559 of the 562 references it cites were found in a registry or an index; 10 of the 349 sources its claims cite were checked for support.
Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future
Open accessAbstract
Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer’s drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer’s diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment.
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TL;DR
This review argues that Aβ accumulation remains a central driver of AD and that recent anti-Aβ successes—including FDA approval of aducanumab and lecanemab—have revived the amyloid cascade hypothesis. It summarizes Aβ biology, biomarkers, and anti-Aβ drug development while outlining persistent challenges such as insufficient specificity, inadequate animal models, late treatment, and loss of physiological Aβ functions.
Key findings
- Of 298 AD therapies in clinical trials (ALZFORUM, March 2023), 76 target Aβ or its aggregates; 38 were discontinued due to ineffectiveness or toxic side effects, and two antibody-based drugs—aducanumab and lecanemab—have been approved by the FDA.
- Lecanemab’s Phase 3 trial reduced cognitive and functional decline as measured by CDR-SB by 27% versus placebo; ARIA occurred in around 21% of lecanemab-treated individuals versus just over 9% of placebo controls. Donanemab’s partial Phase 3 results showed a 35% slowing of cognitive and functional decline, with 47% of treated participants showing no clinical progression at 1 year versus 29% on placebo.
- BACE1 inhibitors and γ-secretase inhibitors/modulators largely failed or were discontinued because of toxicity, lack of substrate specificity, or insufficient efficacy; examples include LY2886721, atabecestat, elenbecestat, lanabecestat, umibecestat, avagacestat, and several γ-secretase modulators.
- Soluble Aβ at physiological levels has reported functions including enhancement of LTP, stimulation of neuronal differentiation, promotion of injury recovery, antimicrobial activity, tumor suppression, antioxidant effects, neurogenesis, and maintenance of BBB integrity, so therapies should ideally target fibrils, protofibrils, or oligomers while preserving normal Aβ monomers.
Methods
- Narrative review; no systematic review protocol, search strategy, or formal evidence appraisal is stated.
- Sources include published literature and clinical trial registries, specifically ALZFORUM (March 2023) and clinicaltrials.gov (accessed March 19, 2023), plus cited references.
- Main analysis is a narrative synthesis of the amyloid cascade hypothesis, Aβ aggregation and pathological roles, Aβ-based biomarkers, anti-Aβ therapies, challenges, and future directions.
Limitations
- The paper states that anti-Aβ therapy faces disturbed physiological functions of soluble Aβ, insufficient specificity (e.g., γ-secretase and BACE1 off-target effects), lack of accurate animal models, and late application relative to biomarker onset.
- It states that current animal models mainly mimic familial AD and cannot fully reflect late-onset sporadic AD complexity, including aging, human immune differences, and extensive neuronal loss.
- Evident from the text: as a narrative review, it does not describe systematic search or selection criteria, quality appraisal, or quantitative synthesis; conclusions rely on author interpretation of the cited literature.
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Claims the paper makes
199 Not checked yet · 21 Own interpretation · 9 No basis given · 5 Partly supported · 1 Supported · 1 Supported so far · 1 Own result · accuracy not yet measured
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In the paper
“Both genetic (e.g., ApoE4, TREM2) and non-genetic (e.g. diabetes, obesity, stroke, or physical inactivity) risk factors for late-onset sporadic Alzheimer’s disease (SAD) have also been identified to increase Aβ generation and/or reduce Aβ clearance for its accumulation.4,41–45”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Partly supportedcites [4] Liu, X. et al. Clusterin transduces Alzheimer-risk signals to amyloidogenesis. Signal Transduct. Target Ther. 7, 325 (2022). sourceExperimental — accuracy not yet measured
The paper’s main text (page unavailable) reports that ageing, type-2-diabetes models and stroke models upregulate CLU, and concludes that CLU inhibits Aβ degradation and promotes Aβ generation. It does not establish that the cited examples ApoE4, TREM2, obesity or physical inactivity act through those mechanisms; its mention of AD-associated CLU variants does not establish the genetic part of the claim. (LLM, conf=0.86)
- Partly supportedcites [41] DeMattos, R. B. et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41, 193–202 (2004). sourceExperimental — accuracy not yet measured
The Introduction identifies ApoE ε4 as a genetic risk factor for AD, and the paper reports that apoE affects soluble Aβ metabolism in mice. It does not establish that ApoE4 reduces Aβ clearance, or address TREM2 or the listed non-genetic risk factors. The Introduction also says there was no definitive evidence linking increased Aβ production to late-onset AD. (LLM, conf=0.87)
- Not checked yetcites [42] Ridler, C. Alzheimer Disease: Misfolded diabetes-mellitus peptide seeds amyloid-beta aggregation. Nat. Rev. Neurol. 13, 128 (2017). source
- Not checked yetcites [43] Fewlass, D. C. et al. Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J. 18, 1870–1878 (2004). source
- Not checked yetcites [44] Ashok, A., Rai, N. K., Tripathi, S. & Bandyopadhyay, S. Exposure to As-, Cd-, and Pb-mixture induces Abeta, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats. Toxicol. Sci. 143, 64–80 (2015). source
- Not checked yetcites [45] Brown, B. M. et al. Physical activity and amyloid-beta plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Mol. Psychiatry 18, 875–881 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Down syndrome (DS) patients with trisomy-21 having extra copy of APP gene develop typical Alzheimer’s neuropathology including amyloid plaques and neurofibrillary tangles.35–37”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [35] Glenner, G. G. & Wong, C. W. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys. Res Commun. 122, 1131–1135 (1984). source
- Not checked yetcites [36] Burger, P. C. & Vogel, F. S. The development of the pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome. Am. J. Pathol. 73, 457–476 (1973).
- Supportedcites [37] Lemere, C. A. et al. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3, 16–32 (1996). source
The Introduction states that the APP gene is on chromosome 21 and is overexpressed in trisomy 21. It also says that most Down syndrome patients over 40 develop classical Alzheimer’s neuropathology, including amyloid-bearing plaques and neurofibrillary tangles; this age qualification matters because the changes develop over time. (LLM, conf=0.94)
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In the paper
“Inhibition of APP changed the expressions of post-synaptic proteins such as GluA1subunit of AMPA receptors, suggesting the involvement of APP in synaptic formation.391”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Partly supportedcites [391] Martinsson, I. et al. APP depletion alters selective pre- and post-synaptic proteins. Mol. Cell Neurosci. 95, 86–95 (2019). sourceExperimental — accuracy not yet measured
The knockdown results report increased GluA1, a post-synaptic AMPA receptor subunit, after APP depletion. The Discussion interprets this as evidence that APP affects synaptic composition, not specifically synaptic formation; the knockdown was deliberately performed after synapses had formed. (LLM, conf=0.88)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It has been identified that ATG5-dependent autophagy regulates APP degradation.493”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Partly supportedcites [493] Cavieres, V. A. et al. Tetrahydrohyperforin inhibits the proteolytic processing of amyloid precursor protein and enhances its degradation by Atg5-dependent autophagy. PLoS One 10, e0136313 (2015). sourceExperimental — accuracy not yet measured
The Results section reports that Atg5-dependent autophagy facilitates degradation of immature APP following IDN5706 treatment. It also says APP was not significantly degraded by autophagy under basal conditions, so the unqualified claim is broader than the finding. (LLM, conf=0.86)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“A change in CSF Aβ levels can be detected even up to 25 years before a patient begins to show symptoms.478”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Supportedcites [478] McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018). source
The Results report that Aβ showed detectable change beginning at least 25 years before estimated symptom onset and identify CSF Aβ42 as one of the measures. The Discussion says CSF Aβ42 and PET amyloid began changing at nearly the same time. This timing is an estimate from people with dominantly inherited Alzheimer disease, not an observation of each patient's eventual symptom onset. (LLM, conf=0.90)
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In the paper
“Abundant evidence from animal and clinical studies shows a correlation between ocular pathology and AD development.553–555”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Partly supportedcites [553] Tsai, Y. et al. Ocular changes in TgF344-AD rat model of Alzheimer’s disease. Invest Ophthalmol. Vis. Sci. 55, 523–534 (2014). sourceExperimental — accuracy not yet measured
The Abstract describes increasing evidence of retinal changes in AD patients, and the Implications section reports ocular pathology in AD-model rats and choroidal thinning in a limited number of human AD retinas. These passages support an association between ocular pathology and AD, but do not establish a correlation with AD development over time; the authors say further study is needed to relate the ocular changes to changes in the brain. (LLM, conf=0.82)
- Not checked yetcites [554] Chang, L. Y. et al. Alzheimer’s disease in the human eye. Clinical tests that identify ocular and visual information processing deficit as biomarkers. Alzheimers Dement 10, 251–261 (2014). source
- Partly supportedcites [555] Frost, S. et al. Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease. Transl. Psychiatry 3, e233 (2013). sourceExperimental — accuracy not yet measured
The Discussion (page not provided) reports retinal vascular abnormalities in people with AD and an association between some retinal abnormalities and brain amyloid plaque burden. This supports a clinical association, but the paper does not present animal-study evidence or establish that ocular pathology tracks AD development over time; it says longitudinal studies are planned. (LLM, conf=0.85)
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In the paper
“There is an elevation of Aβ peptides during traumatic brain injury (TBI), indicating that Aβ may belong to the pathological cascade of TBI or be an agent for improving recovery.395,396”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [395] Chen, X. H., Johnson, V. E., Uryu, K., Trojanowski, J. Q. & Smith, D. H. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol. 19, 214–223 (2009). source
- Not checked yetcites [396] Pajoohesh-Ganji, A. et al. Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. Brain Res. 1560, 73–82 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Animal models with the expression of human Aβ showed stronger resistance to bacterial and viral infections.365”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [365] Kumar, D. K. et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl. Med 8, 340ra372 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ40 peptides were intracerebroventricularly injected into TBI-impacted BACE1–/– mice, which significantly improved motor memory deficits in these injured mice, suggesting the protective effect of Aβ.362”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [362] Mannix, R. C., Zhang, J., Berglass, J., Qui, J. & Whalen, M. J. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 27, 743–748 (2013). source
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In the paper
“reduction of endogenous Aβ levels by using γ-secretase inhibitor DAPT or deleting the enzyme BACE1 attenuated the functional recovery in mice with spinal cord injury (SCI).396”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [396] Pajoohesh-Ganji, A. et al. Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. Brain Res. 1560, 73–82 (2014). source
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In the paper
“overexpression of human APP (hAPP695) leads to an obvious lower infarct volume in the cortex of mice suffering from cerebral ischemia.363”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [363] Clarke, J. et al. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur. J. Neurosci. 26, 1845–1852 (2007). source
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In the paper
“Aβ peptides are able to interact and entrap various bacterial strains and viruses, such as HSV1 and HSV6, block their entry into the host cells to replicate.402–404”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [402] Spitzer, P. et al. Amyloidogenic amyloid-beta-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci. Rep. 6, 32228 (2016). source
- Not checked yetcites [403] Eimer, W. A. et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56–63.e53 (2018). source
- Not checked yetcites [404] Bourgade, K. et al. beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16, 85–98 (2015). source
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In the paper
“Aβ stimulated the aggregation of viral particles, which facilitated leukocyte-mediated uptake of viruses.405”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [405] White, M. R. et al. Alzheimer’s associated beta-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One 9, e101364 (2014). source
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In the paper
“Aβ42 peptides enhanced the transcription of p53, which is responsible for controlling cell apoptosis.412,413”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [412] Ohyagi, Y. et al. Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB J. 19, 255–257 (2005). source
- Not checked yetcites [413] Alves da Costa, C. et al. Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer’s disease. J. Neurosci. 26, 6377–6385 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both Aβ40 and Aβ42 in physiological concentrations prevented lipoprotein oxidation in CSF and plasma.364,421”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [364] Kontush, A. et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med 30, 119–128 (2001). source
- Not checked yetcites [421] Zou, K., Gong, J. S., Yanagisawa, K. & Michikawa, M. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J. Neurosci. 22, 4833–4841 (2002). source
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In the paper
“Particularly notable is toxicity resulting from inhibition of Notch-1 cleavage, which disrupts essential signaling from this receptor.15,313”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [15] Song, W. et al. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl Acad. Sci. USA 96, 6959–6963 (1999). source
- Not checked yetcites [313] Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999). source
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In the paper
“Bcl-2, another key anti-apoptotic protein, was also shown to be blocked by Aβ42 peptides.416”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [416] Clementi, M. E. et al. Alzheimer’s amyloid beta-peptide (1–42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35. Biochem Biophys. Res. Commun. 342, 206–213 (2006). source
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In the paper
“familial AD mutations accelerated the clearance of C. albicans from brains in mice.408”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [408] Wu, Y. et al. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits. Nat. Commun. 10, 58 (2019). source
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In the paper
“Physiological amounts (picomolar concentrations) of Aβ peptides could function as anti-oxidants by inhibiting redox metals, such as Cu, Fe and Zn to bind with ligands in redox cycling.364”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [364] Kontush, A. et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med 30, 119–128 (2001). source
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In the paper
“Both Aβ40 and Aβ42 peptides have been identified to induce the proliferation and differentiation of neural progenitor cells (NPCs).359,432”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [359] Chen, Y. & Dong, C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 16, 386–394 (2009). source
- Not checked yetcites [432] Lopez-Toledano, M. A. & Shelanski, M. L. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J. Neurosci. 24, 5439–5444 (2004). source
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In the paper
“a study including 45 Alzheimer’s patients between 52 and 97 years of age identified that the number of DCX-positive cells declined with the neuropathological progression.431”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [431] Tobin, M. K. et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell 24, 974–982 (2019). e973. source
plaincorrelationaln = 45- Asserted: passes — The authors put it forward as true.
