The DOI matches its Crossref record; 559 of the 562 references it cites were found in a registry or an index; 11 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.
Overview
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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
198 Not checked yet · 21 Own interpretation · 9 No basis given · 6 Partly supported · 1 Supported · 1 Supported so far · 1 Own result · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
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
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The Results sections report that 100 nM synthetic Aβ42 monomers increased CREB phosphorylation and BDNF transcription and release in cultured neurons. Cell-secreted Aβ monomers also increased CREB phosphorylation, but their measured concentration was a few hundred picomolar, not nanomolar; the paper does not report a BDNF response to cell-secreted monomers. The experiments were in cultured cells, rather than normal brains. (LLM, conf=0.88)
- 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
“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)
plaindirect- Asserted: passes — The authors put it forward as true.
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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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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)
boostedcorrelational- 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
“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
plaindirect- 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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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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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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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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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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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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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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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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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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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
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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
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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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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
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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
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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
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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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
boosteddirect- Asserted: passes — The authors put it forward as true.
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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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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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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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It may state two separate claims as one.
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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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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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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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.
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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
“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.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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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.
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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.
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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.
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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
“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.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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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
“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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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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.
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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.
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- 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
Items 401–559 of 559
(2008) · doi:10.1074/jbc.m801487200 · Cited by 105
Clementi, M. E., Pezzotti, M., Orsini, F., Sampaolese, B., Mezzogori, D., Grassi, C., Giardina, B., & Misiti, F. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.01.137 · Cited by 105 · cited 1×
“416 In contrast, Aβ42 stimulated the expression of Bax, which induced cell apoptosis and was commonly observed in many cancers.(416,417)”
BackgroundCalvo-Rodríguez, M., Hernando-Pérez, E., Núñez, L., & Villalobos, C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00022 · Cited by 103
Nilsson, P., Sekiguchi, M., Akagi, T., Izumi, S., Komori, T., Hui, K. K., Sörgjerd, K. M., Tanaka, M., Saito, T., Iwata, N., et al. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.10.011 · Cited by 102
Glycogen Synthase Kinase-3 (GSK-3) Inhibitors for the Treatment of Alzheimers Disease
Medina, M., & Ávila, J. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210793176581 · Cited by 102 · cited 1×
“Thus, inhibitors of GSK-3β or CDK-5 such as AZD1080 and roscovitine, markedly reduced the levels of tau phosphorylation and prevented further tau aggregation.(122,123) Further studies have found that mitogen-activated protein kinases (MAPKs) including ERK1/2, SAPKs and p38 are also involved in Aβ-induced formation of…”
BackgroundPreferential degradation of cognitive networks differentiates Alzheimer’s disease from ageing
Chhatwal, J. P., Schultz, A. P., Johnson, K. A., Hedden, T., Jaimes, S., Benzinger, T. L. S., Jack, C., Ances, B. M., Ringman, J. M., Marcus, D. S., et al. (2018) · Brain · doi:10.1093/brain/awy053 · Cited by 101 · cited 1×
“Decrease of default-mode network (DMN) functional connectivity has been found in prodromal stages of AD, which is associated with loss of gray matter volume in neocortex and hippocampus.(239,240) Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.”
BackgroundMastrangelo, M. A., Sudol, K. L., Narrow, W. C., & Bowers, W. J. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.090059 · Cited by 100 · cited 1×
“The produced interferon-γ (IFN-γ) further facilitated Aβ generation to form a positive feedback loop.(407) Similar to anti-viral activity, Aβ peptides also bound to fungal cells and stimulated the phagocytosis of microglia.”
BackgroundKaniyappan, S., Chandupatla, R., Mandelkow, E., & Mandelkow, E. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.04.002 · Cited by 100 · cited 1×
“AβOs induce tau hyperphosphorylation and accumulation in dendritic spine, which further lead to synaptic loss and dysfunction.(94,95) The level of pathological tau in AD patients is correlated with the severity of impaired synaptic plasticity and cognitive dysfunction.”
BackgroundGulisano, W., Melone, M., Ripoli, C., Tropea, M. R., Li Puma, D. D., Giunta, S., Cocco, S., Marcotulli, D., Origlia, N., Palmeri, A., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0163-19.2019 · Cited by 100 · cited 1×
“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) Thus, α7-nAChR KO mice at 12-month-old showed Aβ elevation as a compensatory response of α7-nAChRs and exhibited AD-like pathologies.”
BackgroundWang, P., Liao, W., Fang, J., Liu, Q., Yao, J., Hu, M., & Ding, K. (2014) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2014.03.060 · Cited by 99
Baruch-Suchodolsky, R., & Fischer, B. (2009) · Biochemistry · doi:10.1021/bi802361k · Cited by 98
Maccecchini, M. L., Chang, M. Y., Pan, C., John, V., Zetterberg, H., & Greig, N. H. (2012) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-302589 · Cited by 98
Site-specific UBITh® amyloid-β vaccine for immunotherapy of Alzheimer's disease
Wang, C. Y., Finstad, C. L., Walfield, A. M., Sia, C., Sokoll, K. K., Chang, T.-Y., Fang, X. D., Hung, C. H., Hutter-Paier, B., & Windisch, M. (2007) · Vaccine · doi:10.1016/j.vaccine.2007.01.031 · Cited by 98
Chabrier, M. A., Cheng, D., Castello, N. A., Green, K. N., & LaFerla, F. M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.01.007 · Cited by 97
Biological function of Presenilin and its role in AD pathogenesis
Zhang, S., Zhang, M., Cai, F., & Song, W. (2013) · Translational Neurodegeneration · doi:10.1186/2047-9158-2-15 · Cited by 97
Self-citationPavoni, S., Jarray, R., Nassor, F., Guyot, A.-C., Cottin, S., Rontard, J., Mikol, J., Mabondzo, A., Deslys, J.-P., & Yates, F. (2018) · PLOS ONE · doi:10.1371/journal.pone.0209150 · Cited by 97
Dale, J. E., Alcorn, N., Capell, H. A., et al. (2007) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0562 · Cited by 96 · cited 2×
“Accordingly, combination therapy should be considered for the clinical phase of the disease, which is already the standard of care for many diseases, including rheumatoid arthritis and HIV/AIDS.479,480 Growing evidence indicates that Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leadi…”
BackgroundIijima, K., Gatt, A., & Iijima-Ando, K. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq200 · Cited by 96 · cited 1×
“GSK-3β, which is inextricably associated with Aβ production and accumulation,(119) is a key trigger of tau phosphorylation and aggravates Aβ-induced tau toxicity.(120) CDK5-P25 phosphorylates tau at sites of Thr181, Ser199, Ser202, Thr205, Thr212, Ser214, Ser217, Thr231, Ser235, Ser396, and Ser404.”
