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Cited by 3,204Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Open access
Long, Justin M., Holtzman, David M.·2019·Cell
DOI 10.1016/j.cell.2019.09.001PMC PMC6778042
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Abstract

Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes Alzheimer disease pathobiology and treatment strategies, covering amyloid, tau, ApoE, neuroimmune activation, infection, and sleep. It concludes that no disease-modifying therapy exists and argues for earlier/preclinical anti-amyloid trials plus tau-, ApoE-, immune-modulating, and combination approaches.

Key findings

  • AD is biologically defined by extracellular Aβ plaques and intracellular hyperphosphorylated tau tangles; preclinical pathology begins roughly 10–20 years before symptoms, and death generally occurs within 5–12 years of symptom onset.
  • APOE ε4 is the strongest late-onset AD genetic risk factor: one copy raises risk about 3–4-fold and two copies about 12-fold, while ε2 is protective. Amyloid accumulation appears required but not sufficient; tau burden tracks cognitive decline more closely than amyloid.
  • Four FDA-approved symptomatic drugs exist (three cholinesterase inhibitors and memantine), with modest effects; more than 20 compounds completed phase 3 trials without slowing decline, and many Aβ antibodies, BACE1 inhibitors, and γ-secretase inhibitors failed or caused adverse effects.
  • Emerging areas include context-dependent microglial/innate immune roles, ApoE effects on amyloid seeding/clearance, tau-mediated neurodegeneration, blood-brain barrier integrity, and neuronal activity; sleep loss raises Aβ and tau, and infectious/microbiome hypotheses remain under study.

Methods

  • Narrative review: the authors synthesize recent advances in AD pathobiology and treatment rather than conducting a systematic review or meta-analysis.
  • Evidence base includes human neuropathology, CSF/plasma biomarkers, PET/MRI, genetic studies, animal and cell models, and clinical trial reports.
  • Main analysis is qualitative integration; no primary data collection or formal statistical analysis is described.

Limitations

  • Paper-stated: no disease-modifying therapy is available; many phase 3 trials failed; some negative amyloid trials were not designed to definitively test the amyloid hypothesis; herpesvirus–dementia associations need replication in large prospective cohorts; human relevance of microglial mechanisms remains unclear.
  • Evident from the text: as a narrative review, it lacks systematic search/quality appraisal and reports no new experimental data; many mechanistic conclusions rely on preclinical models, and several cited findings are described as conflicting or unreplicated.

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

Integrity signals

Registry

Crossref · 10.1016/j.cell.2019.09.001

Cites

330 of 330 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    AD has a preclinical phase that precedes clinical symptoms by at least 10-20 years.

    “Longitudinal studies of cognitive function and CSF and neuroimaging biomarker changes in ADAD and LOAD have identified a significant preclinical phase of disease preceding onset of clinical symptoms by at least 10-20 years”
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    • cites Vermunt et al., 2019 source

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  • Premisecitation

    CNS Aβ deposition can be detected via plasma assessment of Aβ species.

    “Recent studies demonstrate the ability to detect CNS Aβ deposition via the use of plasma assessment of Aβ species”
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    • cites Nakamura et al., 2018 source

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    • cites Ovod et al., 2017 source

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    • cites Palmqvist et al., 2019 source

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  • Premisenone given

    No disease-modifying treatment for AD currently exists.

    “Despite this, no disease modifying treatment currently exists and numerous phase 3 clinical trials have failed to demonstrate benefit.”
    • Also stated in: § INTRODUCTION · plain
      “There is a dire need for disease modifying therapies that may prevent or slow rate of disease progression, but unfortunately none are currently available.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Synaptic and neuronal loss in the entorhinal cortex correlates with the onset of cognitive impairment.

    “Synaptic and neuronal loss in the entorhinal cortex generally correlates well with onset of cognitive impairment”
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    • cites Gómez-Isla et al., 1996 source

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  • Premisecitation

    Antemortem AD neuropathologic diagnosis can be made with reasonable validity using CSF or PET biomarkers as surrogate markers for cerebral Aβ and tau deposition.