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In the paper
“the expression of microtubule-associated protein (MAP) isoforms MAP2a, a marker of the mature neuron, was dramatically decreased in the dentate gyrus of human AD brains, indicating a reduction of neuronal maturation in the hippocampus.429”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [429] Li, B. et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J. Neuropathol. Exp. Neurol. 67, 78–84 (2008). source
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In the paper
“In transgenic mice with the expression of human Aβ, the growth rates of implanted glioma tumor masses are inhibited by 40–50% compared to tumor masses in age-matched wild-type mice.411”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [411] Paris, D. et al. Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 30, 11251–11258 (2010). source
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In the paper
“In vitro, application of media containing Aβ successfully inhibits the proliferation of cells, including human glioblastoma, human breast adenocarcinoma, and mouse melanoma cells.409”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [409] Zhao, H. et al. Bioluminescence imaging reveals inhibition of tumor cell proliferation by Alzheimer’s amyloid beta protein. Cancer Cell Int 9, 15 (2009). source
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In the paper
“Aβ peptides stimulate neurogenesis in the subventricular zone (SVZ) through interacting with the p75 neurotrophin receptors in adult mice.433”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [433] Sotthibundhu, A., Li, Q. X., Thangnipon, W. & Coulson, E. J. Abeta(1–42) stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor. Neurobiol. Aging 30, 1975–1985 (2009). source
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In the paper
“In vivo, injection of Aβ into mice transplanted with human glioblastoma and lung adenocarcinoma suppresses the tumor growth.410”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [410] Paris, D. et al. Inhibition of angiogenesis by Abeta peptides. Angiogenesis 7, 75–85 (2004). source
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In the paper
“application of Aβ to primary hippocampal neurons from PSEN1 mutant knock-in mice significantly increased superoxide production.423”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [423] Guo, Q. et al. Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activation. J. Neurochem 72, 1019–1029 (1999). source
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In the paper
“AD patients have significantly lower incidences of several types of cancers, including skin cancer, lung cancer, breast cancer and bladder cancer.366,367”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [366] Frain, L. et al. Association of cancer and Alzheimer’s disease risk in a national cohort of veterans. Alzheimers Dement 13, 1364–1370 (2017). source
- Not checked yetcites [367] Shafi, O. Inverse relationship between Alzheimer’s disease and cancer, and other factors contributing to Alzheimer’s disease: a systematic review. BMC Neurol. 16, 236 (2016). source
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In the paper
“A large amount of studies have shown the anti-oxidant properties of Aβ peptides.418–420”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [418] Baruch-Suchodolsky, R. & Fischer, B. Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. Biochemistry 48, 4354–4370 (2009). source
- Not checked yetcites [419] Faller, P. Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer. Chembiochem 10, 2837–2845 (2009). source
- Not checked yetcites [420] Smith, D. G., Cappai, R. & Barnham, K. J. The redox chemistry of the Alzheimer’s disease amyloid beta peptide. Biochim. Biophys. Acta 1768, 1976–1990 (2007). source
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In the paper
“Our study also showed that PSEN1S169del (a deletion mutation in PSEN1 gene exon 6) has distinct effects on APP processing and Notch1 cleavage.39”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source
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In the paper
“Previous clinical trials of γ-secretase inhibitors have failed, in large part due to the toxicity induced by lack of substrate-specific inhibition.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [15] Song, W. et al. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl Acad. Sci. USA 96, 6959–6963 (1999). source
- Not checked yetcites [313] Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999). source
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In the paper
“the increased generation of Aβ by cells from Alzheimer’s patients with mutant PSEN1 was accompanied by a reduction of ROS levels.422”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [422] Gibson, G. E., Zhang, H., Sheu, K. R. & Park, L. C. Differential alterations in antioxidant capacity in cells from Alzheimer patients. Biochim Biophys. Acta 1502, 319–329 (2000). source
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In the paper
“a reduced number of DCX- and Sox2-positive cells in the AD hippocampus as compared with non-demented controls.430”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [430] Crews, L. et al. Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J. Neurosci. 30, 12252–12262 (2010). source
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In the paper
“AD brains had increased expressions of DCX, PSA-NCAM, TOAD-64/Ulip/CRMP (TUC-4) and NeuroD, indicating the enhanced neurogenesis.428”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [428] Jin, K. et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 101, 343–347 (2004). source
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In the paper
“The produced interferon-γ (IFN-γ) further facilitated Aβ generation to form a positive feedback loop.407”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [407] Mastrangelo, M. A., Sudol, K. L., Narrow, W. C. & Bowers, W. J. Interferon-gamma differentially affects Alzheimer’s disease pathologies and induces neurogenesis in triple transgenic-AD mice. Am. J. Pathol. 175, 2076–2088 (2009). source
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In the paper
“TCM treatment such as morroniside, rutin, resveratrol, triptolide and berberine have already shown their beneficial effects for AD509–527 (Table 3).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [509] Durairajan, S. S. et al. Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol. Aging 33, 2903–2919 (2012). source
- Not checked yetcites [510] Wu, Y. et al. Berberine reduces Abeta42 deposition and tau hyperphosphorylation via ameliorating endoplasmic reticulum stress. Front Pharm. 12, 640758 (2021). source
- Not checked yetcites [511] Zang, C. et al. Gardenia jasminoides J.Ellis extract GJ-4 alleviated cognitive deficits of APP/PS1 transgenic mice. Phytomedicine 93, 153780 (2021). source
- Not checked yetcites [512] Zhang, Z. et al. GJ-4 alleviates Abeta25-35-induced memory dysfunction in mice through protecting the neurovascular unit. Biomed. Pharmacother. 127, 110131 (2020). source
- Not checked yetcites [513] Li, F., Zhang, Y., Lu, X., Shi, J. & Gong, Q. Icariin improves the cognitive function of APP/PS1 mice via suppressing endoplasmic reticulum stress. Life Sci. 234, 116739 (2019). source
- Not checked yetcites [514] Zhu, T. et al. Long-term icariin treatment ameliorates cognitive deficits via CD4(+) T cell-mediated immuno-inflammatory responses in APP/PS1 mice. Clin. Inter. Aging 14, 817–826 (2019). source
- Not checked yetcites [515] Liu, Q. et al. Characterization of a pectin from Lonicera japonica Thunb. and its inhibition effect on Abeta42 aggregation and promotion of neuritogenesis. Int J. Biol. Macromol. 107, 112–120 (2018). source
- Not checked yetcites [516] Wang, P. et al. A glucan isolated from flowers of Lonicera japonica Thunb. inhibits aggregation and neurotoxicity of Abeta42. Carbohydr. Polym. 110, 142–147 (2014). source
- Not checked yetcites [517] Chen, K. et al. Morroniside prevents H2O2 or Abeta1-42-induced apoptosis via attenuating JNK and p38 MAPK phosphorylation. Eur. J. Pharm. 834, 295–304 (2018). source
- Not checked yetcites [518] Ji, Y. J. et al. Crude saponin from platycodon grandiflorum attenuates abeta-induced neurotoxicity via antioxidant, anti-inflammatory and anti-apoptotic signaling pathways. Antioxid. (Basel) 10, 1968 (2021). source
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In the paper
“Accumulation of immature autophagosome in dystrophic neurites has been observed in the brain of Alzheimer’s patients due to the defective axonal transportation of autophagosomes.498”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [498] Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122 (2005). source
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In the paper
“The neurotoxic soluble Aβ oligomers have been identified to affect synaptic plasticity and synaptic transmission in various AD animal models.488”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [488] Klyubin, I. et al. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat. Med. 11, 556–561 (2005). source
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In the paper
“Recent studies identified that 3xTg-AD mice had enhanced mTOR activity in the hippocampus and neocortex, two areas known to have high concentrations of Aβ plaques.502”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [502] Juenemann, K. & Reits, E. A. Alternative macroautophagic pathways. Int J. Cell Biol. 2012, 189794 (2012). source
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In the paper
“Furthermore, the extensive neuronal loss in AD patients has not been replicated in the murine models.476”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [476] Franco, R. & Cedazo-Minguez, A. Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans? Front Pharm. 5, 146 (2014). source
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In the paper
“This AD pathogenic mutation altered APP processing and Aβ generation without affecting Notch-1 cleavage and Notch signaling in vitro and in vivo.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the complex of APP and γ-secretases was found in autophagosomes, suggesting the role of authophgic pathway in the generation of Aβ peptides.494”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [494] Di Meco, A., Curtis, M. E., Lauretti, E. & Pratico, D. Autophagy dysfunction in Alzheimer’s disease: Mechanistic insights and new therapeutic opportunities. Biol. Psychiatry 87, 797–807 (2020). source
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In the paper
“It has been observed that the CSF level of progranulin elevates as early as ten years before the presentation of symptoms in patients with familial or sporadic AD.544”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [544] Suarez-Calvet, M. et al. CSF progranulin increases in the course of Alzheimer’s disease and is associated with sTREM2, neurodegeneration and cognitive decline. EMBO Mol. Med. 10, e9712 (2018). source
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In the paper
“there is a significant reduction of plasma neuronal-derived exosomal neurogranin in AD patients compared with the healthy controls.549”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [549] Goetzl, E. J. et al. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer’s disease. FASEB J. 30, 4141–4148 (2016). source
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In the paper
“Several studies have revealed an elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.547,548”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [547] Portelius, E. et al. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease. Brain 138, 3373–3385 (2015). source
- Not checked yetcites [548] Kester, M. I. et al. Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease. JAMA Neurol. 72, 1275–1280 (2015). source
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In the paper
“Mutations in APP, presenilin 1 (PSEN1) and PSEN2 genes that increase Aβ production, elevate Aβ42/Aβ40 ratio and promote plaque formation cause autosomal dominant early-onset familial AD (FAD)”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [7] Deng, Y. et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962–1969 (2013). source
- Not checked yetcites [38] Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991). source
- Not checked yetcites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source
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In the paper
“Aducanumab, a monoclonal antibody against Aβ aggregates, has obtained the FDA’s approval as an Alzheimer’s drug for its ability to reduce the level of Aβ plaques in patients with early AD or mild cognitive impairment (MCI).46–48”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [46] Sevigny, J. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537, 50–56 (2016). source
- Not checked yetcites [47] Alexander, G. C., Emerson, S. & Kesselheim, A. S. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 325, 1717–1718 (2021). source
- Not checked yetcites [48] Dunn, B., Stein, P. & Cavazzoni, P. Approval of aducanumab for Alzheimer disease-The FDA’s perspective. JAMA Intern Med 181, 1276–1278 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent study showed that it is the classical plaques with inflammatory cells rather than diffuse plaques that correlate with the cognitive impairment during AD.60”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Morphology of Aβ aggregates
What the sources say
- Not checked yetcites [60] Liu, F. et al. Focal-type, but not diffuse-type, amyloid beta plaques are correlated with alzheimer’s neuropathology, cognitive dysfunction, and neuroinflammation in the human hippocampus. Neurosci. Bull. 38, 1125–1138 (2022). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Abstract
What the sources say
- Not checked yetcites [2] Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992). source
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In the paper