BackgroundIzzo, N. J., Yuede, C. M., LaBarbera, K. M., Limegrover, C. S., Rehak, C., Yurko, R., Waybright, L., Look, G., Rishton, G., Safferstein, H., et al. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12302 · Cited by 95
Aβ40 promotes neuronal cell fate in neural progenitor cells
Chen, Y., & Dong, C. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2008.94 · Cited by 94
Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease
Salazar, S. V., & Strittmatter, S. M. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.062 · Cited by 94
Park, J., Choi, H., Min, J., Kim, B., Lee, S., Yun, J. W., Choi, M., Chang, K., & Lee, D. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.12984 · Cited by 93 · cited 1×
“Soluble Aβ oligomers disrupted the balance between mitochondrial fission and fusion, leading to significant mitochondrial dysfunction.(197,198) Excessive mitocondrial fission is a key modulator of Aβ toxicity.”
BackgroundLau, D. H. W., Hogseth, M., Phillips, E. C., O’Neill, M. J., Pooler, A. M., Noble, W. J., & Hanger, D. P. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0317-4 · Cited by 93
Chaudhary, A. K., Yadav, N., Bhat, T. A., O’Malley, J., Kumar, S., & Chandra, D. (2015) · Drug Discovery Today · doi:10.1016/j.drudis.2015.07.014 · Cited by 92 · cited 1×
“In addition, 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) Bcl-2, another key anti-apoptotic protein, was also shown to be blocked by Aβ42 peptides.”
BackgroundGrant, J. L., Ghosn, E. E. B., Axtell, R. C., Herges, K., Kuipers, H. F., Woodling, N. S., Andreasson, K., Herzenberg, L. A., Herzenberg, L. A., & Steinman, L. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004145 · Cited by 92 · cited 3×
“One potential explanation for the activated glia cells in AD brain could be the response to Aβ produced largely by neurons.157,158 Aβ shares structural similarities with antimicrobial peptides (AMPs) and viral fusion domains, which stimulates glia cells to secrete a mass of pro-inflammatory cytokines.159 Similar to AM…”
BackgroundKellar, D., Lockhart, S. N., Aisen, P. S. S., Raman, R., Rissman, R. A., Brewer, J. B., & Craft, S. (2021) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2021.14 · Cited by 92
Glenn, J. A., Ward, S. A., Stone, C. R., Booth, P. L., & Thomas, W. E. (1992) · PubMed · Cited by 89
Consequences of Metabolic Disruption in Alzheimer's Disease Pathology
Ryu, J. C., Zimmer, E. R., Rosa‐Neto, P., & Yoon, S. O. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00755-y · Cited by 87 · cited 1×
“Disrupted energy metabolism has been found in early AD and precedes the disease development, suggesting the core role of mitochondria dysfunction in Alzheimer’s pathogenesis.(195,196) Soluble Aβ oligomers disrupted the balance between mitochondrial fission and fusion, leading to significant mitochondrial dysfunction.”
BackgroundPannee, J., Portelius, E., Minthon, L., Gobom, J., Andréasson, U., Zetterberg, H., Hansson, O., & Blennow, K. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13838 · Cited by 85
Zhang, Y., Guo, O., Huo, Y., Wang, G., & Man, H. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170879 · Cited by 84
Self-citationHampel, H., Williams, C., Etcheto, A., Goodsaid, F., Parmentier, F., Sallantin, J., Kaufmann, W. E., Missling, C. U., & Afshar, M. (2020) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12013 · Cited by 84 · cited 1×
“ANAVEX®2-73 (Blarcamesine), which targets sigma-1 and M1 muscarinic receptors, has also demonstrated its diseasemodifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies as well as improving cognitive deficits.(51,52) The results of its Phase 2B/3 study, presented at the Clinic…”
BackgroundAddendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2017) · Nature · doi:10.1038/nature22809 · Cited by 83 · cited 1×
“It has been shown to reduce plaques in imaging studies.(347) However, in 2019, Biogen and Eisai announced they would not start an anticipated Phase 3 secondary prevention program and would terminate all ongoing trials as aducanumab treatment was predicted to miss its primary endpoint based on the interim analysis (Mar…”
BackgroundAdvances in Alzheimer's disease research over the past two decades
Jack, C. R. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00298-8 · Cited by 83
Cai, W., Li, L., Sang, S., Pan, X., & Zhong, C. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-022-00985-9 · Cited by 83 · cited 1×
“Although Aβ aggregates, especially the soluble oligomeric species impair synaptic plasticity by inhibition of LTP and induction of LTD, 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) It has been shown that the KLVFF (16~…”
BackgroundJustice, N. J., Huang, L., Tian, J.-B., Cole, A., Pruski, M., Hunt, A. J., Flores, R., Zhu, M. X., Arenkiel, B. R., & Zheng, H. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3333-14.2015 · Cited by 81
Aβ1–42 stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor
Sotthibundhu, A., Li, Q.-X., Thangnipon, W., & Coulson, E. J. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.02.004 · Cited by 81
Human Monoclonal Antibodies: The Benefits of Humanization
Waldmann, H. (2019) · Methods in Molecular Biology · doi:10.1007/978-1-4939-8958-4_1 · Cited by 80 · cited 1×
“antibodies, enhance human effector functions, and increase the serum half-life of the antibodies in humans.(330) 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.”
BackgroundIslet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis?
Zhang, Y., & Song, W. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.001 · Cited by 79 · cited 1×
“2) In 1984, Aβ was identified as the primary component of extracellular amyloid plaques in AD,(1) which is the unique pathological hallmark of the disease.(53) 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, r…”
BackgroundSelf-citationZimbone, S., Monaco, I., Gianì, F., Pandini, G., Copani, A. G., Giuffrida, M. L., & Rizzarelli, E. (2018) · Aging Cell · doi:10.1111/acel.12684 · Cited by 79 · cited 1×
“endogenous Aβ42 monomers in nanomolar concentrations stimulated the activity of cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) and brainderived neurotrophic factor (BDNF), which possessed key roles in the regulation of gene expressions related to neuronal functions and survival in norm…”
BackgroundBeach, T. G., Honer, W. G., & Hughes, L. H. (1997) · Acta Neuropathologica · doi:10.1007/s004010050595 · Cited by 78
Babu, H. (2009) · Frontiers in Neuroscience · doi:10.3389/neuro.22.001.2009 · Cited by 78 · cited 1×
“Adult brains contain resident neural stem/progenitor cells (NSPCs), which have multipotency and show great potential for self-renewal.(426,427) Adult neurogenesis in AD brains was also widely investigated.”
