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Cited by 988Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future

Open access
Zhang, Yun, Chen, Huaqiu, Li, Ran, Sterling, Keenan, Song, Weihong·2023·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-023-01484-7PMC PMC10310781
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Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41392-023-01484-7

Cites

559 of 559 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 349 cited sources checked · 0 supported · 0 flagged

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    Aβ peptide levels are elevated during traumatic brain injury (TBI).

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  • Findingcitation

    Animal models expressing human Aβ showed stronger resistance to bacterial and viral infections.

    “Animal models with the expression of human Aβ showed stronger resistance to bacterial and viral infections.365”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Findingcitation

    Intracerebroventricular injection of Aβ40 peptides into TBI-impacted BACE1-/- mice significantly improved motor memory deficits.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Findingcitation

    Reduction of endogenous Aβ levels by γ-secretase inhibitor DAPT or deletion of BACE1 attenuated functional recovery in mice with spinal cord injury.

    “reduction of endogenous Aβ levels by using γ-secretase inhibitor DAPT or deleting the enzyme BACE1 attenuated the functional recovery in mice with spinal cord injury (SCI).396”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Findingcitation

    Overexpression of human APP (hAPP695) leads to lower infarct volume in the cortex of mice with cerebral ischemia.

    “overexpression of human APP (hAPP695) leads to an obvious lower infarct volume in the cortex of mice suffering from cerebral ischemia.363”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Findingcitation

    Aβ treatment inhibits production of proinflammatory TH1 and TH17 cells and related cytokines IL-6, IFN-γ and IL-17, and improves motor paralysis in EAE animal models.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Findingcitation

    Aβ peptides bound to fungal cells and stimulated phagocytosis of microglia.

    “Aβ peptides also bound to fungal cells and stimulated the phagocytosis of microglia.408”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [408] Wu, Y. et al. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits. Nat. Commun. 10, 58 (2019). source

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    Findingcitation

    Aβ42 induced oxidative stress and decreased expression of XIAP, which directly inhibited key proteases of the apoptosis pathway including caspase 3, 7 and 9.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Findingcitation

    Brain tissues from AD patients show higher anti-microbial activity than samples from age-matched non-AD individuals, correlated with Aβ levels in brain.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Findingcitation

    Aβ40 mainly drove differentiation of NPCs into neurons, whereas Aβ42 increased glia markers in NPCs.

    “Aβ40 mainly drived differentiation of NPCs into neurons, differing from Aβ42, which increased glia markers in NPCs.359”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Findingcitation

    Verteporfin only bound with the APP transmembrane domain rather than the Notch-1 receptor transmembrane domain, indicating its inhibitory effect is C99-specific.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Findingcitation

    Aβ42 stimulated expression of Bax, which induced cell apoptosis and is commonly observed in many cancers.

    “Aβ42 stimulated the expression of Bax, which induced cell apoptosis and was commonly observed in many cancers.416,417”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Findingcitation

    Damaged host cells released nucleic acids containing Aβ aggregates, which were immunogenic and elicited secretion of type I interferons by adjacent microglia to accomplish the antiviral response.

    “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”
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    • cites [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

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    Findingcitation

    Genetic deletion of CatB significantly increased Aβ42 burden and worsened amyloid deposition in AD mice, whereas overexpression of CatB reduced amyloid plaques.

    “genetic deletion of CatB significantly increased Aβ42 burden and worsened amyloid deposition in AD mice, whereas overexpression of CatB reduced amyloid plaques.497”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Findingcitation

    Treatment with rapamycin significantly stimulated autophagy associated with markedly reduced intracellular Aβ and extracellular amyloid deposition in brains as well as improved cognitive deficits in AD mice.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Findingcitation

    PET imaging allows visualization of Aβ fibrils in patients, which accumulate in an Alzheimer's brain as early as 15 years before symptom onset.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Findingcitation

    Crenezumab did not significantly improve cognitive impairment in participants but showed some favorable effects.