“In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.30”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [30] Baranello, R. J. et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr. Alzheimer Res 12, 32–46 (2015). source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies suggest that Aβ accumulation drives disease progression in both FAD and SAD”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
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In the paper
“Failure of perivascular drainage of Aβ altered Aβ homeostasis associated with synaptic dysfunction and cognitive impairment, leading to the development of AD.27”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [27] Hampel, H. et al. The amyloid-beta pathway in Alzheimer’s Disease. Mol. Psychiatry 26, 5481–5503 (2021). source
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In the paper
“Aβ clearance depends on different pathways including enzyme degradation, crossing the blood–brain barrier (BBB), interstitial fluid (ISF) bulk-flow and CSF absorption.19,20”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [19] Bateman, R. J. et al. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat. Med. 12, 856–861 (2006). source
- Not checked yetcites [20] Engelhardt, B. et al. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132, 317–338 (2016). source
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In the paper
“Aβ aggregates and hyperphosphorylated tau protein exert synergistic effect on impairing synapse function.91–93”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [91] Chabrier, M. A., Cheng, D., Castello, N. A., Green, K. N. & LaFerla, F. M. Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol. Dis. 64, 107–117 (2014). source
- Not checked yetcites [92] Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010). source
- Not checked yetcites [93] Marcatti, M. et al. Abeta/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer’s disease. Cell Mol. Life Sci. 79, 222 (2022). source
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In the paper
“the first active comparator study (TRAILBLAZER-ALZ 4), which showed that donanemab, another monoclonal antibody targeting deposited plaques had outperformed aducanumab-avwa treatment in terms of brain amyloid clearance in patients with early symptomatic AD.49”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [49] Mintun, M. A., Wessels, A. M. & Sims, J. R. Donanemab in early Alzheimer’s disease. Reply. N. Engl. J. Med 385, 667 (2021). source
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In the paper
“Aβ oligomers change the morphology and density of synapses, leading to the impairment of synaptic plasticity.76,77”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [76] Shankar, G. M. et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med 14, 837–842 (2008). source
- Not checked yetcites [77] Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M. & Selkoe, D. J. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol. 572, 477–492 (2006). source
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In the paper
“18 months of treatment with lecanemab, a humanized IgG1 monoclonal antibody targeting Aβ soluble protofibrils, reduced markers of amyloid and moderately improved cognitive decline in patients with early AD.50”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [50] van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023). source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Extensive genetic studies have supported the causative role of Aβ accumulation in AD pathogenesis.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
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In the paper
“However, the non-amyloidogenic pathway is the predominant pathway in vivo.7”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [7] Deng, Y. et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962–1969 (2013). source
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In the paper
“Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD)”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Abstract
What the sources say
- Not checked yetcites [1] Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys. Res Commun. 120, 885–890 (1984). source
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In the paper
“Soluble Aβ oligomers disrupted the balance between mitochondrial fission and fusion, leading to significant mitochondrial dysfunction.197,198”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [197] Wang, X. et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J. Neurosci. 29, 9090–9103 (2009). source
- Not checked yetcites [198] Park, J. et al. Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells. J. Neurochem 132, 687–702 (2015). source
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“reduction of tau could ameliorate Aβ-induced Ca2+ influx into neurons and AD-related excitotoxicity in vivo.103”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [103] Pallo, S. P., DiMaio, J., Cook, A., Nilsson, B. & Johnson, G. V. W. Mechanisms of tau and Abeta-induced excitotoxicity. Brain Res. 1634, 119–131 (2016). source
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In the paper
“patients who are with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) for treating other diseases such as rheumatoid arthritis, showed a 50% reduction in the risk for developing AD.155”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [155] Rich, J. B. et al. Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease. Neurology 45, 51–55 (1995). source
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“the absence of tau proteins prevent Aβ-induced LTP impairment mouse hippocampal slices.102”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [102] Shipton, O. A. et al. Tau protein is required for amyloid beta-induced impairment of hippocampal long-term potentiation. J. Neurosci. 31, 1688–1692 (2011). source
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In the paper
“There is an increased Aβ-PET signal within the CEN and the SN in the progression of AD.244,245”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [244] Myers, N. et al. Within-patient correspondence of amyloid-beta and intrinsic network connectivity in Alzheimer’s disease. Brain 137, 2052–2064 (2014). source
- Not checked yetcites [245] Grothe, M. J. & Teipel, S. J., Alzheimer’s Disease Neuroimaging, I. Spatial patterns of atrophy, hypometabolism, and amyloid deposition in Alzheimer’s disease correspond to dissociable functional brain networks. Hum. Brain Mapp. 37, 35–53 (2016). source
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In the paper
“In the development of AD, it has been suggested that Aβ aggregates are the primary driver to activate microglia and set them into motion. Activated microglia migrated to the Aβ deposition and stimulated the phagocytosis of Aβ.166–168”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [166] Baik, S. H., Kang, S., Son, S. M. & Mook-Jung, I. Microglia contributes to plaque growth by cell death due to uptake of amyloid beta in the brain of Alzheimer’s disease mouse model. Glia 64, 2274–2290 (2016). source
- Not checked yetcites [167] Grubman, A. et al. Transcriptional signature in microglia associated with Abeta plaque phagocytosis. Nat. Commun. 12, 3015 (2021). source
- Not checked yetcites [168] Johansson, J. U. et al. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models. J. Clin. Invest 125, 350–364 (2015). source
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In the paper
“Aβ accumulation inhibited the synaptic transmission, resulting in early cognitive impairment.224”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [224] Malinow, R. New developments on the role of NMDA receptors in Alzheimer’s disease. Curr. Opin. Neurobiol. 22, 559–563 (2012). source
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In the paper
“study found that plasma concentrations of soluble β-secretase cleaved n-terminal APP (sAPPβ) were significantly reduced in AD patients compared with age-matched cognitively healthy individuals or patients with behavioral variant frontotemporal dementia (bvFTD)”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [270] Perneczky, R. et al. Soluble amyloid precursor protein beta as blood-based biomarker of Alzheimer’s disease. Transl. Psychiatry 3, e227 (2013). source
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In the paper
“PET and CSF tests also indicate the synergy between Aβ and tau, which leads to brain dysfunction and cognitive impairment.146–148”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [146] Hanseeuw, B. J. et al. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann. Neurol. 81, 583–596 (2017). source
- Not checked yetcites [147] Schultz, A. P. et al. Phases of hyperconnectivity and hypoconnectivity in the default mode and salience networks track with amyloid and tau in clinically normal individuals. J. Neurosci. 37, 4323–4331 (2017). source
- Not checked yetcites [148] Albert, M. et al. Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years. Brain 141, 877–887 (2018). source
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In the paper
“These findings suggest that the synaptic toxicity induced by Aβ was dependent on pathological tau proteins to some extent.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
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In the paper
“The basal forebrain cholinergic system is one of the earliest brain regions vulnerable to degeneration during AD.233”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [233] Geula, C. & Mesulam, M. M. Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer’s disease. Cereb. Cortex 6, 165–177 (1996). source
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In the paper
“Aβ accelerated the tau hyperphosphorylation by the activation of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK-3).116–118”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [116] Plattner, F., Angelo, M. & Giese, K. P. The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J. Biol. Chem. 281, 25457–25465 (2006). source
- Not checked yetcites [117] Hernandez, P., Lee, G., Sjoberg, M. & Maccioni, R. B. Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25–35): involvement of lipid rafts. J. Alzheimers Dis. 16, 149–156 (2009). source
- Not checked yetcites [118] Terwel, D. et al. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am. J. Pathol. 172, 786–798 (2008). source
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In the paper
“The reactive astrocytes are close to Aβ plaques in brains from AD patients and rodent models.183,184”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [183] van Tijn, P. et al. Mutant ubiquitin decreases amyloid beta plaque formation in a transgenic mouse model of Alzheimer’s disease. Neurochem Int 61, 739–748 (2012). source
- Not checked yetcites [184] Vehmas, A. K., Kawas, C. H., Stewart, W. F. & Troncoso, J. C. Immune reactive cells in senile plaques and cognitive decline in Alzheimer’s disease. Neurobiol. Aging 24, 321–331 (2003). source
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In the paper
“APP blocked mitochondrial import machinery and impaired mitochondrial function in AD brain by forming a complex with translocases of the inner and outer mitochondrial membranes.204”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [204] Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G. & Anandatheerthavarada, H. K. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J. Neurosci. 26, 9057–9068 (2006). source
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In the paper
“reduced concentrations of Aβ42 in CSF and increased retention of Aβ tracers in the brain have been considered as early biomarkers of AD.255–258”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [255] Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016). source
- Not checked yetcites [256] Seppala, T. T. et al. CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings. Neurology 78, 1568–1575 (2012). source
- Not checked yetcites [257] Wolk, D. A. et al. Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. Arch. Neurol. 68, 1398–1403 (2011). source
- Not checked yetcites [258] Palmqvist, S., Mattsson, N., Hansson, O. & Alzheimer’s Disease Neuroimaging, I. Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. Brain 139, 1226–1236 (2016). source
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In the paper
“Although the vaccine showed some therapeutic effects, including slowed cognitive decline”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [319] Orgogozo, J. M. et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61, 46–54 (2003). source
- Not checked yetcites [320] Bayer, A. J. et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64, 94–101 (2005). source
- Not checked yetcites [321] Gilman, S. et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562 (2005). source
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In the paper
“indicating the potential role of sAPPβ as a promising new biomarker of AD.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [270] Perneczky, R. et al. Soluble amyloid precursor protein beta as blood-based biomarker of Alzheimer’s disease. Transl. Psychiatry 3, e227 (2013). source
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In the paper
“However, it was halted in the Phase 2 study due to abnormal liver biochemistry values in four participants.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
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In the paper
“LY2886721 was the first BACE inhibitor to reach Phase 2 clinical trials.304”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [304] May, P. C. et al. The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans. J. Neurosci. 35, 1199–1210 (2015). source
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In the paper
“In 1999, BACE1 was identified as an enzyme required for Aβ production.300–303”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [300] Vassar, R. et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999). source