BackgroundSerneels, L., T’Syen, D., Pérez‐Benito, L., Theys, T., Holt, M. G., & Strooper, B. D. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00399-z · Cited by 78
Ullah, R., Park, T. J., Huang, X., & Kim, M. O. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101451 · Cited by 78 · cited 1×
“THE STUMBLING BLOCK OF ANTI-AΒ THERAPY Disturbed physiological functions of soluble Aβ Aβ peptides exist in both the brain and blood throughout an individual’s life.(354) Although the aggregates have been considered to be toxic, soluble Aβ at physiological levels have been identified to have biological functions, incl…”
BackgroundKellar, D., Register, T. C., Lockhart, S. N., Aisen, P. S. S., Raman, R., Rissman, R. A., Brewer, J. B., & Craft, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-05165-3 · Cited by 77
Turner, R. T., Lin, H., Koelsch, G., Ghosh, A. K., & Tang, J. (2004) · Biochemistry · doi:10.1021/bi048106k · Cited by 75 · cited 1×
“BACE2, pepsin, renin, cathepsin D and cathepsin E) has conserved catalytic aspartic acid residues, the subsites in the active sites may be unique.(439) Targeting these subsites to develop BACE1 inhibitors may increase their specificity.”
BackgroundRogers, K., Felsenstein, K. M., Hrdlicka, L., Tu, Z., Albayya, F., Lee, W., Hopp, S., Miller, M.-J., Spaulding, D., Yang, Z., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-61 · Cited by 75 · cited 1×
“It also improved the memory deficits in AD model mice.(317) Unfortunately, all of them have been discontinued in the clinical trials.”
Backgroundα7 nicotinic acetylcholine receptors in the hippocampal circuit: taming complexity
Letsinger, A. C., Gu, Z., & Yakel, J. L. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2021.11.006 · Cited by 74 · cited 1×
“α7-nAChRs are involved in a variety of biological functions, including neurotransmitter release, synaptic plasticity and neurogenesis.(384,385) In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.”
BackgroundUpregulation of MIF as a defense mechanism and a biomarker of Alzheimer’s disease
Zhang, S., Zhao, J., Zhang, Y., Zhang, Y., Cai, F., Wang, L., & Song, W. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0508-x · Cited by 73
Self-citationMicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms
Dehghani, R., Rahmani, F., & Rezaei, N. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0042 · Cited by 72 · cited 1×
“Therefore, they become an attractive target for developing AD biomarkers.(551,552) In addition to body fluids, ocular markers also gain increasing interest.”
BackgroundNeuropathology of Alzheimer's Disease
Mott, R. T., & Hulette, C. M. (2005) · Neuroimaging Clinics of North America · doi:10.1016/j.nic.2005.09.003 · Cited by 71 · cited 1×
“The corona consists of both neuronal and glial elements, including degenerative neuronal processes (neurites) along with reactive astrocytes and microglia.(55,56) Diffuse plaques comprise very small, often stellate assemblies scattered about the parenchyma.”
BackgroundIsmail, R., Hansen, A. K., Parbo, P., Brændgaard, H., Gottrup, H., Brooks, D. J., & Borghammer, P. (2018) · International Journal of Alzheimer s Disease · doi:10.1155/2018/6852303 · Cited by 71
FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm
Mullard, A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/d41573-021-00099-3 · Cited by 69
Koch, G., Lorenzo, F. D., Fernández‐del‐Olmo, M., Bonnı̀, S., Ponzo, V., Caltagirone, C., Bozzali, M., & Martorana, A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150813 · Cited by 68 · cited 1×
“The level of pathological tau in AD patients is correlated with the severity of impaired synaptic plasticity and cognitive dysfunction.(96) The pathological tau interacts with the presynaptic compartments including synapsin-1, synaptophysin, to inhibit the mobility and release of synaptic vesicles, leading to the deve…”
BackgroundThe Effect of Lipoic Acid Therapy on Cognitive Functioning in Patients with Alzheimer's Disease
Fava, A., Pirritano, D., Plastino, M., Cristiano, D., Puccio, G., Colica, C., Ermio, C., Bartolo, M. D., Mauro, G. F., & Bosco, D. (2013) · Journal of Neurodegenerative Diseases · doi:10.1155/2013/454253 · Cited by 67
A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling
Zhang, S., Cai, F., Wu, Y., Bozorgmehr, T., Wang, Z., Zhang, S., Huang, D., Guo, J., Shen, L., Rankin, C., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-018-0101-x · Cited by 66 · cited 5×
“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), implicating a role of altering APP processing in AD pathogenesis.(7,38,39) In contrast, an APP mutation identified in the Icel…”
BackgroundInfluentialSelf-citationTau pathology-mediated presynaptic dysfunction
Moreno, H., Morfini, G. A., Buitrago, L., Ujlaki, G., Choi, S., Yu, E., Moreira, J. E., Ávila, J., Brady, S. T., Pant, H., et al. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.03.044 · Cited by 65
Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat
Albright, C. F., Dockens, R. C., Meredith, J. E., Olson, R. E., Slemmon, R., Lentz, K. A., Wang, J.-S., Denton, R., Pilcher, G. D., Rhyne, P., et al. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.199356 · Cited by 63 · cited 1×
“Avagacestat is a recently developed arylsulfonamide γsecretase inhibitor with high selectivity for APP over Notch, which successfully reduces CSF Aβ levels in the animal models without any Notch-related toxicity.(314) Avagacestat was considered as a promising AD treatment with the ability to selectively inhibit the AP…”
BackgroundSakamoto, K., Matsuki, S., Matsuguma, K., Yoshihara, T., Uchida, N., Azuma, F., Russell, M., Hughes, G., Haeberlein, S. B., Alexander, R., et al. (2017) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.950 · Cited by 62
Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimer's Disease
Willuweit, A., Velden, J., Godemann, R., Manook, A., Jetzek, F., Tintrup, H., Kauselmann, G., Zevnik, B., Henriksen, G., Drzezga, A. E., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007931 · Cited by 60
Arai, H., Suzuki, H., & Yoshiyama, T. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150302154121 · Cited by 60 · cited 1×
“However, all clinical trials using vanutide cridificar were also discontinued following a serious adverse event.(323) Another example is Lu AF20513, which is a mixed peptide containing three repeats of the first 12 amino acids of Aβ peptide interspersed with tetanus toxin sequences.”