    “Antemortem AD neuropathologic diagnoses can now be made with reasonable validity using cerebrospinal fluid (CSF) or positron emission tomography (PET) imaging biomarkers as surrogate markers for cerebral Aβ and tau deposition”
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    • cites Brier et al., 2016

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    • cites Fagan et al., 2006, 2007

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    • cites Lowe et al., 2019 source

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    Premisecitation

    AD is defined biologically and diagnosed primarily by extracellular Aβ plaques and intraneuronal hyperphosphorylated tau tangles and neuropil threads.

    “The presence of extracellular amyloid-β deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remain the primary neuropathologic criteria for AD diagnosis.”
    • Also stated in: § INTRODUCTION · plain
      “AD as a distinct entity is now defined biologically by the presence of a specific neuropathological profile (Jack et al., 2018a): extracellular deposition of amyloid-β (Aβ) in the form of diffuse and neuritic plaques and the presence of intraneuronal neurofibrillary tangles and neuropil threads within dystrophic neurites consisting of aggregated hyperphosphorylated tau protein (Duyckaerts et al.,”
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    • cites Jack et al., 2018a

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    • cites Duyckaerts et al., 2009

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    Premisecitation

    Tau is subject to post-translational modifications, and aberrant phosphorylation often decreases tau binding affinity for microtubules.

    “Tau protein is subject to numerous post-translational modifications, including phosphorylation, acetylation, glycation, O-GlcNAcylation, nitration, SUMOylation, ubiquitination and truncation”
    • Also stated in: § Tau · plain
      “In many cases, aberrant phosphorylation results in decreased binding affinity for microtubules”
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    • cites Marcelli et al., 2018

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    • cites Biernat et al., 1993

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    • cites Mandelkow et al., 2007

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    Interpretationreasoning

    Available data strongly supports the central role of pathologic Aβ accumulation in mediating AD pathogenesis as outlined in the original amyloid cascade hypothesis, although its mechanism may be less direct than originally anticipated.

    “In summary, the available data still strongly supports the central role of pathologic Aβ accumulation in mediating AD pathogenesis as outlined in the original description of the amyloid cascade hypothesis, although its mechanism may be less direct than originally anticipated”
    Quote in the paperSubstantial claim

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    Premisenone given

    The γ-secretase complex consists of four protein subunits: presenilin, presenilin enhancer, APH, and Nicastrin.

    “The γ-secretase complex consists of four protein subunits: presenilin (PSEN), presenilin enhancer (PEN), APH and Nicastrin.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The cellular phase extension proposes that cerebral amyloid and tau pathology accumulate slowly and are tolerated early, serving as a risk factor, but clinical disease manifests when cellular homeostatic mechanisms fail, leading to impaired clearance, cellular stress, and breakdown of intercellular functions that cause neurodegeneration.

    “This extension proposes that accumulation of cerebral amyloid and tau pathology (the “biochemical phase”) is a slow, gradual process that is tolerated by CNS cells early in the course of disease, serving as a risk factor for development of clinical disease, but that the disease is only manifest clinically when cellular homeostatic mechanisms fail, leading to impaired clearance of aggregated”
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    • cites De Strooper and Karran, 2016 source

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    Interpretationcitation

    Hypoxia can induce increased Aβ production, possibly via increased BACE1 expression, suggesting a pathological feedforward loop.

    “Hypoxia can induce increased Aβ production, possibly via increased BACE1 expression (Sun et al., 2006), suggesting the possibility of a pathological feedforward loop.”
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    • cites Sun et al., 2006 source

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    Interpretationreasoning

    Aβ is necessary but not sufficient for AD, and other downstream factors play key roles.