- Not checked yetcites [301] Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell Neurosci. 14, 419–427 (1999). source
- Not checked yetcites [302] Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402, 533–537 (1999). source
- Not checked yetcites [303] Sinha, S. et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537–540 (1999). source
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In the paper
“It also improved the memory deficits in AD model mice.317”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [317] Rogers, K. et al. Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol. Neurodegener. 7, 61 (2012). source
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In the paper
“The first AD vaccine tested in a clinical study was AN1792, a synthetic full-length Aβ42 peptide.318”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [318] Fox, N. C. et al. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 64, 1563–1572 (2005). source
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In the paper
“Vanutide cridificar (ACC-001) is a conjugate of multiple short Aβ fragments to avoid the safety concerns associated with AN1792.322”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [322] Ryan, J. M. & Grundman, M. Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J. Alzheimers Dis. 17, 243 (2009). source
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In the paper
“However, the existing GSIs act too generally, which causes serious side effects through inhibiting the processing of other proteins, such as Notch, a transmembrane receptor involved in regulating cell-fate decisions.15,313”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [15] Song, W. et al. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl Acad. Sci. USA 96, 6959–6963 (1999). source
- Not checked yetcites [313] Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999). source
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In the paper
“Compared to the previous compound, it has better brain penetrance.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [304] May, P. C. et al. The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans. J. Neurosci. 35, 1199–1210 (2015). source
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In the paper
“BACE1 possesses structural similarities with many other aspartyl proteases, such as BACE2, pepsin, renin, cathepsin D and cathepsin E, a significant challenge to achieve the selectivity in BACE1 inhibition without affecting other proteases that cause off-target side effects.310”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [310] Al-Tel, T. H. et al. Design, synthesis, and qualitative structure-activity evaluations of novel beta-secretase inhibitors as potential Alzheimer’s drug leads. J. Med Chem. 54, 8373–8385 (2011). source
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In the paper
“However, it was terminated in Phase 2 trials due to gastrointestinal and dermatological side effects.315”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [315] Coric, V. et al. Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial. JAMA Neurol. 72, 1324–1333 (2015). source
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In the paper
“In addition, the size of the BACE1 active site is relatively large, including catalytic aspartic acid residues, flap, and 10 S loop.311”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [311] Benjannet, S. et al. Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production. J. Biol. Chem. 276, 10879–10887 (2001). source
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In the paper
“Its toxicity was considered to be an off-target effect of the compound, which was not related to BACE1 inhibition (The 11th International Conference on Alzheimer’s & Parkinson’s Disease, 2013).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites The 11th International Conference on Alzheimer’s & Parkinson’s Disease, 2013
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In the paper
“A possible explanation for this side effect is the induction of T helper 2 (Th2) cell responses by the excipients applied to produce C-terminus region of Aβ peptides.321”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [321] Gilman, S. et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562 (2005). source
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In the paper
“the clinical trials were terminated due to the occurrence of aseptic meningoencephalitis in 6% of the participants.319–321”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [319] Orgogozo, J. M. et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61, 46–54 (2003). source
- Not checked yetcites [320] Bayer, A. J. et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64, 94–101 (2005). source
- Not checked yetcites [321] Gilman, S. et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562 (2005). source
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In the paper
“So far, two antibody-based drugs aducanumab and lecanemab have been approved by the FDA”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
What the sources say
- Not checked yetcites [47] Alexander, G. C., Emerson, S. & Kesselheim, A. S. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 325, 1717–1718 (2021). source
- Not checked yetcites [48] Dunn, B., Stein, P. & Cavazzoni, P. Approval of aducanumab for Alzheimer disease-The FDA’s perspective. JAMA Intern Med 181, 1276–1278 (2021). source
- Not checked yetcites [50] van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023). source
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In the paper
“76 of them target the Aβ peptide or its aggregates, including small molecules (Table 1) and immunotherapies (Table 2)”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
What the sources say
- Not checked yetcites ALZFORUM
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In the paper
“Since all the developed BACE1 inhibitors are small molecules, it may be difficult to occupy this large active site to efficiently block BACE1 activity.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
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In the paper
“Low penetrance of blood-brain barrier (BBB) is also another concern.312”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [312] Yuan, J. et al. Structure-based design of beta-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease. J. Med Chem. 56, 4156–4180 (2013). source
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In the paper
“However, all clinical trials using vanutide cridificar were also discontinued following a serious adverse event.323”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [323] Arai, H., Suzuki, H. & Yoshiyama, T. Vanutide cridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer’s disease: results from two phase 2 studies. Curr. Alzheimer Res 12, 242–254 (2015). source
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In the paper
“Accordingly, the subsequent vaccines do not include this region of Aβ peptides.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In the blood, the mAbs interact with Aβ to reduce Aβ concentration, resulting in a concentration gradient that stimulates the efflux of Aβ from the brain.333”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [333] DeMattos, R. B. et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 98, 8850–8855 (2001). source
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In the paper
“The Fc domain of mAbs binds to the Fc-γ receptors on the microglia, leading to the phagocytosis of the Aβ-mAb complex.332”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [332] Bard, F. et al. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc. Natl. Acad. Sci. USA 100, 2023–2028 (2003). source
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In the paper
“It is a humanized version of the mouse anti-Aβ monoclonal 3D6 antibody specifically targeting the N-terminal region of Aβ (residues 1–5).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [330] Waldmann, H. Human monoclonal antibodies: The benefits of humanization. Methods Mol. Biol. 1904, 1–10 (2019). source
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In the paper
“In early of this month (May 3, 2023), Eli Lilly announced partial results of the Phase 3 study showing that donanemab significantly slowed cognitive and functional decline by 35% in patients with early symptomatic AD.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
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In the paper
“Similar to gantenerumab, crenezumab also recognizes multiple forms of Aβ aggregates. It has high affinity with the oligomeric and fibril species and amyloid plaques.339,340”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [339] Adolfsson, O. et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J. Neurosci. 32, 9677–9689 (2012). source
- Not checked yetcites [340] Meilandt, W. J. et al. Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Abeta. Alzheimers Res Ther. 11, 97 (2019). source
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In the paper
“Aβ peptides exist in both the brain and blood throughout an individual’s life.354”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [354] Ullah, R., Park, T. J., Huang, X. & Kim, M. O. Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer’s pathology: Insights and therapeutic approaches from periphery. Ageing Res Rev. 71, 101451 (2021). source
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, 47% of the participants with donanemab for 1 year showed no clinical progression compared with 29% participants on placebo.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
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In the paper
“Compared with unmodified ganterumab, 50 folds more trontinemab entered the brain and bound to Aβ plaques.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“While Lu AF20513 was shown to successfully remove brain amyloid deposits in the initial preclinical study”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [324] Davtyan, H. et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J. Neurosci. 33, 4923–4934 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Passive immunotherapy prevents some issues of the active immunization by using monoclonal antibodies (mAbs) directly targeting different forms of Aβ peptides, including monomers, oligomers and fibrils to inhibit the formation of toxic aggregates.328–331”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [328] Petrushina, I. et al. Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials. Neurobiol. Dis. 139, 104823 (2020). source
- Not checked yetcites [329] Davtyan, H. et al. Testing a MultiTEP-based combination vaccine to reduce Abeta and tau pathology in Tau22/5xFAD bigenic mice. Alzheimers Res Ther. 11, 107 (2019). source
- Not checked yetcites [330] Waldmann, H. Human monoclonal antibodies: The benefits of humanization. Methods Mol. Biol. 1904, 1–10 (2019). source
- Not checked yetcites [331] van Lengerich, B. et al. A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models. Nat. Neurosci. 26, 416–429 (2023).
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The failure may be due to the too low concentrations of the antibody reaching to the brain.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“ALZ-101 is a vaccine specific to soluble Aβ oligomers rather than Aβ monomers or fibrils.325”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [325] Sandberg, A. et al. Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering. Proc. Natl. Acad. Sci. USA 107, 15595–15600 (2010). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Aducanumab is the first FDA-approved therapy for Alzheimer’s.47,48”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [47] Alexander, G. C., Emerson, S. & Kesselheim, A. S. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 325, 1717–1718 (2021). source
- Not checked yetcites [48] Dunn, B., Stein, P. & Cavazzoni, P. Approval of aducanumab for Alzheimer disease-The FDA’s perspective. JAMA Intern Med 181, 1276–1278 (2021). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, routine MRI scans showed around 21% of individuals on lecanemab experienced side effects such as ARIA, compared with just over 9% in placebo-treated controls.352”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [352] Couzin-Frankel, J. & Piller, C. Alzheimer’s drug stirs excitement-and concerns. Science 378, 1030–1031 (2022). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“UB-311 consists of the Aβ1-14 peptides in combination with a Th-cell epitope, which was designed to specifically stimulate Th2 cells regulatory immune responses over Th1-mediated autoimmune responses.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [327] Wang, C. Y. et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 25, 3041–3052 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the Phase 3 clinical trials revealed that bapineuzumab could not improve clinical outcomes in mild to moderate AD patients.335”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [335] Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med 370, 322–333 (2014). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“It has been shown to reduce plaques in imaging studies.347”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [347] Sevigny, J. et al. Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 546, 564 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“clinical trials were terminated due to a lack of efficacy.324”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [324] Davtyan, H. et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J. Neurosci. 33, 4923–4934 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“However, it is considered controversial due to the lack of sufficient evidence to support its efficacy.348,349”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [348] Knopman, D. S., Jones, D. T. & Greicius, M. D. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement 17, 696–701 (2021). source
- Not checked yetcites [349] Mullard, A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat. Rev. Drug Disco. 20, 496 (2021).