    “Although crenezumab did not significantly improve cognitive impairment in the participants, it showed some favorable effects (Alzheimer’s Association International Conference, 2022).”
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    • cites Alzheimer’s Association International Conference, 2022

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    Findingcitation

    Gantenerumab had a positive impact on reduction of cortical amyloid, leading to further study by an exploratory open-label extension.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Findingcitation

    Antibodies with Fc fragment reduced Aβ burden but also induced engulfment of neuronal synapses by activating CR3 or FcγRIIB, which exacerbates cognitive impairment in AD mice.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Findingcitation

    AD model mice with ATG7 KO showed deficient autophagy associated with drastically reduced extracellular Aβ plaques and markedly accumulated intraneuronal Aβ, suggesting Aβ secretion was compromised due to impaired autophagy.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [495] Nilsson, P. et al. Abeta secretion and plaque formation depend on autophagy. Cell Rep. 5, 61–69 (2013). source

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    Findingcitation

    Depressive symptoms in middle-aged individuals correlate with time to onset of cognitive decline, suggesting a role of psychiatric disorders as early markers of Alzheimer's disease.

    “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”
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    Findingcitation

    Unlike cell models, AD brain organoids are capable of generating the blood-brain barrier (BBB) as well as connections with other organs.

    “Unlike cell models, AD brain organoids are capable of generating the blood-brain barrier (BBB) as well as connections with other organs.535”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Findingcitation

    Three-dimensional brain organoids derived from human pluripotent stem cells have shown significant advantages in modeling neurological disorders including autism, microcephaly and Parkinson's disease.

    “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”
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    • cites [528] Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). source

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    Findingcitation

    CSF neurogranin increases exclusively in AD patients and has not been observed in other neurodegenerative disorders, such as frontotemporal dementia or Parkinson's disease.

    “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”
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    • cites [550] Wellington, H. et al. Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835 (2016). source

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    Premisecitation

    AβOs directly disturb the activity of NMDARs and impair NMDAR-mediated signaling pathways, leading to synaptic loss and reduction of spine density.

    “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”
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    Premisecitation

    AβOs induce AMPAR ubiquitination and degradation, leading to loss of AMPARs followed by suppression of synaptic transmission.

    “AβOs induce AMPAR ubiquitination and degradation, leading to the loss of AMPARs followed by the suppression of synaptic transmission.85,86”
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    Premisecitation

    The amyloid cascade hypothesis posits that Aβ deposits in the brain are the initiating event of AD pathogenesis, resulting in subsequent tau tangle formation, neuronal loss and dysfunction, and cognitive decline.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Growing evidence supports that Aβ oligomers exist and exert their neurotoxicity independently of mature fibrils.

    “growing evidence supports that the Aβ oligomers exist and exert their neurotoxicity independently of mature fibrils.61”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448–6453 (1998). source

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    Premisecitation

    In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.

    “In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.29”
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    Premisecitation

    An APP mutation identified in the Icelandic population reduces Aβ production and leads to protection against cognitive decline in the elderly.

    “an APP mutation identified in the Icelandic population reduces Aβ production, leading to protection against cognitive decline in the elderly.40”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012). source

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    Premisecitation

    AβOs destroy glutamate recycling at the synapse by increasing glutamate release, reducing glutamate uptake and impairing glutamate transporters, causing overactivation of extrasynaptic NMDARs, ultimately leading to LTP suppression, LTD enhancement, and synaptic loss.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    The expressions of LRP1 and ABCB1 were reduced during AD, whereas the expression of RAGE is elevated.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [25] Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008). source

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    Interpretationreasoning

    The positive results indicate that Aβ-based therapy may be the right direction to be followed.

    “This series of positive results offers a fresh hope and indicates that Aβ-based therapy may be indeed the right direction to be followed.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    ANAVEX2-73 (Blarcamesine) targets sigma-1 and M1 muscarinic receptors and demonstrated disease-modifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies and improving cognitive deficits.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [52] Hampel, H. et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study. Alzheimers Dement (N. Y.) 6, e12013 (2020). source

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    Premisecitation

    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+ entry, leading to LTP inhibition and neuronal death.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    • cites [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

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    Premisecitation

    Partial or complete deletion of TREM2 markedly reduced the number of Aβ-associated macrophages and increased cerebral Aβ plaques in AD model mice.