    “it seems clear that Aβ is necessary but not sufficient and that there are other downstream factors that play a key role.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Longitudinal amyloid and tau PET suggests that the rate of amyloid accumulation predicts onset of tau accumulation, whereas the rate of tau accumulation predicts onset of cognitive impairment.

    “Longitudinal assessment of amyloid and tau PET imaging suggests that rate of amyloid accumulation predicts onset of tau accumulation whereas rate of tau accumulation predicts onset of cognitive impairment”
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    • cites Hanseeuw et al., 2019 source

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    Interpretationcitation

    Cognitive decline and neurodegeneration in AD is primarily driven by the onset and spread of tau pathology.

    “These findings have led to the hypothesis that cognitive decline and neurodegeneration in AD is primarily driven by onset and spread of tau pathology.”
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    Premisecitation

    Tau acetylation reduces degradation of phosphorylated tau and increases tau pathology.

    “Tau acetylation has been shown to reduce degradation of phosphorylated tau and increase tau pathology”
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    • cites Min et al., 2010 source

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    Interpretationcitation

    A 3D in vitro culture of human iPSC-derived neurons overexpressing APP with FAD mutations generates robust Aβ42 production and amyloid deposition, and also develops elevated phospho-tau and fibrillary tau aggregates, suggesting elevated Aβ alone is sufficient to drive tau pathology in human neurons.

    “A 3D in vitro culture system consisting of human neurons differentiated from induced pluripotent stem cells overexpressing human APP containing FAD mutations generates robust Aβ42 production and amyloid deposition. Importantly, this model also develops elevated phospho-tau levels and fibrillary tau aggregates, suggesting that elevated Aβ levels alone are sufficient to drive tau pathology in human”
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    • cites Choi et al., 2014 source

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    Premisecitation

    Soluble oligomers isolated from AD brain inhibit long-term potentiation, enhance long-term depression, and reduce dendritic spine density in rodent hippocampal slice cultures.

    “Soluble oligomers isolated from AD brain have been shown to potently inhibit long-term potentiation (LTP), enhance long-term depression (LTD) and reduce dendritic spine density in rodent hippocampal slice cultures”
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    • cites Kamenetz et al., 2003 source

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    Premisecitation

    Tau pathology propagates throughout the AD brain in a stereotyped fashion across neuroanatomically connected networks, forming the basis of Braak staging.

    “Clinico-neuropathologic correlation analyses have demonstrated that tau pathology propagates throughout the AD brain in a stereotyped fashion across neuroanatomically connected networks (Figure 2C) forming the basis of Braak staging”
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    • cites Braak and Braak, 1991 source

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    Premisecitation

    Genetic forms of AD such as ADAD, Down syndrome, and APP locus duplications cause increased Aβ42/40 ratio, increased total Aβ production, or increased Aβ fibrillogenic properties and are sufficient to induce typical AD pathology.

    “The hypothesis is supported by the discovery that exclusively genetic forms of AD, such as in autosomal dominant AD (ADAD), Down syndrome (trisomy 21), or APP locus duplications, cause an increase in the Aβ42/40 ratio, increased total Aβ production, or increased Aβ fibrillinogenic properties and are sufficient to induce typical AD pathology”
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    • cites Tcw and Goate, 2017

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    Premisecitation

    Exogenously supplied tau fibrils seed aggregation of transgenic human and endogenous mouse tau in mouse tauopathy models by enhancing nucleation, and these aggregates spread transsynaptically to remote connected brain regions.

    “Exogenously supplied fibrils will seed aggregation of transgenic human and endogenous mouse tau fibrils in mouse tauopathy models by enhancing nucleation of new fibrils. These aggregates then spread transsynaptically to remote anatomically connected brain regions inducing further seeding and aggregation”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites de Calignon et al., 2012 source

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    • cites Clavaguera et al., 2009, 2013

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    • cites Frost et al., 2009 source

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Interpretationreasoning

    Amyloid accumulation may be key in beginning the pathological process, but other downstream events such as neuroinflammation and tau accumulation may be the main drivers of neurodegeneration.