MethodChen, H., Lin, Y., Huang, J.-W., & Chen, Y. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.04.002 · Cited by 59
Self-citationAlternative Macroautophagic Pathways
Juenemann, K., & Reits, E. A. (2012) · International Journal of Cell Biology · doi:10.1155/2012/189794 · Cited by 58 · cited 1×
“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) Treatment with rapamycin significantly stimulated autophagy associated with markedly reduced both intracellular Aβ and extracellular amyloid depositio…”
BackgroundLiu, Q., Fang, J., Wang, P., Du, Z., Li, Y., Wang, S., & Ding, K. (2018) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2017.08.154 · Cited by 58
Kutzsche, J., Jürgens, D., Willuweit, A., Adermann, K., Fuchs, C., Simons, S., Windisch, M., Humpel, M., Rossberg, W. M., Wolzt, M., et al. (2020) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12001 · Cited by 58
Cerebral organoids as tools to identify the developmental roots of autism
Chan, W. K., Griffiths, R., Price, D. J., & Mason, J. O. (2020) · Molecular Autism · doi:10.1186/s13229-020-00360-3 · Cited by 58
Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles
Deng, Z., Dong, Y., Zhou, X., Lu, J.-H., & Yue, Z. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.12.009 · Cited by 58 · cited 1×
“Thus, autophagy modulation becomes a promising stategy for Alzheimer’s treatment.(499,500) Rapamycin is a commonly used autophagy activator, which inhibits the mTOR pathway by binding with immunophilin FK506-binding protein (FKBP12).”
BackgroundAnti-Amyloid-β Immunotherapy in Alzheimer's Disease: ACC-001 Clinical Trials Are Ongoing
Ryan, J. M., & Grundman, M. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1118 · Cited by 57 · cited 2×
“Vanutide cridificar (ACC-001) is a conjugate of multiple short Aβ fragments to avoid the safety concerns associated with AN1792.”
BackgroundChen, K., Lu, Y., Liu, C., Zhang, L., Fang, Z., & Yu, G. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.047 · Cited by 57
Serdons, K., Verduyckt, T., Vanderghinste, D., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.12.069 · Cited by 56 · cited 1×
“amyloid in the human brain, including (11)C-Pittsburgh compound B ((11)C-PiB),(251) Amyvid (flobetapir F18),(252) Neuraceq (florbetaben F18)(253) and Vizamyl (flutemetamol F18).(254) In practice, reduced concentrations of Aβ42 in CSF and increased retention of Aβ tracers in the brain have been considered as early biom…”
MethodAmyloid-Beta Mediates Homeostatic Synaptic Plasticity
Galanis, C., Fellenz, M., Becker, D., Bold, C. S., Lichtenthaler, S. F., Müller, U., Deller, T., & Vlachos, A. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.1820-20.2021 · Cited by 56
Alzheimer disease: modeling an Aβ-centered biological network
Campion, D., Pottier, C. P., Nicolas, G., Guennec, K. L., & Rovelet‐Lecrux, A. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.38 · Cited by 55 · cited 1×
“Aβ promoted the phosphorylation and activation of Fyn kinase, which further migrated into dendritic spines, leading to synaptic impariment.(141,142) Tau protein mediated Aβ toxicity by interacting with Fyn kinase via its amino-terminal projection domain (PD).”
BackgroundDomizio, J. D., Dorta-Estremera, S. M., Gagea, M., Ganguly, D., Meller, S., Li, P., Zhao, B., Tan, F. K., Bi, L., Gilliet, M. F., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206923109 · Cited by 54 · cited 1×
“In addition, 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) The produced interferon-γ (IFN-γ) further facilitated Aβ generation to form a positive fee…”
BackgroundHe, Y., Ruganzu, J. B., Lin, C., Ding, B., Zheng, Q., Wu, X., Ma, R., Liu, Q., Wang, Y., Jin, H. M., et al. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104610 · Cited by 54
Wu, Y., Chen, Q., Wen, B., Wu, N., He, B., & Chen, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.640758 · Cited by 54
ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease
Krafft, G. A., Jerecı̀ć, J., Siemers, E., & Cline, E. N. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.848215 · Cited by 54
Therapeutic approaches in the improvement of cognitive performance in Down syndrome
de la Torre, R., & Dierssen, M. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-54299-1.00001-7 · Cited by 53
Soluble amyloid precursor protein β as blood-based biomarker of Alzheimer’s disease
Perneczky, R., Guo, L.-H., Kagerbauer, S. M., Werle, L., Kurz, A., Martin, J., & Alexopoulos, P. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.11 · Cited by 53 · cited 1×
“One such study found that plasma concentrations of soluble β-secretase cleaved n-terminal APP (sAPPβ) were significantly reduced in AD patients compared with agematched cognitively healthy individuals or patients with behavioral variant frontotemporal dementia (bvFTD), indicating the potential role of sAPPβ as a promi…”
BackgroundAl-Tel, T. H., Semreen, M. H., Al-Qawasmeh, R. A., Schmidt, M. F., El-Awadi, R., Ardah, M., Zaarour, R., Rao, S. N., & El-Agnaf, O. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm201181f · Cited by 53 · cited 1×
“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 offtarget side effects.(310) In addition, the size of the BACE1 acti…”
BackgroundSayed, N. S. E., & Bayan, Y. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-08927-0_12 · Cited by 52
Giuffrida, M. L., Tomasello, M. F., Pandini, G., Caraci, F., Battaglia, G., Busceti, C., Di Pietro, P., Pappalardo, G., Attanasio, F., Chiechio, S., et al. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00297 · Cited by 52 · cited 1×
“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) In addition, both synthetic and Amyloid β-based therapy for Alzheimer’s.”
BackgroundTan, Y. J., Ng, A. S., Vipin, A., Lim, J. K. W., Chander, R. J., Ji, F., Qiu, Y., Ting, S. K. S., Hameed, S., Lee, T.-S. W., et al. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161277 · Cited by 52 · cited 1×
“Increased TERM2 experession has been found in human AD blood, indicating the important role of peripheral TREM2 in Alzheimer’s pathogenesis.(176,177) Using flow cytometry identified that these cells also contained high levels of CD45, Ly6c, and CD11b, which highly express in peripheral macrophages as well.”