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.377,378”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, conditional KO of PSEN1 and PSEN2 to inhibit Aβ production also led to impaired synaptic plasticity and cognitive deficits in animal models.393”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [393] Saura, C. A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the nanomolar concentrations of Aβ used in the study deviate too far from the physiological level of Aβ in picomolar concentrations.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, both synthetic and endogenous Aβ42 monomers in nanomolar concentrations stimulated the activity of cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), which possessed key roles in the regulation of gene expressions related to neuronal functions and survival in normal brains.371,372”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [371] Zimbone, S. et al. Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type-1 insulin-like growth factor receptors in neuronal cells. Aging Cell 17, e12684 (2018). source
- Not checked yetcites [372] Nagahara, A. H. & Tuszynski, M. H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat. Rev. Drug Disco. 10, 209–219 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“To address this concern, other studies injected picomolar concentrations of Aβ peptides into the mice, which also significantly enhanced synaptic plasticity and memory formation.394”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [394] Puzzo, D. et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 28, 14537–14545 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“growing evidence indicates that a normal level of Aβ peptides may play a key role in the maintenance of synaptic function and cognition.368,369”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [368] Lanni, C. et al. Beta-amyloid short- and long-term synaptic entanglement. Pharm. Res. 139, 243–260 (2019). source
- Not checked yetcites [369] Cai, W., Li, L., Sang, S., Pan, X. & Zhong, C. Physiological Roles of beta-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology. Neurosci. Bull. https://doi.org/10.1007/s12264-022-00985-9 (2022). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“An obvious reduction of LTP was found in cultured hippocampal neurons with knockdown of APP expression.392”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [392] Young-Pearse, T. L. et al. A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J. Neurosci. 27, 14459–14469 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although Aβ aggregates, especially the soluble oligomeric species impair synaptic plasticity by inhibition of LTP and induction of LTD”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [368] Lanni, C. et al. Beta-amyloid short- and long-term synaptic entanglement. Pharm. Res. 139, 243–260 (2019). source
- Not checked yetcites [369] Cai, W., Li, L., Sang, S., Pan, X. & Zhong, C. Physiological Roles of beta-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology. Neurosci. Bull. https://doi.org/10.1007/s12264-022-00985-9 (2022). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Among the isofroms, the α7-nAChRs had the highest Ca2+ permeability.381”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [381] Castro, N. G. & Albuquerque, E. X. alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys. J. 68, 516–524 (1995). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, there was an increase of Aβ/nAChR-like complexes in carriers of APOE ε4, a strong risk factor for LOAD.387”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [387] Belloy, M. E., Napolioni, V. & Greicius, M. D. A quarter century of APOE and Alzheimer’s disease: Progress to date and the path forward. Neuron 101, 820–838 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Under physiological conditions, low level of Aβ particularly interacted with the α7 isoform via the nitric oxide/cGMP/protein kinase G pathway to activate the channels.388,389”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [388] Cecon, E. et al. Quantitative assessment of oligomeric amyloid beta peptide binding to alpha7 nicotinic receptor. Br. J. Pharm. 176, 3475–3488 (2019). source
- Not checked yetcites [389] Gulisano, W. et al. Neuromodulatory action of picomolar extracellular Abeta42 oligomers on presynaptic and postsynaptic mechanisms underlying synaptic function and memory. J. Neurosci. 39, 5986–6000 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, application of nanomolar synthetic Aβ successfully enhanced the cognitive and memory performance of the mice.357”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [357] Morley, J. E. et al. A physiological role for amyloid-beta protein:enhancement of learning and memory. J. Alzheimers Dis. 19, 441–449 (2010). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It has been shown that the KLVFF (16~20 amino acid sequence) of Aβ peptides has a protective effect against excitotoxicity, which prevents neuronal death.370”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [370] Giuffrida, M. L. et al. Monomeric ss-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons. Front Cell Neurosci. 9, 297 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“a low level of Aβ peptides may act as a seal to maintain the integrity of the BBB.434”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [434] Atwood, C. S., Bishop, G. M., Perry, G. & Smith, M. A. Amyloid-beta: a vascular sealant that protects against hemorrhage? J. Neurosci. Res. 70, 356 (2002). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The absence of Aβ in neurons may inhibit adequate chelation of metal ions and appropriate removal of O2-, resulting in an increased rather than a reduced oxidative stress.424”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [424] Wang, L. et al. Current understanding of metal ions in the pathogenesis of Alzheimer’s disease. Transl. Neurodegener. 9, 10 (2020). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Aβ has been demonstrated to inhibit tumor cell growth.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, a lack of accurate disease models leads to a translational gap between animal research and the clinical setting.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, a non-selective BACE1 inhibitor also inhibits BACE2’s protective functions, leading to off target side effects.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unfortunately, the current animal models are unable to exactly reflect this complexity, such as aging, which is the major risk factor of sporadic AD.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Growing evidence shows that dysfunction of autophagy is closely linked with Aβ metabolism and accmulation in AD progression.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [493] Cavieres, V. A. et al. Tetrahydrohyperforin inhibits the proteolytic processing of amyloid precursor protein and enhances its degradation by Atg5-dependent autophagy. PLoS One 10, e0136313 (2015). source
- Not checked yetcites [494] Di Meco, A., Curtis, M. E., Lauretti, E. & Pratico, D. Autophagy dysfunction in Alzheimer’s disease: Mechanistic insights and new therapeutic opportunities. Biol. Psychiatry 87, 797–807 (2020). source
- Not checked yetcites [495] Nilsson, P. et al. Abeta secretion and plaque formation depend on autophagy. Cell Rep. 5, 61–69 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Growing evidence shows that elevation of brain Aβ levels in AD could be the consequence of upstream problems including neurovascular dysfunction, disturbed glucose homeostasis, failed control of cell cycle and inflammation.490–492”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [490] Sagare, A. P., Bell, R. D. & Zlokovic, B. V. Neurovascular dysfunction and faulty amyloid beta-peptide clearance in Alzheimer disease. Cold Spring Harb. Perspect. Med 2, a011452 (2012). source
- Not checked yetcites [491] Drachman, D. A. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimers Dement 10, 372–380 (2014). source
- Not checked yetcites [492] Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794–799 (2015). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, such mouse models only mimic the familial AD with an early onset of the disease.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The results indicate that serine169 in PS1 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch-1 cleavage to treat AD.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Autophagy is implicated in Aβ metabolism likely via modulation of its production, secretion and clearance.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“However, murine immune system is notably different from humans.475”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [475] Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004). source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The late-onset sporadic AD is induced by a combination of genetic (e.g. Apolipoprotein E4 and TREM-2),101,102 lifestyle and environmental factors.471–473”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [471] Sims-Robinson, C., Kim, B., Rosko, A. & Feldman, E. L. How does diabetes accelerate Alzheimer disease pathology? Nat. Rev. Neurol. 6, 551–559 (2010). source
- Not checked yetcites [472] Justice, N. J. et al. Posttraumatic stress disorder-like induction elevates beta-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. J. Neurosci. 35, 2612–2623 (2015). source
- Not checked yetcites [473] Migliore, L. & Coppede, F. Gene-environment interactions in Alzheimer disease: the emerging role of epigenetics. Nat. Rev. Neurol. 18, 643–660 (2022). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the current application of Aβ therapies may be too late for symptomatic patients, whose therapeutic window has already closed.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since Aβ aggregates act as the unique specific pathological hallmark of AD and play a causative role in the disease development, they are believed as a promising target for Alzheimer’s modification.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
hedged- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 79
- Probably not a substantial claim. 16
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Besides LY2886721, many other candidates have also reached late stages of clinical trials, including atabecestat (Phase 2/3),305 elenbecestat (Phase 3),306 lanabecestat (Phase 2/3)307,308 and umibecestat (Phase 2/3).309 However, all of them have failed to receive final approval to reach the market.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [305] Sperling, R. et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: A truncated randomized phase 2b/3 clinical trial. JAMA Neurol. 78, 293–301 (2021). source
- Not checked yetcites [306] Madrasi, K. et al. Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer’s disease. Alzheimers Dement 17, 1487–1498 (2021). source
- Not checked yetcites [307] Sakamoto, K. et al. BACE1 inhibitor lanabecestat (AZD3293) in a phase 1 study of healthy Japanese subjects: Pharmacokinetics and effects on plasma and cerebrospinal fluid abeta peptides. J. Clin. Pharm. 57, 1460–1471 (2017). source
- Partly supportedcites [308] Zimmer, J. A. et al. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease. Alzheimers Dement (N. Y) 7, e12123 (2021). sourceExperimental — accuracy not yet measured
The Background reports that lanabecestat reached Phase 2/3 and Phase 3 trials, which were stopped early for futility. It also reports no clinical benefit, but does not state whether lanabecestat received final regulatory approval or reached the market. The other named drugs are not the part of the sentence attached to this citation. (LLM, conf=0.84)
- Partly supportedcites [309] Neumann, U. et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med. 10, e9316 (2018). sourceExperimental — accuracy not yet measured
The Additional information section (page unavailable) says CNP520 was being tested in two long-term Generation prevention studies, supporting the claim that the candidate had advanced to further clinical trials. The paper does not call CNP520 “umibecestat,” specify that those studies were Phase 2/3, or report a later failure to obtain market approval. The other named candidates have separate citations in the citing sentence and are not assessed against this source. (LLM, conf=0.74)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Aβ treatment was found to effectively inhibit the production of proinflammatory T helper cells (TH1 and TH17) and the related cytokines including IL-6, IFN-γ and IL-17, which improved motor paralysis in EAE animal models.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [397] Grant, J. L. et al. Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci. Transl. Med 4, 145ra105 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Aβ peptides also bound to fungal cells and stimulated the phagocytosis of microglia.408”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [408] Wu, Y. et al. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits. Nat. Commun. 10, 58 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ42 induced oxidative stress and decreased the expression of X-linked inhibitor of apoptosis (XIAP), which directly inhibited key proteases of the apoptosis pathway including caspase 3, 7 and 9.414,415”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [414] Yamamori, H., Tanaka, T., Kudo, T. & Takeda, M. Amyloid-beta down-regulates XIAP expression in human SH-SY5Y neuroblastoma cells. Neuroreport 15, 851–854 (2004). source
- Not checked yetcites [415] Chaudhary, A. K. et al. A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy. Drug Disco. Today 21, 38–47 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“brain tissues from AD patients show higher anti-microbial activity than samples from age-matched non-AD individuals, which was correlated with Aβ levels in brain.398”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [398] Soscia, S. J. et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Aβ40 mainly drived differentiation of NPCs into neurons, differing from Aβ42, which increased glia markers in NPCs.359”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [359] Chen, Y. & Dong, C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 16, 386–394 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“verteporfin only bound with the APP transmembrane domain rather than the transmembrane domain of the Notch-1 receptor, indicating its inhibitory effect is in a C99-specific manner.437”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [437] Castro, M. A. et al. Verteporfin is a substrate-selective gamma-secretase inhibitor that binds the amyloid precursor protein transmembrane domain. J. Biol. Chem. 298, 101792 (2022). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ42 stimulated the expression of Bax, which induced cell apoptosis and was commonly observed in many cancers.416,417”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [416] Clementi, M. E. et al. Alzheimer’s amyloid beta-peptide (1–42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35. Biochem Biophys. Res. Commun. 342, 206–213 (2006). source
- Not checked yetcites [417] Liu, Z. et al. Direct activation of Bax protein for cancer therapy. Med Res Rev. 36, 313–341 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“the damaged host cells released nucleic acids containing Aβ aggregates, which were immunogenic and elicited the secretion of type I interferons (IFNs) by adjacent microglia to accomplish the antiviral response.406”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [406] Di Domizio, J. et al. Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity. Proc. Natl Acad. Sci. USA 109, 14550–14555 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“genetic deletion of CatB significantly increased Aβ42 burden and worsened amyloid deposition in AD mice, whereas overexpression of CatB reduced amyloid plaques.497”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [497] Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron 51, 703–714 (2006). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Treatment with rapamycin significantly stimulated autophagy associated with markedly reduced both intracellular Aβ and extracellular amyloid deposition in brains as well as improved cognitive deficits in AD mice.503,504”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [503] Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107–13120 (2010). source
- Not checked yetcites [504] Majumder, S., Richardson, A., Strong, R. & Oddo, S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6, e25416 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“PET imaging allows us to visualize Aβ fibrils in patients, which accumulate in an Alzheimer’s brain as early as 15 years before the onset of symptoms.477”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Not checked yetcites [477] Benzinger, T. L. et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 110, E4502–E4509 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Although crenezumab did not significantly improve cognitive impairment in the participants, it showed some favorable effects (Alzheimer’s Association International Conference, 2022).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Not checked yetcites Alzheimer’s Association International Conference, 2022
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“The data showed that gantenerumab had a positive impact on the reduction of cortical amyloid, leading to its further study by an exploratory open-label extension (OLE).338”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Not checked yetcites [338] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“antibodies with Fc fragment reduced Aβ burden but also induced the engulgment of neuronal synapses by activating complement receptor 3 (CR3) or Fcγ receptor IIB (FcγRIIB), which exacerbates cognitive impairment in AD mice.440”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [440] Sun, X. Y. et al. Fc effector of anti-Abeta antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model. Signal Transduct. Target Ther. 8, 30 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“AD model mice with ATG7 KO showed deficient autophagy associated with drastically reduced extracellular Aβ plaques and markedly accumulated intraneuronal Aβ, suggesting that Aβ secretion was compromised due to the impaired autophagy.495,496”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [495] Nilsson, P. et al. Abeta secretion and plaque formation depend on autophagy. Cell Rep. 5, 61–69 (2013). source
- Not checked yetcites [496] Nilsson, P. et al. Autophagy-related protein 7 deficiency in amyloid beta (Abeta) precursor protein transgenic mice decreases Abeta in the multivesicular bodies and induces Abeta accumulation in the Golgi. Am. J. Pathol. 185, 305–313 (2015). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent study also suggests that depressive symptoms in middle-aged individuals correlates with time to onset of cognitive decline, suggesting the role of psychiatric disorders as early markers of Alzheimer’s disease.556”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [556] Chan, C. K. et al. Depressive symptoms and CSF Alzheimer’s disease biomarkers in relation to clinical symptom onset of mild cognitive impairment. Alzheimers Dement (Amst.) 12, e12106 (2020).