    “These data suggest that while amyloid accumulation may be key in beginning the pathological process, other downstream events such as neuroinflammation and tau accumulation may be the main drivers of neurodegeneration.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Hardy and Higgins proposed the amyloid cascade hypothesis in 1992, positing Aβ deposition as the initiating step leading to tau deposition, neuron and synaptic loss, and cognitive decline.

    “Based on a number of lines of evidence, Hardy and Higgins proposed the amyloid cascade hypothesis in 1992, positing that deposition of Aβ in the brain is the initiating step of AD pathogenesis, leading to subsequent tau deposition, neuron and synaptic loss and cognitive decline”
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    • cites Hardy and Higgins, 1992 source

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    Premisecitation

    In mouse studies crossing tau transgenic with APP transgenic mice or injecting Aβ42 fibrils into tau transgenic mice, tau pathology and neurodegeneration are enhanced in mice with both pathologies, whereas amyloid pathology is generally unaffected.

    “In these studies, tau pathology and neurodegeneration is enhanced in mice with both pathologies, whereas amyloid pathology is generally unaffected”
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    • cites Bolmont et al., 2007

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    • cites Götz et al., 2001

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    • cites Hurtado et al., 2010

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Premisecitation

    Hyperphosphorylated tau is redirected from the axonal to the somatodendritic compartment, where it can impair synaptic function by inhibiting glutamate receptor trafficking or synaptic anchoring.

    “Hyperphosphorylated tau is also redirected from the axonal compartment to the somatodendritic compartment where it can impair synaptic function by inhibiting glutamate receptor trafficking or synaptic anchoring”
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    • cites Hoover et al., 2010 source

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    Premisecitation

    GABAergic inhibitory networks are impaired in AD and may contribute to cognitive impairment; ApoE4-TR mice have decreased numbers of GABAergic interneurons in the hippocampus correlating with learning deficits.

    “GABAergic inhibitory networks are impaired in AD and may contribute to cognitive impairment”
    • Also stated in: § ApoE · plain
      “ApoE4-TR mice have decreased numbers of GABAergic interneurons in the hippocampus and this correlates with learning deficits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Najm et al., 2019 source

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Premisecitation

    In vivo microdialysis and stable isotope labeling kinetics show that ApoE regulates clearance of Aβ in an isoform-dependent manner, with ApoE4-TR mice having diminished clearance, whereas Aβ production was not influenced by ApoE isoform.

    “Detailed in vivo microdialysis and stable isotope labeling kinetics experiments have demonstrated that ApoE regulates clearance of Aβ in the brain in an isoform-dependent manner (ApoE4-TR mice have diminished Aβ clearance relative to other TR mice), whereas Aβ production was not influenced by ApoE isoform”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castellano et al., 2011 source

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Premisecitation

    One inherited APOE ε4 allele increases LOAD risk by approximately 3-4 fold, two copies increase risk by about 12-fold, and inheritance of APOE ε2 is protective.

    “A single inherited copy of the APOE ε4 allele increases risk of developing LOAD by approximately 3-4 fold, while two inherited copies increases risk by ~12-fold”
    • Also stated in: § ApoE · plain
      “Inheritance of the APOE ε2 allele is protective.”
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    • cites Roses, 1996

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    Premisecitation

    TREM2 loss reduces plaque-associated microglia, impairs plaque compaction, and increases dystrophic neurites around plaques.

    “Importantly, there was also a reduction in plaque-associated microglia with associated impairments in plaque compaction and increased levels of dystrophic neurites around plaques (Leyns et al., 2017; Song et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Leyns et al., 2017; Song et al., 2018

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    Premisecitation

    Human single-nuclear transcriptomics identified microglial subtypes with increased Apoe expression but did not identify DAM/MGnD subpopulations similar to mouse.