BackgroundIcariin improves the cognitive function of APP/PS1 mice via suppressing endoplasmic reticulum stress
Li, F., Zhang, Y., Lu, X., Shi, J., & Gong, Q. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116739 · Cited by 51
Self-citationClarke, J., Thornell, A., Corbett, D., Soininen, H., Hiltunen, M., & Jolkkonen, J. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05807.x · Cited by 50 · cited 1×
“It has been demonstrated that overexpression of human APP (hAPP695) leads to an obvious lower infarct volume in the cortex of mice suffering from cerebral ischemia.(363) Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease with inflammation in brain.”
BackgroundDonanemab in Early Alzheimer’s Disease
(2021) · New England Journal of Medicine · doi:10.1056/nejmc2109455 · Cited by 50
Petrushina, I., Hovakimyan, A., Harahap-Carrillo, I. S., Davtyan, H., Antonyan, T., Chailyan, G., Kazarian, K., Antonenko, M., Jullienne, A., Hamer, M. M., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104823 · Cited by 48
Why does the Aβ peptide of Alzheimer share structural similarity with antimicrobial peptides?
Pastore, A., Raimondi, F., Rajendran, L., & Temussi, P. A. (2020) · Communications Biology · doi:10.1038/s42003-020-0865-9 · Cited by 48 · cited 1×
“Aβ shares structural similarities with antimicrobial peptides (AMPs) and viral fusion domains, which stimulates glia cells to secrete a mass of pro-inflammatory cytokines.(159) Similar to AMPs, Aβ aggregates can also induce pores in cell membranes, which allow a variety of stimuli to activate glia cells.”
BackgroundAdvances in Brain Amyloid Imaging
Krishnadas, N., Villemagne, V. L., Doré, V., & Rowe, C. C. (2021) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2020.12.005 · Cited by 48 · cited 1×
“CSF analysis offers a quantitative result of the net effect of Aβ peptides, while.(249,250) There are four tracers used to detected levels of Amyloid β-based therapy for Alzheimer’s.”
BackgroundLiu, F., Sun, J., Wang, X., Jin, S., Sun, F., Wang, T., Yuan, B., Qiu, W., & Ma, C. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00927-5 · Cited by 48 · cited 1×
“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)”
BackgroundMechanisms of tau and Aβ-induced excitotoxicity
Pallo, S. P., DiMaio, J., Cook, A., Nilsson, B., & Johnson, G. V. W. (2016) · Brain Research · doi:10.1016/j.brainres.2015.12.048 · Cited by 46 · cited 1×
“Another study also indentified that reduction of tau could ameliorate Aβ-induced Ca influx into neurons and AD-related excitotoxicity in vivo.(103) These findings suggest that the synaptic toxicity induced by Aβ was dependent on pathological tau proteins to some extent.”
BackgroundBird, S., Sohrabi, H. R., Sutton, T. A., Weinborn, M., Rainey‐Smith, S. R., Brown, B. M., Patterson, L. C., Taddei, K., Gupta, V. B., Carruthers, M. E., et al. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.01.004 · Cited by 46
PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients
Wang, H.-Y., Pei, Z., Lee, K.-C., Lopez‐Brignoni, E., Nikolov, B., Crowley, C., Marsman, M. R., Barbier, R., Friedmann, N., & Burns, L. H. (2020) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2020.6 · Cited by 46
Guadaño-Ferraz, A., Viñuela, A., Oeding, G., Bernal, J., & Rausell, E. (2005) · The Journal of comparative neurology · doi:10.1002/cne.20774 · Cited by 45 · cited 1×
“Neurogranin is expressed in the cortex and hippocampus, the brain areas most affected by AD.(545) As a synaptic marker, it is involved in the modulation of synaptic strength and plasticity.”
BackgroundMeilandt, W. J., Maloney, J. A., Imperio, J., Lalehzadeh, G., Earr, T., Crowell, S., Bainbridge, T. W., Lu, Y., Ernst, J. A., Fuji, R. N., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0553-5 · Cited by 45 · cited 1×
“It has high affinity with the oligomeric and fibril species and amyloid plaques.(339,340) Crenezumab is being tested in both prevention and treatment paradigms.”
BackgroundDecourt, B., Wilson, J., Ritter, A. R., Dardis, C., DiFilippo, F. A., Zhuang, X., Cordes, D., Lee, G., Fulkerson, N., Rose, T. S., et al. (2020) · Open Access Journal of Clinical Trials · doi:10.2147/oajct.s221914 · Cited by 45
Clusterin transduces Alzheimer-risk signals to amyloidogenesis
Liu, X., Che, R., Liang, W., Zhang, Y., Wu, L., Han, C., Lu, H., Song, W., Wu, Y., & Wang, Z. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01157-x · Cited by 45 · cited 1×
“The apolipoprotein E (APOE) and clusterin (CLU), the strongest genetic risk factors for late-onset Alzheimer’s disease (LOAD), has also been identified to influence Aβ seeding and clearance.(4,41)”
BackgroundSelf-citationAmyloid‐β: A vascular sealant that protects against hemorrhage?
Atwood, C. S., Bishop, G. M., Perry, G., & Smith, M. A. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10388 · Cited by 44
Differential alterations in antioxidant capacity in cells from Alzheimer patients
Gibson, G. E., Zhang, H., Sheu, K.-F. R., & Park, L. C. H. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00057-0 · Cited by 44 · cited 1×
“In addition, the increased generation of Aβ by cells from Alzheimer’s patients with mutant PSEN1 was accompanied by a reduction of ROS levels.(422) Conversely, application of Aβ to primary hippocampal neurons from PSEN1 mutant knock-in mice significantly increased superoxide production.”
BackgroundHampton, O. L., Buckley, R. F., Manning, L. K., Scott, M. R., Properzi, M. J., Peña-Gómez, C., Jacobs, H. I. L., Chhatwal, J. P., Johnson, K. A., Sperling, R. A., et al. (2020) · NeuroImage Clinical · doi:10.1016/j.nicl.2020.102407 · Cited by 44 · cited 1×
“Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.(241) Consistent with the findings in humans, aging and AD animal models also show disruptions of functional connectivity in the DMN.”
BackgroundCavieres, V. A., González, A., Muñoz, V. C., Yefi, C. P., Bustamante, H. A., Barraza, R. R., Tapia-Rojas, C., Otth, C., Barrera, M. J., González, C., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0136313 · Cited by 43 · cited 1×
“It has been identified that ATG5-dependent autophagy regulates APP degradation.(493) In addition, the complex of APP and γ-secretases was found in autophagosomes, suggesting the role of authophgic pathway in the generation of Aβ peptides.”