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Unlike cell models, AD brain organoids are capable of generating the blood-brain barrier (BBB) as well as connections with other organs.535”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Patient-based research models
What the sources say
- Not checked yetcites [535] Cazzaniga, A., Fedele, G., Castiglioni, S. & Maier, J. A. The presence of blood-brain barrier modulates the response to magnesium salts in human brain organoids. Int J. Mol. Sci. 23, 5133 (2022). source
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In the paper
“Three-dimensional brain organoids derived from human pluripotent stem cells (hPSCs) have shown significant advantages in modeling neurological disorders including autism, microcephaly and Parkinson’s disease.528–530”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Patient-based research models
What the sources say
- Not checked yetcites [528] Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). source
- Not checked yetcites [529] Chan, W. K., Griffiths, R., Price, D. J. & Mason, J. O. Cerebral organoids as tools to identify the developmental roots of autism. Mol. Autism 11, 58 (2020). source
- Not checked yetcites [530] Smits, L. M. et al. Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis. 5, 5 (2019). source
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the CSF neurogranin increases exclusively in AD patients and has not been observed in other neurodegenerative disorders, such as frontotemporal dementia or Parkinson’s disease.550”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [550] Wellington, H. et al. Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AβOs directly disturb the activity of NMDARs and impair NMDAR-mediated signaling pathways (e.g. Wnt/β-catenin signaling pathway), leading to synaptic loss and the reduction of spinal density.79”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [79] Magdesian, M. H. et al. Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling. J. Biol. Chem. 283, 9359–9368 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AβOs induce AMPAR ubiquitination and degradation, leading to the loss of AMPARs followed by the suppression of synaptic transmission.85,86”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [85] Hsieh, H. et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006). source
- Not checked yetcites [86] Zhang, Y., Guo, O., Huo, Y., Wang, G. & Man, H. Y. Amyloid-beta Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer’s Disease. J. Alzheimers Dis. 62, 1789–1801 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hardy and Higgins then proposed “the amyloid cascade hypothesis” in 1992, positing that Aβ deposits in the brain are the initiating event of AD pathogenesis, resulting in subsequent tau tangle formation, neuronal loss and dysfunction as well as cognitive decline.2”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2)
What the sources say
- Not checked yetcites [2] Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“growing evidence supports that the Aβ oligomers exist and exert their neurotoxicity independently of mature fibrils.61”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [61] Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448–6453 (1998). source
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In the paper
“In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.29”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [29] Silverberg, G. D., Mayo, M., Saul, T., Rubenstein, E. & McGuire, D. Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2, 506–511 (2003). source
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In the paper
“an APP mutation identified in the Icelandic population reduces Aβ production, leading to protection against cognitive decline in the elderly.40”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [40] Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012). source
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In the paper
“AβOs destroy Glu-recycling at the synapse by increasing glutamate release, reducing glutamate uptake and impairing glutamate transporters, which causes the overactivation of extrasyaptic NMDARs, ultimately leading to LTP suppression, LTD enhancement, and synaptic loss.80”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [80] Li, S. et al. Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31, 6627–6638 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It has been identified that the expressions of the two blood efflux transporters LRP1 and ABCB1 were reduced during AD, whereas the expression of the blood influx transporter RAGE is elevated.21,25”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [21] Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018). source
- Not checked yetcites [25] Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This series of positive results offers a fresh hope and indicates that Aβ-based therapy may be indeed the right direction to be followed.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
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In the paper
“ANAVEX®2-73 (Blarcamesine), which targets sigma-1 and M1 muscarinic receptors, has also demonstrated its disease-modifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies as well as improving cognitive deficits.51,52”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [51] Lahmy, V. et al. Blockade of Tau hyperphosphorylation and Abeta(1)(-)(4)(2) generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma(1) receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 38, 1706–1723 (2013). source
- Not checked yetcites [52] Hampel, H. et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study. Alzheimers Dement (N. Y.) 6, e12013 (2020). source
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In the paper
“Aβ aggregates can directly interact with the lipid and cholesterol components of the cell membrane, forming channels and destroying membrane integrity and permeability, which allows Ca2+ entering into the cell, leading to LTP inhibition and neuronal death.62,63”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [62] Bode, D. C., Freeley, M., Nield, J., Palma, M. & Viles, J. H. Amyloid-beta oligomers have a profound detergent-like effect on lipid membrane bilayers, imaged by atomic force and electron microscopy. J. Biol. Chem. 294, 7566–7572 (2019). source
- Not checked yetcites [63] Yasumoto, T. et al. High molecular weight amyloid beta(1-42) oligomers induce neurotoxicity via plasma membrane damage. FASEB J. 33, 9220–9234 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Partial or completed deletion of TREM2 markedly reduced the number of Aβ-associated macrophages and increased cerebral Aβ plaques in AD model mice.174,175,178”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [174] Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med 212, 287–295 (2015). source
- Not checked yetcites [175] Ulrich, J. D. et al. Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014). source
- Not checked yetcites [178] Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Considering the greater availability of blood sampling, blood-based biomarkers become the primary goal in screening for and diagnosing AD in the population and many studies now focus on examining the role of peripheral Aβ and APP in AD development.267–269”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [267] Halle, M. et al. Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies. J. Immunol. Methods 424, 64–79 (2015). source
- Not checked yetcites [268] Frenkel, D. et al. Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat. Commun. 4, 2030 (2013). source
- Not checked yetcites [269] Cheng, Y., Tian, D. Y. & Wang, Y. J. Peripheral clearance of brain-derived Abeta in Alzheimer’s disease: pathophysiology and therapeutic perspectives. Transl. Neurodegener. 9, 16 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Aβ produced by neurons induced the complement protein C3a released by astrocytes via NFκB signaling, which interacted with the receptors (C3aRs) on microglia and neurons to aggravate Aβ aggregate loads and cognitive impairment.191”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [191] Lian, H. et al. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J. Neurosci. 36, 577–589 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both biomarkers have been demonstrated to have high diagnostic and prognostic value as they start changing decades before the onset of dementia symptoms.259–266”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [259] Jack, C. R. Jr. Advances in Alzheimer’s disease research over the past two decades. Lancet Neurol. 21, 866–869 (2022). source
- Not checked yetcites [260] Pike, K. E. et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease. Brain 130, 2837–2844 (2007). source
- Not checked yetcites [261] Rowe, C. C. et al. Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann. Neurol. 74, 905–913 (2013). source
- Not checked yetcites [262] Blennow, K., Mattsson, N., Scholl, M., Hansson, O. & Zetterberg, H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharm. Sci. 36, 297–309 (2015). source
- Not checked yetcites [263] Shaw, L. M. et al. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 121, 597–609 (2011). source
- Not checked yetcites [264] Villemagne, V. L. et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013). source
- Not checked yetcites [265] Toledo, J. B., Shaw, L. M. & Trojanowski, J. Q. Plasma amyloid beta measurements - a desired but elusive Alzheimer’s disease biomarker. Alzheimers Res Ther. 5, 8 (2013). source
- Not checked yetcites [266] Jack, C. R. Jr. & Holtzman, D. M. Biomarker modeling of Alzheimer’s disease. Neuron 80, 1347–1358 (2013). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.241”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [241] Hampton, O. L. et al. Resting-state functional connectivity and amyloid burden influence longitudinal cortical thinning in the default mode network in preclinical Alzheimer’s disease. Neuroimage Clin. 28, 102407 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Redox active metal ions, such as Cu and Fe bind to Aβ to produce the ROS, which contributes to the oxidative damage on proteins and lipids leading to impaired membrane integrity, neuronal dysfunction and DNA damage.217–220”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [217] Smith, M. A., Harris, P. L., Sayre, L. M. & Perry, G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94, 9866–9868 (1997). source
- Not checked yetcites [218] Mao, P. & Reddy, P. H. Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and therapeutics. Biochim Biophys. Acta 1812, 1359–1370 (2011). source
- Not checked yetcites [219] Nakamura, M. et al. Three histidine residues of amyloid-beta peptide control the redox activity of copper and iron. Biochemistry 46, 12737–12743 (2007). source
- Not checked yetcites [220] Bousejra-ElGarah, F., Bijani, C., Coppel, Y., Faller, P. & Hureau, C. Iron(II) binding to amyloid-beta, the Alzheimer’s peptide. Inorg. Chem. 50, 9024–9030 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ aggregates interact with glutamatergic neurotransmission, which impairs excitatory synaptic plasticity, leading to cognitive decline.222–225”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [222] Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8, 1051–1058 (2005). source
- Not checked yetcites [223] Busche, M. A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321, 1686–1689 (2008). source
- Not checked yetcites [224] Malinow, R. New developments on the role of NMDA receptors in Alzheimer’s disease. Curr. Opin. Neurobiol. 22, 559–563 (2012). source
- Not checked yetcites [225] Brito-Moreira, J. et al. Abeta oligomers induce glutamate release from hippocampal neurons. Curr. Alzheimer Res 8, 552–562 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“AβOs induce tau hyperphosphorylation and accumulation in dendritic spine, which further lead to synaptic loss and dysfunction.94,95”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [94] Tai, H. C. et al. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease. Acta Neuropathol. Commun. 2, 146 (2014).