    “Single nuclear transcriptomic techniques have recently been applied to human AD brain specimens and have identified microglial subtypes with increased Apoe expression but have failed to identify DAM or MGnD subpopulations similar to what has been seen in the mouse brain (Mathys et al., 2019).”
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    • cites Mathys et al., 2019 source

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    Premisecitation

    ApoE expression in microglia is required for phenotypic expression of disease-associated microglia, and ApoE promotes microglial clustering around Aβ plaques.

    “ApoE expression in microglia is required for the phenotypic expression of disease-associated microglia”
    • Also stated in: § ApoE · plain
      “ApoE also promotes microglial clustering around Aβ plaques”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ulrich et al., 2018 source

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Interpretationreasoning

    Microglial activation in Alzheimer disease may be protective during amyloid deposition and damaging during tau accumulation, depending on disease stage.

    “This may be because of disease stage specific effects with activation being protective in the setting of amyloid deposition and damaging in the setting of tau accumulation (Figure 4B).”
    Quote in the paperSubstantial claim

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    Premisecitation

    MGnD/DAM microglia are defined by upregulation of inflammatory transcripts and downregulation of homeostatic transcripts.

    “Termed microglial neurodegenerative phenotype (MGnD) or disease-associated microglia (DAM), these cells are defined by a unique expression profile consisting of upregulation of certain inflammatory transcripts (e.g. Apoe, Trem2, Clec7a) and downregulation of homeostatic transcripts (e.g. P2ry12, Tmeml19).”
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    • cites Keren-Shaul et al., 2017; Krasemann et al., 2017

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    Premisecitation

    In TREM2 deletion and haploinsufficiency mouse models of Aβ deposition, Aβ levels are lower before plaque deposition but higher after plaque deposition.

    “In TREM2 deletion and haploinsufficiency studies using mouse models of Aβ deposition (APPPS1-21 and 5xFAD), levels of Aβ were decreased at 2 months of age (before plaque deposition) but increased at 8.5 months of age (after plaque deposition), suggesting an age or amyloid burden effect (Ulrich et al., 2014).”
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    • cites Ulrich et al., 2014 source

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    Premisecitation

    In preclinical AD, APOE ε4 carriers develop enhanced cerebral amyloid deposition with age, do so at an earlier age, and accumulate amyloid faster than non-carriers.

    “Longitudinal CSF, MRI and PET imaging studies of the preclinical phase of AD have established that APOE ε4 allele carriers develop enhanced cerebral amyloid deposition with age, do so at an earlier age and accumulate amyloid at a more rapid rate relative to non-carriers”
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    Premisecitation

    The proportion of activated microglia is strongly associated with total Aβ load and neuritic plaque number, and less strongly with PHF tau amount.

    “PAM was also strongly associated with total Aβ load and number of neuritic plaques and less strongly associated with amount of PHF tau.”
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    • cites Felsky et al., 2019 source

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    Interpretationcitation

    ApoE4 may mediate neuropathological effects by directly modulating blood-brain barrier integrity; ApoE4 does not efficiently engage LRP1 on pericytes, leading to a proinflammatory cascade and BBB breakdown.

    “ApoE4 may also mediate neuropathological effects by directly modulating BBB integrity”
    • Also stated in: § ApoE · boosted
      “Studies in the Zlokovic lab have demonstrated that ApoE4 does not efficiently engage LRP1 on pericytes.”
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    • cites Bell et al., 2012 source

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    • cites Zlokovic, 2013

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Premisenone given

    TREM2 protein is expressed on microglia, promotes microglial phagocytosis, modulates inflammatory signaling, and supports microglial survival.

    “TREM2 protein is expressed on microglia, promotes microglial phagocytosis, modulates inflammatory signaling and promotes microglial survival.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    ApoE4 may cause neuronal dysfunction via direct neurotoxic effects and by promoting hyperactivity in hippocampal neuronal networks.