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    Premisereasoning

    Blood-based biomarkers have become the primary goal in screening for and diagnosing AD in the population, and many studies focus on examining the role of peripheral Aβ and APP in AD development.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ produced by neurons induces the complement protein C3a released by astrocytes via NFκB signaling, which interacts with C3aRs on microglia and neurons to aggravate Aβ aggregate loads and cognitive impairment.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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    Premisecitation

    Both CSF Aβ42 and Aβ PET biomarkers have high diagnostic and prognostic value as they start changing decades before the onset of dementia symptoms.

    “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”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [266] Jack, C. R. Jr. & Holtzman, D. M. Biomarker modeling of Alzheimer’s disease. Neuron 80, 1347–1358 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced default-mode network connectivity occurs only in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.

    “Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.241”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Redox active metal ions such as Cu and Fe bind to Aβ to produce ROS, which contributes to oxidative damage on proteins and lipids leading to impaired membrane integrity, neuronal dysfunction and DNA damage.

    “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”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ aggregates interact with glutamatergic neurotransmission, which impairs excitatory synaptic plasticity, leading to cognitive decline.

    “Aβ aggregates interact with glutamatergic neurotransmission, which impairs excitatory synaptic plasticity, leading to cognitive decline.222–225”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [222] Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8, 1051–1058 (2005). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [225] Brito-Moreira, J. et al. Abeta oligomers induce glutamate release from hippocampal neurons. Curr. Alzheimer Res 8, 552–562 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AβOs induce tau hyperphosphorylation and accumulation in dendritic spines, which further lead to synaptic loss and dysfunction.

    “AβOs induce tau hyperphosphorylation and accumulation in dendritic spine, which further lead to synaptic loss and dysfunction.94,95”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EVP-0962 reduced Aβ42 levels and increased Aβ38 levels without affecting Notch signaling in vitro.

    “EVP-0962 is another GSM that was shown to reduce Aβ42 levels and increase Aβ38 levels without affecting Notch signaling in vitro.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Avagacestat is a recently developed arylsulfonamide γ-secretase inhibitor with high selectivity for APP over Notch, which successfully reduces CSF Aβ levels in animal models without Notch-related toxicity.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [314] Albright, C. F. et al. Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J. Pharm. Exp. Ther. 344, 686–695 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circulating Aβ can pass the blood-brain barrier and enter the brain, contributing to the development of AD.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [276] Bu, X. L. et al. Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol. Psychiatry 23, 1948–1956 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical data showed vanutide cridificar induced generation of N-terminal anti-Aβ antibodies and improved cognitive impairment in AD animal models.

    “Preclinical data showed that vanutide cridificar induced the generation of N-terminal anti-Aβ antibodies and successfully improved cognitive impairment in AD animal models.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plasma Aβ acts as an endophenotype of AD, simultaneously changing with Aβ status in the brain.

    “there is increasing evidence to support that plasma Aβ acts as an endophenotype of AD, which simultaneously changes with Aβ status in the brain.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood levels of APP669-711/Aβ42 and Aβ40/Aβ42 ratios, as well as peripheral Aβ-bound extracellular vesicles, predict brain Aβ burden.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [274] Nakamura, A. et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atabecestat, elenbecestat, lanabecestat, and umibecestat reached late stages of clinical trials but all failed to receive final approval to reach the market.

    “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.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • cites [308] Zimmer, J. A. et al. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease. Alzheimers Dement (N. Y) 7, e12123 (2021). source

      Not checked in the free run.

    • cites [309] Neumann, U. et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med. 10, e9316 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    According to ALZFORUM (March 2023), 298 AD therapies have been under clinical trials.