BackgroundTropea, M. R., Puma, D. D. L., Melone, M., Gulisano, W., Arancio, O., Grassi, C., Conti, F., & Puzzo, D. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102154 · Cited by 42 · cited 1×
“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) Inhibition of APP changed the expressions of post-synaptic proteins such as GluA1subunit of AMPA receptors, suggesting the involvement of APP in synaptic formation.”
BackgroundSun, X., Yu, X., Zhu, J., Li, L.-J., Zhang, L., Huang, Y., Liu, D., Ji, M., Sun, X., Zhang, L. L., et al. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01273-8 · Cited by 42 · cited 1×
“A recent study identified that 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)”
BackgroundSathya, M., Ponnusamy, M., Palanisamy, P., Kandasamy, M., Jayachandran, K. S., & Anusuyadevi, M. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161034 · Cited by 41
Formation of Toxic Amyloid Fibrils by Amyloid β‐Protein on Ganglioside Clusters
Matsuzaki, K. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/956104 · Cited by 40 · cited 1×
“As a nucleation process, cholesterol and GM1-rich lipid rafts accelerate Aβ aggregation by binding with Aβ to stabilize its structure.(72,73) Thus, reduction of cholesterol in endosomes or lysosomes ameliorates Aβ aggregation and its toxicity in mouse models.”
BackgroundChiesa, P. A., Cavedo, E., Grothe, M. J., Houot, M., Teipel, S. J., Potier, M., Habert, M., Lista, S., Dubois, B., Hampel, H. J., et al. (2018) · Radiology · doi:10.1148/radiol.2018180268 · Cited by 40
Schwarz, A. J., Sundell, K. L., Charil, A., Case, M. G., Jaeger, R. K., Scott, D., Bracoud, L., Oh, J., Suhy, J., Pontecorvo, M. J., et al. (2019) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.05.007 · Cited by 40 · cited 1×
“Although solanezumab was well tolerated in the participants, it was not able to show the significant therapeutic benefits to AD patients.(345,346) The failure may be due to the too low concentrations of the antibody reaching to the brain.”
BackgroundMadrasi, K. J., Das, R., Abdul, H. M., Lin, L., Hyman, B. T., Lauffenburger, D. A., Albers, M. W., Rissman, R. A., Burke, J. M., Apgar, J. F., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12312 · Cited by 40
Damotte, V., van der Lee, S. J., Chouraki, V. A., Grenier‐Boley, B., Simino, J. M., Adams, H. H. H., Tosto, G., White, C. C., Terzikhan, N., Cruchaga, C., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12333 · Cited by 40
van Tijn, P., Dennissen, F. J. A., Gentier, R. J. G., Hobo, B., Hermes, D., Steinbusch, H. W. M., Van Leeuwen, F. W., & Fischer, D. F. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.07.007 · Cited by 39 · cited 1×
“The reactive astrocytes are close to Aβ plaques in brains from AD patients and rodent models.(183,184) Astrocytes response to Aβ aggregates in a TLR-dependent manner, which further activates the target genes to produce proinflammatory factors.”
Backgroundβ-Amyloid Enhances Glial Glutamate Uptake Activity and Attenuates Synaptic Efficacy
Ikegaya, Y., Matsuura, S., Ueno, S., Baba, A., Yamada, M. K., Nishiyama, N., & Matsuki, N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203764200 · Cited by 39 · cited 1×
“Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.(377,378) Aβ can also be released into the synaptic cleft, where it acts on presynaptic neurons to induce the release of neurotransmitters (e.”
BackgroundQuantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor
Cecon, E., Dam, J., Luka, M., Gautier, C., Chollet, A., Delagrange, P., Danober, L., & Jockers, R. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14688 · Cited by 38
Marcatti, M., Fracassi, A., Montalbano, M., Natarajan, C., Krishnan, B., Kayed, R., & Taglialatela, G. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04255-9 · Cited by 38
Davtyan, H., Hovakimyan, A., Kiani Shabestari, S., Antonyan, T., Coburn, M. A., Zagorski, K., Chailyan, G., Petrushina, I., Svystun, O., Danhash, E., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0556-2 · Cited by 37
Interactions between amyloid, amyloid precursor protein, and mitochondria
Wilkins, H. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220518 · Cited by 37 · cited 1×
“APP and Aβ can be imported into mitochondria, where they can interact with mitochondrial components, impair ATP production, and increase oxidative damage.(481,482) Antioxidants such as lipoic acid,(483) Amyloid β-based therapy for Alzheimer’s.”
BackgroundTakahashi, R. H., Tobiume, M., Sato, Y., Sata, T., Gouras, G. K., & Takahashi, H. (2010) · Neuropathology · doi:10.1111/j.1440-1789.2010.01158.x · Cited by 36
Neurogranin and synaptic plasticity balance
Zhong, L., & Gerges, N. Z. (2010) · Communicative & Integrative Biology · doi:10.4161/cib.3.4.11763 · Cited by 35 · cited 1×
“As a synaptic marker, it is involved in the modulation of synaptic strength and plasticity.(546) Several studies have revealed an elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.”
BackgroundRaven, F., Ward, J. F., Zoltowska, K. M., Wan, Y., Bylykbashi, E., Miller, S., Shen, X., Choi, S. H., Rynearson, K. D., Berezovska, O., et al. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.08.028 · Cited by 35 · cited 3×
“1 Amyloidogenic and non-amyloidogenic processing pathways of APP.”
BackgroundInfluentialHenry, S., Bercu, N., Bobo, C., Cullin, C., Molinari, M., & Lecomte, S. (2017) · Nanoscale · doi:10.1039/c7nr07489a · Cited by 35 · cited 1×
“As a nucleation process, cholesterol and GM1-rich lipid rafts accelerate Aβ aggregation by binding with Aβ to stabilize its structure.(72,73) Thus, reduction of cholesterol in endosomes or lysosomes ameliorates Aβ aggregation and its toxicity in mouse models.”
BackgroundZhao, H., Zhu, J., Cui, K., Xu, X., O'Brien, M., Wong, K. K., Kesari, S., Xia, W., & Wong, S. T. (2009) · Cancer Cell International · doi:10.1186/1475-2867-9-15 · Cited by 33 · cited 1×
“In vitro, application of media containing Aβ successfully inhibits the proliferation of cells, including human glioblastoma, human breast adenocarcinoma, and mouse melanoma cells.(409) In vivo, injection of Aβ into mice transplanted with human glioblastoma and lung adenocarcinoma suppresses the tumor growth.”