    “These data suggest that ApoE4 may cause neuronal dysfunction via direct neurotoxic effects and by promoting hyperactivity in hippocampal neuronal networks.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In APP transgenic-ApoE targeted replacement mice, ApoE isoforms have differential effects on amyloid pathology, and ApoE4-TR mice have enhanced amyloid deposition and higher Aβ levels.

    “In APP transgenic-ApoE targeted replacement (ApoE-TR) mice, where human apoE isoforms are expressed under the influence of endogenous murine ApoE regulatory sequences, ApoE isoforms have differential effects on amyloid pathology. ApoE4-TR mice have enhanced amyloid deposition and higher Aβ levels”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bales et al., 2009

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

  • May combine two claims.

    Premisecitation

    TREM2 knockout or R47H expression in amyloid-depositing mice enhances amyloid seeding and tau seeding/spreading near neuritic plaques.

    “Either TREM2 KO or TREM2 R47H transgene expression in mice that develop amyloid deposition results in enhanced amyloid seeding as well as enhanced tau seeding and spreading near neuritic plaques (Leyns et al., 2019; Parhizkar et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Leyns et al., 2019; Parhizkar et al., 2019

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    Premisecitation

    ApoE4-TR mice have enhanced neural activity in the hippocampus and entorhinal cortex, evidenced by hypermetabolism on fMRI, increased high frequency oscillations, and reduced inhibitory input to entorhinal cortex neurons.

    “ApoE4-TR mice have enhanced neural activity in the hippocampus and entorhinal cortex, as evidenced by hypermetabolism on fMRI, increased high frequency oscillations measured by in vivo electrophysiology, and reduced inhibitory input to neurons of entorhinal cortex”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nuriel et al., 2017

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

  • May combine two claims.

    Premisecitation

    A recent study failed to replicate the neurotoxic effect of ApoE4 in tauopathy mice; in that study ApoE2 mice rather than ApoE4 had enhanced tau pathology, astrogliosis, and behavioral impairment.

    “A recent study failed to replicate the neurotoxic effect of ApoE4 in tauopathy mice.”
    • Also stated in: § ApoE · plain
      “They found that ApoE2 mice, rather than ApoE4, had enhanced tau pathology, astrogliosis and behavioral impairment”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhao et al., 2018 source

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

  • May combine two claims.

    Interpretationcitation

    ApoE directly binds to Aβ present in plaques, and ApoE knockout in APP transgenic models markedly reduces fibrillar Aβ deposition and Aβ levels, suggesting ApoE inhibits clearance and/or promotes Aβ seeding.

    “ApoE directly binds to Aβ present in plaques”
    • Also stated in: § ApoE · hedged
      “APP transgenic animal models demonstrate markedly reduced fibrillar Aβ deposition and Aβ levels in the setting of ApoE KO, suggesting ApoE inhibits clearance and/or promotes Aβ seeding”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Namba et al., 1991

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    • cites Bales et al., 1997, 1999

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    • cites Huynh et al., 2017b

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    • Rests on an assumption: Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

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    Premisenone given

    TREM2 binds soluble Aβ oligomers and promotes phagocytosis of Aβ.

    “TREM2 also binds to soluble oligomers of Aβ and promotes phagocytosis of Aβ.”
    Quote in the paperSubstantial claim

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    Premisecitation

    MGnD can be induced in wild-type mouse brain by injection of apoptotic neurons and requires ApoE expression.

    “In one study, MGnD could be induced in WT mouse brain by injection of apoptotic neurons, and required ApoE expression for induction (Keren-Shaul et al., 2017; Krasemann et al., 2017).”
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    • cites Keren-Shaul et al., 2017; Krasemann et al., 2017

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    Premisecitation

    NLRP3 and caspase-1 deletion decreases Aβ deposition, reduces microglial IL-1β release, and improves cognition in APPPS1 mice.