    “According to ALZFORUM (March 2023, www.alzforum.org), 298 AD therapies have been under clinical trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites ALZFORUM

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ peptides in the CNS can move into the circulatory system, where they are phagocytosed by monocytes or neutrophils, directly degraded by enzymes, or further transported to peripheral organs or tissues for degradation or excretion.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SGSM-36 reduced the level of toxic Aβ42 peptides without changing proteolytic processing of Notch or α- and β-secretase processing of APP.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 2012, Eli Lilly announced that LY2886721 produced expected results in Phase 1 studies with reduced CSF levels of Aβ40 and Aβ42 as well as increased sAPPα levels.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites P3-359, Alzheimer’s Association International Conference, 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UB-311 was shown to neutralize Aβ toxicity and enhance plaque clearance in preclinical studies.

    “UB-311 was shown to neutralize Aβ toxicity and enhance plaque clearance in preclinical studies.327”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [327] Wang, C. Y. et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 25, 3041–3052 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although aggregates have been considered toxic, soluble Aβ at physiological levels has biological functions, including enhancement of long-term potentiation, stimulation of neuronal differentiation, improvement of brain recovery from injuries, inhibition of oxidative stress, antimicrobial activity, and tumor suppression.

    “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”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [355] Cirrito, J. R. et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913–922 (2005). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [359] Chen, Y. & Dong, C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 16, 386–394 (2009). source

      Not checked in the free run.

    • cites [360] Scott, G. et al. Amyloid pathology and axonal injury after brain trauma. Neurology 86, 821–828 (2016). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [364] Kontush, A. et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med 30, 119–128 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Most initial crenezumab trials including the prevention trial failed to achieve primary endpoints, and crenezumab is now discontinued.

    “Unfortunately, most of the initial trials including the prevention trial failed to achieve their primary endpoints, and crenezumab is now discontinued.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In preclinical studies, ACI-24 generated high titers of anti-Aβ IgG1 and IgG2b antibodies and improved novel object recognition in AD mice.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Donanemab is a humanized IgG1 monoclonal antibody targeting existing amyloid plaques and clearing them from the brain.

    “Donanemab is a humanized IgG1 monoclonal antibody targeting the existing amyloid plaques and clearing them from the brain.344”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Results showed that patients with lecanemab treatment had lower brain amyloid levels and reduced cognitive and functional decline as measured by CDR-SB by 27% compared with placebo.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Later, Biogen announced that the interim futility analysis was wrong and the highest dose of aducanumab treatment significantly improved cognitive deficit in participants.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oct 2019 news, investors.biogen.com

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Currently four vaccines are under clinical trials: ALZ-101 (Phase 1), ACI-24 (Phase 2), ABvac 40 (Phase 2), and UB311 (Phase 3).

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In preclinical studies, 3D6 binds to monomeric, oligomeric and fibril forms of Aβ, leading to reduced levels of Aβ and improved cognitive deficits in AD model mice.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Phase 2 trial, lecanemab successfully reduced brain amyloid and improved cognitive decline in the highest-dose group (twice-monthly 10 mg/kg).

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gantenerumab treatment significantly reduced amyloid loads and normalized CSF Aβ42 levels.

    “Gantenerumab treatment significantly reduced the amyloid loads and normalized CSF Aβ42 levels.338”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [338] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Lecanemab (BAN2401) is the humanized IgG1 version of mouse mAb158, which specifically binds to large, soluble Aβ protofibrils.

    “Lecanemab (BAN2401) is the humanized IgG1 version of the mouse mAb158, which specifically binds to large, soluble Aβ protofibrils.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Humanized antibodies are generated by modifying protein sequences from non-human species to increase similarity to natural human antibody variants, reducing immunogenicity, enhancing human effector functions, and increasing serum half-life.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [330] Waldmann, H. Human monoclonal antibodies: The benefits of humanization. Methods Mol. Biol. 1904, 1–10 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ABvac40 targets the C-terminus of Aβ peptides and is currently being evaluated in Phase 2 clinical studies.

    “Another vaccine called ABvac40 targets the C-terminus of Aβ peptides and is also currently being evaluated in Phase 2 clinical studies.326”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Phase 2 studies, UB-311 showed safety and generated Aβ antibodies in 96% of patients with mild AD.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 14th International Conference on Alzheimer’s and Parkinson’s Disease, 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gantenerumab was found to be safe and well tolerated during Phase 1 clinical trials, except transient amyloid-related imaging abnormalities (ARIA) appeared in some patients given a high dosage.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although solanezumab was well tolerated, it was not able to show significant therapeutic benefits to AD patients.