BackgroundYang, D.-S., Stavrides, P. H., Kumar, A. R., Jiang, Y., Mohan, P. S., Ohno, M., Dobrenis, K., Davidson, C. D., Saito, M., Pawlik, M., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx001 · Cited by 33 · cited 1×
“Thus, reduction of cholesterol in endosomes or lysosomes ameliorates Aβ aggregation and its toxicity in mouse models.(74)”
BackgroundZhu, T., Zhang, F., Li, H., He, Y., Zhang, G., Huang, N., Guo, M., & Li, X. (2019) · Clinical Interventions in Aging · doi:10.2147/cia.s208068 · Cited by 33
The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers
Kubis-Kubiak, A., Dyba, A. J., & Piwowar, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082744 · Cited by 33
Rezaie, P., Pontikis, C. C., Hudson, L., Cairns, N. J., & Lanto, P. L. (2005) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.4a6551.2005 · Cited by 32
Ríos‐Romenets, S., Lopera, F. J., Sink, K. M., Hu, N., Lian, Q., Guthrie, H., Smith, J. P., Cho, W., Mackey, H. M., Langbaum, J. B. S., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12109 · Cited by 31 · cited 1×
“PSEN1 E280A) but did not meet the criteria for mild cognitive impairment at the time of enrollment.(341) Although crenezumab did not significantly improve cognitive impairment in the participants, it showed some favorable effects (Alzheimer’s Association International Conference, 2022).”
BackgroundParis, D., Ganey, N., Banasiak, M., Laporte, V., Patel, N., Mullan, M., Murphy, S. F., Yee, G.-T., Bachmeier, C., Ganey, C., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2586-10.2010 · Cited by 30 · cited 1×
“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) A hypothesis has been proposed that Aβ may promote apoptosis, which contributes to its anti-tumor effects.”
BackgroundBermejo‐Bescós, P., Jiménez‐Aliaga, K., Benedı́, J., & Martín‐Aragón, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054863 · Cited by 30
Lai, M. K. P., Tsang, S. W. Y., Garcia-Alloza, M., Minger, S. L., Nicoll, J. A. R., Esiri, M. M., Wong, P. T.-H., Chen, C. P. L.-H., Ramírez, M. J., & Francis, P. T. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.12.016 · Cited by 29
Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury
Pajoohesh-Ganji, A., Burns, M. P., Pal-Ghosh, S., Tadvalkar, G., Hokenbury, N. G., Stepp, M. A., & Faden, A. I. (2014) · Brain Research · doi:10.1016/j.brainres.2014.02.049 · Cited by 29 · cited 2×
“inhibitor DAPT or deleting the enzyme BACE1 attenuated the functional recovery in mice with spinal cord injury (SCI).(396) Aside from TBI, Aβ may also have a protective role against other types of brain injury such as cerebral ischemia, which blocks the blood flow in brain.”
Backgroundα7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit
Townsend, M., Whyment, A. D., Walczak, J., Jeggo, R., van den Top, M., Flood, D. G., Leventhal, L., Patzke, H., & Koenig, G. (2016) · Journal of Neurophysiology · doi:10.1152/jn.00243.2016 · Cited by 29 · cited 1×
“α7-nAChRs are involved in a variety of biological functions, including neurotransmitter release, synaptic plasticity and neurogenesis.(384,385) In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.”
BackgroundBeta-amyloid short- and long-term synaptic entanglement
Lanni, C., Fagiani, F., Racchi, M., Preda, S., Pascale, A., Grilli, M., Allegri, N., & Govoni, S. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2018.11.018 · Cited by 29 · cited 1×
“Although Aβ aggregates, especially the soluble oligomeric species impair synaptic plasticity by inhibition of LTP and induction of LTD, 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) It has been shown that the KLVFF (16~…”
BackgroundAPP depletion alters selective pre- and post-synaptic proteins
Martinsson, I., Capetillo-Zarate, E., Faideau, M., Willén, K., Esteras, N., Frykman, S., Tjernberg, L. O., & Gouras, G. K. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.02.003 · Cited by 29 · cited 1×
“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) An obvious reduction of LTP was found in cultured hippocampal neurons with knockdown of APP expression.”
BackgroundInhibition of Cholesterol Biosynthesis Reduces γ -Secretase Activity and Amyloid-β Generation
Kim, Y., Kim, C., Jang, H. Y., & Mook‐Jung, I. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150982 · Cited by 28
The cellular prion protein and its role in Alzheimer disease
Velayos, J. L., Irujo, A., Cuadrado‐Tejedor, M., Paternain, B., Moleres, F. J., & Ferrer, V. (2009) · Prion · doi:10.4161/pri.3.2.9135 · Cited by 27
Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis
Liu, F., Zhang, Y., Liang, Z., Sun, Q., Liu, H., Zhao, J., Xu, J., Zheng, J., Yun, Y., Yu, X., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0060-2 · Cited by 27 · cited 1×
“1-induced neuronal apoptosis.(438) Thus, a non-selective BACE1 inhibitor also inhibits BACE2’s protective functions, leading to off target side effects.”
BackgroundSelf-citationCritical thinking on amyloid-beta-targeted therapy: challenges and perspectives
Sun, B., Chen, Y., Fan, D., Zhu, C., Zeng, F., & Wang, Y. (2020) · Science China Life Sciences · doi:10.1007/s11427-020-1810-y · Cited by 27
Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease
Zimmer, J. A., Shcherbinin, S., Devous, M. D., Bragg, S. M., Selzler, K. J., Wessels, A. M., Shering, C., Mullen, J., Landry, J., Andersen, S. W., et al. (2021) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12123 · Cited by 27
Hallé, M., Tribout-Jover, P., Lanteigne, A.-M., Boulais, J., St-Jean, J. R., Jodoin, R., Girouard, M., Constantin, F., Migneault, A., Renaud, F., et al. (2015) · Journal of Immunological Methods · doi:10.1016/j.jim.2015.05.002 · Cited by 24
BACE 2 degradation mediated by the macroautophagy–lysosome pathway
Liu, X., Wang, Z., Wu, Y., Wang, J., & Song, W. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12204 · Cited by 24
Self-citationXu, P., WU, Z., PENG, Y., GAO, J., Zheng, F., Tan, J., Xu, J., & WANG, T. (2022) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765202220210938 · Cited by 24
Terashima, A., Suh, Y. H., & Isaac, J. T. R. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2425-3 · Cited by 23 · cited 1×
“α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is another glutamate receptor containing four subunits GluA1-4, which makes up to 80% of the excitatory synapses in the CA1 region of hippocampus.(81,82) Many studies have shown that AMPARs also take part in the modulation of synaptic plasticity.”