- Not checked yetcites [95] Kaniyappan, S., Chandupatla, R. R., Mandelkow, E. M. & Mandelkow, E. Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimers Dement 13, 1270–1291 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“EVP-0962 is another GSM that was shown to reduce Aβ42 levels and increase Aβ38 levels without affecting Notch signaling in vitro.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [317] Rogers, K. et al. Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol. Neurodegener. 7, 61 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Avagacestat is a recently developed arylsulfonamide γ-secretase inhibitor with high selectivity for APP over Notch, which successfully reduces CSF Aβ levels in the animal models without any Notch-related toxicity.314”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [314] Albright, C. F. et al. Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J. Pharm. Exp. Ther. 344, 686–695 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Our group has also identified that circulating Aβ could pass the blood brain barrier (BBB) and enter the brain, contributing to the development of AD.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [276] Bu, X. L. et al. Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol. Psychiatry 23, 1948–1956 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Preclinical data showed that vanutide cridificar induced the generation of N-terminal anti-Aβ antibodies and successfully improved cognitive impairment in AD animal models.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [322] Ryan, J. M. & Grundman, M. Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J. Alzheimers Dis. 17, 243 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“there is increasing evidence to support that plasma Aβ acts as an endophenotype of AD, which simultaneously changes with Aβ status in the brain.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [271] Palmqvist, S. et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol. Med 11, e11170 (2019). source
- Not checked yetcites [272] Palmqvist, S. et al. Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status. JAMA Neurol. 76, 1060–1069 (2019). source
- Not checked yetcites [273] Damotte, V. et al. Plasma amyloid beta levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants. Alzheimers Dement 17, 1663–1674 (2021). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The blood levels of APP669-711/Aβ42 and Aβ40/Aβ42 ratios, as well as peripheral Aβ-bound extracellular vesicles (EVs), have been shown to predict brain Aβ burden.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [274] Nakamura, A. et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018). source
- Not checked yetcites [275] Yuyama, K. et al. Immuno-digital invasive cleavage assay for analyzing Alzheimer’s amyloid ss-bound extracellular vesicles. Alzheimers Res Ther. 14, 140 (2022). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“According to ALZFORUM (March 2023, www.alzforum.org), 298 AD therapies have been under clinical trials.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
What the sources say
- Not checked yetcites ALZFORUM
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, Aβ peptides in the CNS can also move into the circulatory system, where the peptides are phagocytosed by the monocytes or neutrophils, directly degraded by the enzymes, or further transported to the peripheral organs or tissues for degradation or excretion.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [28] Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015). source
- Not checked yetcites [277] Wang, J., Gu, B. J., Masters, C. L. & Wang, Y. J. A systemic view of Alzheimer disease - insights from amyloid-beta metabolism beyond the brain. Nat. Rev. Neurol. 13, 612–623 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A recent study found that treatment with one potential candidate, SGSM-36, which successfully reduced the level of toxic Aβ42 peptides, without changing the proteolytic processing of Notch or α- and β-secretase processing of APP.316”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [316] Raven, F. et al. Soluble gamma-secretase modulators attenuate Alzheimer’s beta-amyloid pathology and induce conformational changes in presenilin 1. EBioMedicine 24, 93–101 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In 2012, Eli Lilly announced that the application of LY2886721 produced the expected results in Phase 1 studies with reduced CSF levels of Aβ40 and Aβ42 as well as increased sAPPα levels (P3-359, Alzheimer’s Association International Conference, 2012).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites P3-359, Alzheimer’s Association International Conference, 2012
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“UB-311 was shown to neutralize Aβ toxicity and enhance plaque clearance in preclinical studies.327”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [327] Wang, C. Y. et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 25, 3041–3052 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although the aggregates have been considered to be toxic, soluble Aβ at physiological levels have been identified to have biological functions, including enhancement of long-term potentiation (LTP),355–358 stimulation of neuronal differentiation,359 improvement of the brain’s ability to recover from injuries,360–363 inhibition of oxidative stress,364 antimicrobial activity365 and tumor suppression”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [355] Cirrito, J. R. et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913–922 (2005). source
- Not checked yetcites [356] Abramov, E. et al. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat. Neurosci. 12, 1567–1576 (2009). source
- Not checked yetcites [357] Morley, J. E. et al. A physiological role for amyloid-beta protein:enhancement of learning and memory. J. Alzheimers Dis. 19, 441–449 (2010). source
- Not checked yetcites [358] Dineley, K. T., Bell, K. A., Bui, D. & Sweatt, J. D. beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J. Biol. Chem. 277, 25056–25061 (2002). source
- Not checked yetcites [359] Chen, Y. & Dong, C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 16, 386–394 (2009). source
- Not checked yetcites [360] Scott, G. et al. Amyloid pathology and axonal injury after brain trauma. Neurology 86, 821–828 (2016). source
- Not checked yetcites [361] Bird, S. M. et al. Cerebral amyloid-beta accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies. Neurosci. Biobehav Rev. 64, 215–228 (2016). source
- Not checked yetcites [362] Mannix, R. C., Zhang, J., Berglass, J., Qui, J. & Whalen, M. J. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 27, 743–748 (2013). source
- Not checked yetcites [363] Clarke, J. et al. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur. J. Neurosci. 26, 1845–1852 (2007). source
- Not checked yetcites [364] Kontush, A. et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med 30, 119–128 (2001). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Unfortunately, most of the initial trials including the prevention trial failed to achieve their primary endpoints, and crenezumab is now discontinued.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the preclinical studies, ACI-24 was shown to generate high titers of anti-Aβ IgG1 and IgG2b antibodies and improve novel object recognition in AD mice.324”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [324] Davtyan, H. et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J. Neurosci. 33, 4923–4934 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Donanemab is a humanized IgG1 monoclonal antibody targeting the existing amyloid plaques and clearing them from the brain.344”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [344] Demattos, R. B. et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron 76, 908–920 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The results were just published and showed that patients with lecanemab treatment had lower brain amyloid levels and reduced cognitive and functional decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which quantifies symptom severity across a range of cognitive and function domains, by 27% compared with placebo.50”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [50] van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Later, Biogen announced that the interim futility analysis was wrong and the highest dose of aducanumab treatment significantly improved cognitive deficit in the participants (Oct 2019 news, investors.biogen.com).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites Oct 2019 news, investors.biogen.com
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Currently, four vaccines are under the clinical trials, including ALZ-101 (Phase 1), ACI-24 (Phase 2), ABvac 40 (Phase 2) and UB311 (Phase 3).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In the preclinical studies, 3D6 binds to monomeric, oligomeric and fibril forms of Aβ, leading to the reduced levels of Aβ and improved cognitive deficits in AD model mice.334”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [334] Bard, F. et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 (2000). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the Phase 2 trial, it had been identified to successfully reduce brain amyloid and improved cognitive decline in the highest-dose group (twice-monthly 10 mg/kg).351”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [351] Swanson, C. J. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther. 13, 80 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Gantenerumab treatment significantly reduced the amyloid loads and normalized CSF Aβ42 levels.338”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [338] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Lecanemab (BAN2401) is the humanized IgG1 version of the mouse mAb158, which specifically binds to large, soluble Aβ protofibrils.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Humanized antibodies are generated by modifying protein sequences from non-human species to increase their similarity to natural antibody variants produced in humans, which reduce the immunogenicity of the antibodies, enhance human effector functions, and increase the serum half-life of the antibodies in humans.330”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [330] Waldmann, H. Human monoclonal antibodies: The benefits of humanization. Methods Mol. Biol. 1904, 1–10 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Another vaccine called ABvac40 targets the C-terminus of Aβ peptides and is also currently being evaluated in Phase 2 clinical studies.326”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [326] Lacosta, A. M. et al. Safety, tolerability and immunogenicity of an active anti-Abeta40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res. Ther. 10, 12 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the Phase 2 studies, UB-311 also showed its safety and generated Aβ antibodies in 96% of the patients with mild AD (14th International Conference on Alzheimer’s and Parkinson’s Disease, 2019).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites 14th International Conference on Alzheimer’s and Parkinson’s Disease, 2019
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The antibody was found to be safe and well tolerated during the Phase 1 clinical trials, except that transient amyloid-related imaging abnormalities (ARIA) appeared in some patients given a high dosage.336”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [336] Klein, G. et al. Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 11, 101 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although solanezumab was well tolerated in the participants, it was not able to show the significant therapeutic benefits to AD patients.345,346”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [345] Honig, L. S. et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 378, 321–330 (2018). source
- Not checked yetcites [346] Schwarz, A. J. et al. Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer’s disease. Alzheimers Dement (N. Y.) 5, 328–337 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“ACI-24 is a liposome vaccine based on the Aβ1-15 sequences. It is designed to generate antibodies specifically against the β-sheet folding of Aβ.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [324] Davtyan, H. et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J. Neurosci. 33, 4923–4934 (2013). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Just several months ago (Nov 14, 2022), Roche and Genentech announced that the outcome of the Phase 3 trials were disappointing, in which the drugs failed to slow cognitive impairment.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“genetic deletion of APP significantly aggravated the severity of the disease, suggesting the protective role of Aβ against autoimmune inflammation in CNS.397”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [397] Grant, J. L. et al. Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci. Transl. Med 4, 145ra105 (2012). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings suggest that physiological levels of Aβ monomers are crucial to maintain a normal synaptic function while only Aβ aggregates have the inhibitory and toxic effects.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Evidence from patients and animal models also shows rapidly increased Aβ expressions after being injured are beneficial,360–363 indicating the role of Aβ in stimulating the brain to recover from traumatic and ischemic injuries.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [360] Scott, G. et al. Amyloid pathology and axonal injury after brain trauma. Neurology 86, 821–828 (2016). source
- Not checked yetcites [361] Bird, S. M. et al. Cerebral amyloid-beta accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies. Neurosci. Biobehav Rev. 64, 215–228 (2016). source
- Not checked yetcites [362] Mannix, R. C., Zhang, J., Berglass, J., Qui, J. & Whalen, M. J. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 27, 743–748 (2013). source
- Not checked yetcites [363] Clarke, J. et al. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur. J. Neurosci. 26, 1845–1852 (2007). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.379,380”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [379] Sudweeks, S. N. & Yakel, J. L. Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons. J. Physiol. 527, 515–528 (2000). source
- Not checked yetcites [380] Papouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T. & Haydon, P. G. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron 94, 840–854.e847 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, removal of endogenous Aβ by injection of anti-Aβ antibodies or genetic manipulation greatly decreased LTP and impaired memory, which could be rescued by the addition of human Aβ42.357,373–376”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [357] Morley, J. E. et al. A physiological role for amyloid-beta protein:enhancement of learning and memory. J. Alzheimers Dis. 19, 441–449 (2010). source
- Not checked yetcites [373] Seabrook, G. R. et al. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38, 349–359 (1999). source
- Not checked yetcites [374] Garcia-Osta, A. & Alberini, C. M. Amyloid beta mediates memory formation. Learn Mem. 16, 267–272 (2009). source
- Not checked yetcites [375] Puzzo, D. et al. Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory. Ann. Neurol. 69, 819–830 (2011). source
- Not checked yetcites [376] Galanis, C. et al. Amyloid-beta mediates homeostatic synaptic plasticity. J. Neurosci. 41, 5157–5172 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“α7-nAChRs are involved in a variety of biological functions, including neurotransmitter release, synaptic plasticity and neurogenesis.384,385”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [384] Letsinger, A. C., Gu, Z. & Yakel, J. L. alpha7 nicotinic acetylcholine receptors in the hippocampal circuit: taming complexity. Trends Neurosci. 45, 145–157 (2022). source