    “Although solanezumab was well tolerated in the participants, it was not able to show the significant therapeutic benefits to AD patients.345,346”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACI-24 is a liposome vaccine based on Aβ1-15 sequences, designed to generate antibodies specifically against β-sheet folding of Aβ.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisereasoning

    Two Phase 3 trials of gantenerumab in prodromal or mild AD patients with amyloid deposition failed to slow cognitive impairment.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Genetic deletion of APP significantly aggravated EAE severity, suggesting a protective role of Aβ against autoimmune inflammation in the CNS.

    “genetic deletion of APP significantly aggravated the severity of the disease, suggesting the protective role of Aβ against autoimmune inflammation in CNS.397”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Physiological levels of Aβ monomers are crucial to maintain normal synaptic function while only Aβ aggregates have inhibitory and toxic effects.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Rapidly increased Aβ expression after injury is beneficial and indicates that Aβ stimulates brain recovery from traumatic and ischemic injuries.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [360] Scott, G. et al. Amyloid pathology and axonal injury after brain trauma. Neurology 86, 821–828 (2016). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the CNS, nicotinic acetylcholine receptors are expressed in both neurons and non-neuronal cells.

    “In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.379,380”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Removal of endogenous Aβ by injection of anti-Aβ antibodies or genetic manipulation greatly decreased LTP and impaired memory, which could be rescued by addition of human Aβ42.

    “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”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [374] Garcia-Osta, A. & Alberini, C. M. Amyloid beta mediates memory formation. Learn Mem. 16, 267–272 (2009). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [376] Galanis, C. et al. Amyloid-beta mediates homeostatic synaptic plasticity. J. Neurosci. 41, 5157–5172 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α7-nAChRs are involved in neurotransmitter release, synaptic plasticity and neurogenesis.

    “α7-nAChRs are involved in a variety of biological functions, including neurotransmitter release, synaptic plasticity and neurogenesis.384,385”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.

    “In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.386”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α7-nAChR KO mice at 12-month-old showed Aβ elevation as a compensatory response of α7-nAChRs and exhibited AD-like pathologies.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    As ligand-gated ion channels, nAChRs open in response to depolarization of the membrane, allowing Na+, K+ and Ca2+ to enter cells.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The mechanism behind Aβ-induced α7-nAChR activation could be due to disruption of intracellular signal transduction to stimulate calcium influx.

    “The mechanism behind Aβ-induced α7-nAChR activation could be due to the disruption of intracellular signal transduction to stimulate the calcium influx.383”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aβ42 cannot prevent replication of non-enveloped human adenovirus, suggesting it probably interacts with viral coat proteins.

    “Aβ42 cannot prevent the replication of non-enveloped human adenovirus, suggesting that it probably interacts with viral coat proteins.404”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Rapid generation and deposition of Aβ in stroke and after head trauma could benefit maintenance of BBB integrity and inhibit leakage of serum components into the brain, leading to neuroinflammation.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE2 is a close homolog of BACE1 but plays a neuroprotective role by inhibiting the amyloidogenic pathway of APP processing and reducing potassium channel Kv2.1-induced neuronal apoptosis.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although human tau gene MAPT mutations per se only cause frontotemporal dementia rather than AD, tau mediates Aβ toxicity to promote the pathological process of AD.

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [137] Bloom, G. S. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–508 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Less than 1% of all AD cases are early-onset with symptoms at age 50s and earlier, caused by gene mutations in APP, PSEN1 or PSEN2.

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leading to neurodegeneration.

    “Growing evidence indicates that Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leading to the process of neurodegeneration.112–114”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [112] Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    More than 99% of AD cases occur at age >60 years in a sporadic manner, potentiated by lifestyle-related risk factors.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP and Aβ can be imported into mitochondria, where they interact with mitochondrial components, impair ATP production, and increase oxidative damage.