BackgroundDelBove, C. E., Strothman, C. E., Lazarenko, R. M., Huang, H., Sanders, C. R., & Zhang, Q. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.03.009 · Cited by 22 · cited 1×
“On the other hand, cholesterol-rich lipid rafts provide an optimal environment for Aβ synthesis and enhance the interaction of Aβ with the membrane.(65) Both β- and γ-secretases show increased enzymatic activity in the lipid rafts with higher cholesterol level, while non-amyloidogenic α-secretase activity is inhibited…”
BackgroundMitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
Shields, L. Y., Li, H., Nguyen, K., Kim, H., Doric, Z., Garcia, J. H., Gill, T. M., Haddad, D., Vossel, K. A., Calvert, M., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100469 · Cited by 22 · cited 1×
“Thus, restoration of mitochondrial fission rescued APP- or Aβ-induced mitochondrial abnormality and neuronal damage.(200,201) Only 1% of mitochondrial proteins are synthesized in the mitochondria itself.”
BackgroundGardenia jasminoides J.Ellis extract GJ-4 alleviated cognitive deficits of APP/PS1 transgenic mice
Zang, C., Liu, H., Shang, J., Yang, H., Wang, L., Sheng, C., Zhang, Z., Bao, X., Yu, Y., Yao, X., et al. (2021) · Phytomedicine · doi:10.1016/j.phymed.2021.153780 · Cited by 22
Ji, Y.-J., Kim, S., Kim, J.-J., Jang, G. Y., Moon, M., & Kim, H. D. (2021) · Antioxidants · doi:10.3390/antiox10121968 · Cited by 20
Beneficial effect of amyloid beta after controlled cortical impact
Mannix, R. C., Zhang, J., Berglass, J., Qui, J., & Whalen, M. J. (2013) · Brain Injury · doi:10.3109/02699052.2013.771797 · Cited by 19 · cited 1×
“To answer this question, 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) In contrast, reduction of endogenous Aβ levels by using γ-secretase Fig.”
BackgroundLin, C., Ly, M., Karim, H. T., Wei, W., Snitz, B. E., Klunk, W. E., & Aizenstein, H. J. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0573-1 · Cited by 19 · cited 1×
“A spatial covariance between Aβ aggregates with reduced connectivity and metabolism in the CEN and SN has also been found in AD.(246,247)”
BackgroundGJ-4 alleviates Aβ25-35-induced memory dysfunction in mice through protecting the neurovascular unit
Zhang, Z., Liu, H., Zhao, Z., Zang, C., Ju, C., Li, F., Wang, L., Yang, H., Bao, X., Yu, Y., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110131 · Cited by 19
Hippocampal functional connectivity across age in an App knock-in mouse model of Alzheimer's disease
Morrissey, Z. D., Gao, J., Zhan, L., Li, W., Fortel, I., Saido, T. C., Saito, T., Bakker, A., Mackin, S. R., Ajilore, O., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1085989 · Cited by 18
Alzheimer’s drug stirs excitement—and concerns
Couzin-Frankel, J., & Piller, C. (2022) · Science · doi:10.1126/science.adg1899 · Cited by 17 · cited 1×
“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) ARIA may further cause brain atrophy showing as the increased size of the ventricle.”
BackgroundOur Working Point of View of Tau Protein
Ávila, J. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170600 · Cited by 14 · cited 1×
“A recent study proposed that the phosphorylation of tau at Tyr18 by Fyn kinase also blocked Aβ toxicity.(139,140) Aβ promoted the phosphorylation and activation of Fyn kinase, which further migrated into dendritic spines, leading to synaptic impariment.”
BackgroundCazzaniga, A., Fedele, G., Castiglioni, S., & Maier, J. A. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095133 · Cited by 14 · cited 1×
“Unlike cell models, AD brain organoids are capable of generating the blood-brain barrier (BBB) as well as connections with other organs.(535) This enables them to potentially function as a superior approach in the understanding Alzheimer’s pathogenesis, as well as a better tool for exploration of Alzheimer’s modificat…”
BackgroundMisfolded diabetes-mellitus peptide seeds amyloid-β aggregation
Ridler, C. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.5 · Cited by 13
Nam, Y., Shin, S. J., Park, Y. H., Kim, M., Jeon, S. G., Lee, H., Choi, Y., Kim, T., Shin, S. M., Kim, J.-J., et al. (2021) · Antioxidants · doi:10.3390/antiox10020207 · Cited by 13
Castro, M. A., Parson, K. F., Beg, I., Wilkinson, M. C., Nurmakova, K., Levesque, I., Voehler, M., Wolfe, M. S., Ruotolo, B. T., & Sanders, C. R. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101792 · Cited by 13 · cited 1×
“Recently, a study showed that 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) Our study also showed that PSEN1S169del (a deletion mutation in PSEN1 gene exon 6) has distinct effects…”
BackgroundYuyama, K., Sun, H., Igarashi, Y., Monde, K., Hirase, T., Nakayama, M., & Makino, Y. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01073-w · Cited by 13 · cited 1×
“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.(274,275) Our group has also identified that circulating Aβ could pass the blood brain barrier (BBB) and enter the brain, contributing to the development of…”
BackgroundChan, C. K., Soldan, A., Pettigrew, C. A., Wang, J., Albert, M., & Rosenberg, P. B. (2020) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12106 · Cited by 11 · cited 1×
“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)”
BackgroundAmyloid-β down-regulates XIAP expression in human SH-SY5Y neuroblastoma cells
Yamamori, H., Tanaka, T., Kudo, T., & Takeda, M. (2004) · Neuroreport · doi:10.1097/00001756-200404090-00023 · Cited by 10
Management of the Difficult Airway
(2021) · New England Journal of Medicine · doi:10.1056/nejmc2109513 · Cited by 8
Henryk M. Wisniewski and the amyloid theory of Alzheimer's disease
Masters, C. L., & Beyreuther, K. T. (2001) · Journal of Alzheimer s Disease · doi:10.3233/jad-2001-3112 · Cited by 6
Morley (2010) · doi:10.3233/jad-2009-1230 · cited 1×
“In contrast, application of nanomolar synthetic Aβ successfully enhanced the cognitive and memory performance of the mice.(357) However, the nanomolar concentrations of Aβ used in the study deviate too far from the physiological level of Aβ in picomolar concentrations.”
Background
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
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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.
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