- Not checked yetcites [385] Townsend, M. et al. alpha7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit. J. Neurophysiol. 116, 2663–2675 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.386”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [386] Nagele, R. G., D’Andrea, M. R., Anderson, W. J. & Wang, H. Y. Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110, 199–211 (2002). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Thus, α7-nAChR KO mice at 12-month-old showed Aβ elevation as a compensatory response of α7-nAChRs and exhibited AD-like pathologies.390”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [390] Tropea, M. R. et al. Genetic deletion of alpha7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer’s disease-like pathology. Prog. Neurobiol. 206, 102154 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As ligand-gated ion channels, nAChRs opened in response to the depolarization of the membrane, allowing Na+, K+ and Ca2+ to enter the cells.381,382”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [381] Castro, N. G. & Albuquerque, E. X. alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys. J. 68, 516–524 (1995). source
- Not checked yetcites [382] Unwin, N. Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes. Q Rev. Biophys. 46, 283–322 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The mechanism behind Aβ-induced α7-nAChR activation could be due to the disruption of intracellular signal transduction to stimulate the calcium influx.383”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [383] Dougherty, J. J., Wu, J. & Nichols, R. A. Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J. Neurosci. 23, 6740–6747 (2003). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Aβ42 cannot prevent the replication of non-enveloped human adenovirus, suggesting that it probably interacts with viral coat proteins.404”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [404] Bourgade, K. et al. beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16, 85–98 (2015). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“a rapid generation and deposition of Aβ in stroke and after head trauma, which could benefit to maintain the BBB integrity and inhibit the leakage of serum components into the brain, leading to neuroinflammation.436”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [436] Roberts, G. W. et al. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 57, 419–425 (1994). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“BACE2 is a close homolog of BACE1 but plays a neuroprotective role by inhibiting the amyloidogenic pathway of APP processing7,8,10 and reducing potassium channel Kv2.1-induced neuronal apoptosis.438”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [7] Deng, Y. et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962–1969 (2013). source
- Not checked yetcites [8] Zhang, S. et al. BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis. J. Neurosci. 37, 6915–6925 (2017). source
- Not checked yetcites [10] Sun, X., He, G. & Song, W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer’s disease in Down syndrome. FASEB J. 20, 1369–1376 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although the human tau gene MAPT mutations per se only cause frontotemporal dementia (FTD) rather than AD,462 tau mediates Aβ toxicity to promote the pathological process of AD.92,137”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [462] D’Souza, I. et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc. Natl. Acad. Sci. USA 96, 5598–5603 (1999). source
- Not checked yetcites [92] Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010). source
- Not checked yetcites [137] Bloom, G. S. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–508 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Less than 1% of all AD cases are early-onset with symptoms developed at an age of 50 s and earlier, and caused by gene mutations in APP, PSEN1 or PSEN2.7,38,39”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [7] Deng, Y. et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962–1969 (2013). source
- Not checked yetcites [38] Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991). source
- Not checked yetcites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Growing evidence indicates that Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leading to the process of neurodegeneration.112–114”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [112] Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019). source
- Not checked yetcites [113] Zhang, Y., Dong, Z. & Song, W. NLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease. Signal Transduct. Target Ther. 5, 37 (2020). source
- Not checked yetcites [114] He, Z. et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“More than 99% of AD cases occur at an age >60 years in a sporadic manner, potentiated by various risk factors related to lifestyle.442”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [442] Daviglus, M. L. et al. National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. Ann. Intern Med 153, 176–181 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“APP and Aβ can be imported into mitochondria, where they can interact with mitochondrial components, impair ATP production, and increase oxidative damage.481,482”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [481] Spuch, C., Ortolano, S. & Navarro, C. New insights in the amyloid-Beta interaction with mitochondria. J. Aging Res. 2012, 324968 (2012). source
- Not checked yetcites [482] Wilkins, H. M. Interactions between amyloid, amyloid precursor protein, and mitochondria. Biochem Soc. Trans. 51, 173–182 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biomarkers are needed for identifying patients with preclinical Alzheimer’s disease so that treatment such as mechanism-based therapy could prevent or slow down the disease.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Combination therapy that targets different mechanisms and pathologies would be directed by biomarkers and customized to the individual.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most Aβ-targeting drug trials have failed as a consequence by lack of sufficient specificity and accurate translational models, loss of Aβ physiological homeostasis, and failure to be administered during the best therapeutic window.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since Aβ aggregates act as the unique specific pathological hallmark of AD and play a causative role in the disease development, they are believed as a promising target for Alzheimer’s modification.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been found that miRNAs are involved in Alzheimer’s pathogenesis and are easily detected in body fluids, including CSF, plasma and serum. Therefore, they become an attractive target for developing AD biomarkers.551,552”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [551] Dehghani, R., Rahmani, F. & Rezaei, N. MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms. Rev. Neurosci. 29, 161–182 (2018). source
- Not checked yetcites [552] Xia, X. et al. Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents. Prog. Neurobiol. 183, 101694 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since Aβ aggregates act as the unique specific pathological hallmark of AD and play a causative role in the disease development, they are believed as a promising target for Alzheimer’s modification.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Translational models and tools to mimic the nature of AD more closely are also required to bridge the gap between basic research and the clinical practice.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
The paper relies on this without support.
The single molecular assay (Simoa) allows measurement of Aβ40 and Aβ42 levels at sub-femtomolar concentration.
“Recently, the development of single molecular assay (Simoa), an ultra-sensitive immunoassay technology, allows the measurement of Aβ40 and Aβ42 levels at sub-femtomolar concentration.”
The paper relies on this without support.
The currently approved AD drugs can only help alleviate symptoms instead of modifying the disease.
“However, these drugs can only help alleviate the symptoms instead of modifying the disease.”
The paper relies on this without support.
38 of the Aβ-targeting therapies have been discontinued due to ineffectiveness or toxic side effects.
“So far, two antibody-based drugs aducanumab and lecanemab have been approved by the FDA and 38 of them have been discontinued due to ineffectiveness or toxic side effects.”
The paper relies on this without support.
All γ-secretase modulators have been discontinued in clinical trials.
“Unfortunately, all of them have been discontinued in the clinical trials.”
The paper relies on this without support.
The Aβ-mAb complex induces complement-dependent cytotoxicity, resulting in lysis of target cells.
“In addition, the Aβ-mAb complex induces the complement-dependent cytotoxicity, resulting in the lysis of the target cells.”
The paper relies on this without support.
Most traditional Chinese medicine treatments are derived from natural products with multi-target, multi-pathway capacity and mild adverse events.
“Most TCM treatment are derived from natural products with multi-target, multi-pathway capacity and mild adverse events.”
The paper relies on this without support.
Brain organoids can only be cultured within six months; otherwise volume shrinkage and cellular apoptosis occur because oxygen and nutrients cannot reach the innermost organoid regions.
“So far, brain organoids can only be cultured within six months, otherwise volume shrinkage and cellular apoptosis occur as neither the oxygen nor nutrients will be able to reach the innermost organoid regions.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, mounting evidence indicates that soluble oligomers, rather than insoluble fibrils, are the principal neurotoxic species, disrupting synaptic plasticity, impairing long-term potentiation, and triggering downstream inflammatory cascades [29].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [29]
Experimental — accuracy not yet measuredIn the citing paper
“Several clinical investigations focusing on Aβ have produced contradictory findings, casting doubt on the veracity of the amyloid theory in general.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [86]
In the citing paper
“While lowering Aβ levels can decrease cognitive deterioration, not all patients will definitely see improved clinical outcomes from this strategy, according to certain research [86,93].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [86]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
“Aducanumab is the first FDA-approved therapy for Alzheimer’s.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“To date, five drugs have been approved for the treatment of AD.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
“Currently, four vaccines are under the clinical trials, including ALZ-101 (Phase 1), ACI-24 (Phase 2), ABvac 40 (Phase 2) and UB311 (Phase 3).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“AV-1959D | Intradermal injection | A DNA vaccine fuses coding sequences of three copies of Aβ1-11 to 12 to elicit antibodies to Aβ peptides | NCT05642429 (Phase 2)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“Targeting Aβ monomers | Targeting Aβ monomers | Targeting Aβ monomers”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
“Aducanumab is the first FDA-approved therapy for Alzheimer’s.47,48 It is a human IgG1 mAb against a conformational epitope found on the N-terminus of Aβ (residues 3–6), and thus specifically targeting aggregates rather than monomers.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“To date, five drugs have been approved for the treatment of AD. Four of these medications are classified as cholinesterase inhibitors (CIs), including tacrine, donepezil, rivastigmine, and galantamine.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“So far, two antibody-based drugs aducanumab and lecanemab have been approved by the FDA”
Citations
Cites
2 retracted
Larson, M. E., Sherman, M. A., Amar, F., Nuvolone, M., Schneider, J. A., Bennett, D. A., Aguzzi, A., & Lesné, S. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1858-12.2012 · Cited by 290
RetractedWang, H.-Y., Lee, K.-C., Pei, Z., Khan, A., Bakshi, K. P., & Burns, L. H. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.03.016 · Cited by 48
RetractedAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · cited 2×
“Since then, Aβ has been considered as a driver of Alzheimer’s pathological processes and the “amyloid cascade hypothesis” has become a leading theory of AD pathogenesis.(2) Over the past decades, targeting Aβ has been the main direction of developing AD treatment.”
BackgroundNeurogenesis in the adult human hippocampus
Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998) · Nature Medicine · doi:10.1038/3305 · Cited by 6,369 · cited 1×
“Adult neurogenesis in humans was first reported in 1998, in which bromodeoxyuridine (BrdU)-positive cells were found in the post-mortem brain tissue of cancer patients.(425) Adult brains contain resident neural stem/progenitor cells (NSPCs), which have multipotency and show great potential for self-renewal.”
BackgroundNotch Signaling: Cell Fate Control and Signal Integration in Development
Artavanis-Tsakonas, S., Rand, M. D., & Lake, R. J. (1999) · Science · doi:10.1126/science.284.5415.770 · Cited by 5,909 · cited 2×
“Particularly notable is toxicity resulting from inhibition of Notch-1 cleavage, which disrupts essential signaling from this receptor.(15,313) Thus, we should discover compounds that act as substrate-selective γsecretase inhibitors, which block the cleavage of C99, the immediate precursor of Aβ, while allowing Notch c…”
BackgroundLecanemab in early Alzheimer's disease
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212948 · Cited by 5,678 · cited 2×
“The results were just published and showed that patients with lecanemab treatment had lower brain amyloid levels and reduced cognitive and functional decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which quantifies symptom severity across a range of cognitive and function domains, by 27% com…”
ResultGlenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404
Cerebral organoids model human brain development and microcephaly
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., & Knoblich, J. A. (2013) · Nature · doi:10.1038/nature12517 · Cited by 5,372
Research works printed but not linked: 1
- Walker, L. C. Abeta plaques. Free Neuropathol. 1, 31 (2020).
Cited by
Sorted by citations
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138
Self-citationThe gut microbiota-immune-brain axis: therapeutic implications
O’Riordan, K. J., Moloney, G. M., Keane, L., Clarke, G., & Cryan, J. F. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.101982 · Cited by 333
“115 The disease progresses from the transentorhinal cortex to the hippocampus and cortical areas.”
Tumilaar, S. G., Hardianto, A., Dohi, H., & Kurnia, D. (2024) · Journal of Chemistry · doi:10.1155/2024/5594386 · Cited by 356
The role of inflammasomes in human diseases and their potential as therapeutic targets
Yao, J., Sterling, K., Wang, Z., Zhang, Y., & Song, W. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01687-y · Cited by 260
“205 It is characterized by the formation of neuritic plaques and neuro fi - brillary tangles (NFTs) in the brain.”
BackgroundSelf-citationUpdates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 241
“The extracellular accumulation of insoluble Aβ can also activate neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and neural death [217, 218].”
BackgroundSelf-citation
Metadata
- Authors
- Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W.
- Affiliations
- Capital Medical University (CN)
- Wenzhou Medical University (CN)
- University of British Columbia (CA)
- Corresponding author
- Zhang, Yun
- Song, Weihong
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2023-06-30
- Volume
- 8
- Issue
- 1
- Pages
- 248-248
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC10310781
- OpenAlex
- W4382601497
- Cited by
- 988
- References
- 562
- Citations by year
- 2026: 278 · 2025: 422 · 2024: 257 · 2023: 30
- FWCI
- 35.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82150710557, 82201576)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- amyloid-beta, Alzheimer's disease, amyloid hypothesis, anti-amyloid therapy, neuritic plaques, Alzheimer's disease prevention, Alzheimer's disease treatment, Alzheimer's disease diagnosis
- MeSH terms
- Alzheimer Disease, Humans, Amyloid beta-Peptides, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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