    “APP and Aβ can be imported into mitochondria, where they can interact with mitochondrial components, impair ATP production, and increase oxidative damage.481,482”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [482] Wilkins, H. M. Interactions between amyloid, amyloid precursor protein, and mitochondria. Biochem Soc. Trans. 51, 173–182 (2023). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Combination therapy that targets different mechanisms and pathologies would be directed by biomarkers and customized to the individual.

    “Combination therapy that targets different mechanisms and pathologies would be directed by biomarkers and customized to the individual.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Most Aβ-targeting drug trials have failed as a consequence of lack of sufficient specificity and accurate translational models, loss of Aβ physiological homeostasis, and failure to be administered during the best therapeutic window.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Aβ aggregates play a causative role in AD development.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    miRNAs are involved in Alzheimer's pathogenesis and are easily detected in body fluids, including CSF, plasma and serum.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Aβ aggregates act as the unique specific pathological hallmark of AD.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Translational models and tools to mimic the nature of AD more closely are required to bridge the gap between basic research and clinical practice.

    “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.”
    Quote in the paperNot a substantial claim
93 of 93

  • 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.”
7 of 7

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?

  • Soluble Aβ oligomers, rather than insoluble fibrils, are the principal neurotoxic species, disrupting synaptic plasticity, impairing long-term potentiation, and triggering downstream inflammatory cascades.

    “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]

    In “Pathological role of Aβ aggregates” (page unavailable), the review says growing evidence supports oligomer neurotoxicity independent of mature fibrils and describes oligomers impairing synaptic plasticity and suppressing LTP. Its inflammation discussion attributes glial activation and pro-inflammatory cytokine production to Aβ or Aβ aggregates generally, not specifically to soluble oligomers rather than fibrils. That last distinction is not established for the inflammatory part of the claim. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Several clinical investigations focusing on Aβ have produced contradictory findings, casting doubt on the veracity of the amyloid theory in general.

    “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]

  • While lowering Aβ levels can decrease cognitive deterioration, not all patients will definitely see improved clinical outcomes from this strategy.

    “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.

  • Aducanumab called the first approved Alzheimer's therapy

    Minor

    Aducanumab cannot be the first FDA-approved Alzheimer's therapy if the paper's earlier account of approved AD treatments is correct. The intended distinction may be that it was the first approved antibody therapy.

  • Vaccine count omits an ongoing Phase 2 vaccine

    Minor

    The narrative says four vaccines are under clinical trials, but Table 2 also lists AV-1959D, a DNA vaccine, under ongoing Phase 2 trials. That makes at least five vaccines listed as being in trials.

  • Aducanumab placed under monomer-targeting therapies

    Minor

    Table 2 places Aduhelm under "Targeting Aβ monomers," but the text explicitly says aducanumab targets aggregates rather than monomers.

  • Approved-drug count excludes two approved antibodies

    Minor

    The paper says five AD drugs have been approved and identifies all five as four cholinesterase inhibitors plus memantine. It also says aducanumab and lecanemab have been approved by the FDA, so its stated total does not include those two drugs.

4 of 4

Cites

2 retracted

Flagged first, then by citations

3 of the 562 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Walker, L. C. Abeta plaques. Free Neuropathol. 1, 31 (2020).

Cited by

Sorted by citations

Related

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
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-06-30
Volume
8
Issue
1
Pages
248-248
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-023-01484-7
PMC
PMC10310781
OpenAlex
W4382601497
Cited by
988
References
562
Citations by year
2026: 278 · 2025: 422 · 2024: 257 · 2023: 30 · 2022: 1
FWCI
35.22
Type
journal article
Language
en
Open access
Licence
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
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
amyloid-beta, Alzheimer's disease, amyloid hypothesis, anti-amyloid therapy, neuritic plaques, Alzheimer's disease prevention, Alzheimer's disease treatment, Alzheimer's disease diagnosis
MeSH terms
Alzheimer Disease, Humans, Amyloid beta-Peptides, Plaque, Amyloid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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