    “NLRP3 and caspase-1 genetic deletion results in decreased Aβ deposition, reduced IL-1β release from microglia and improved cognitive performance in APPPS1 mice (Heneka et al., 2013).”
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    • cites Heneka et al., 2013 source

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    Premisenone given

    The NLRP3 inflammasome is activated in Alzheimer disease and mild cognitive impairment brains and in APPPS1 mice.

    “NLRP3 inflammasome is activated in AD and mild cognitive impairment (MCI) brains and in APPPS1 mice.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The antimicrobial protection hypothesis proposes that intracerebral infection may induce Aβ fibrillization as a defense, leading to amyloid seeding and initiating the amyloid cascade.

    “These experiments have led to the antimicrobial protection hypothesis of AD that suggests intracerebral infection by certain pathogens may induce Aβ fibrillization as an antimicrobial defense mechanism, leading to amyloid seeding and deposition, thereby initiating the amyloid cascade. (Moir et al., 2018).”
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    • cites Moir et al., 2018

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  • May combine two claims.

    Premisecitation

    Genetic deletion of ASC or anti-ASC neutralizing antibody reverses ASC speck effects.

    “This can be reversed by genetic deletion of ASC or use of an anti-ASC neutralizing antibody (Venegas et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Venegas et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    TREM2 function suppresses amyloid-induced local toxicity and inhibits tau seeding and spreading.

    “This suggests a role of Trem2 function in suppressing amyloid-induced local toxicity that also inhibits tau seeding/spreading.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    C1q binds synapses and, with soluble Aβ oligomers, promotes microglial phagocytosis of synaptic contents.

    “C1q binds to synapses and, in the presence of soluble Aβ oligomers, promotes microglia phagocytosis of synaptic contents (Hong et al., 2016)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hong et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depleting microglia or inhibiting exosome secretion reduces tau spreading in that model.

    “Depletion of microglia or pharmacological inhibition of exosome secretion led to reduced tau spreading in this model.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Asai et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular ASC specks bind Aβ and cross-seed Aβ oligomerization and plaque formation in APPPS1 mice.

    “Extracellular ASC specks have been found to bind to Aβ and can cross-seed Aβ oligomerization and plaque formation in APPPS1 mice (Figure 4C).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Venegas et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Herpesvirus has been found in Alzheimer disease brains and within amyloid plaques.

    “Dating back to 1991, studies have demonstrated the presence of herpesvirus in brains of patients with AD, as well as within amyloid plaques (Carbone et al., 2014; Jamieson et al., 1991, 1992; Wozniak et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carbone et al., 2014; Jamieson et al., 1991, 1992; Wozniak et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HHV-6 and HSV-1 DNA were detected in Alzheimer disease brain specimens across three cohorts, with viral-host interactions regulating AD-related gene networks.

    “Follow-up analyses in AD brain specimens found detectable human herpesvirus (HHV)-6 and herpes simplex virus (HSV)-1 DNA in 3 separate cohorts, and identified many putative viral-host interactions that regulate gene networks pertinent to AD biology, including innate immunity and APP processing (Readhead et al., 2018)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Readhead et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP/PS1ΔE9 mice given high-dose antibiotics have reduced Aβ plaque load and size, increased soluble Aβ42, and fewer plaque-associated microglia and reactive astrocytes.

    “Indeed, one study demonstrated that APP/PS1ΔE9 mice chronically administered a cocktail of high dose antibiotics to modulate microbiome composition had significantly reduced Aβ plaque load, reduced plaque size, increased soluble Aβ42 levels and reduced plaque-associated microglia and reactive astrocytes (Minter et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Minter et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the J20 amyloid mouse model, CD33 expression reduces microglial phagocytosis of Aβ and increases amyloid pathology.

    “In the J20 amyloid mouse model, CD33 expression resulted in reduced microglial-mediated phagocytosis of Aβ, and increased amyloid pathology (Bradshaw et al., 2013; Griciuc et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bradshaw et al., 2013; Griciuc et al., 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Germ-free mice develop microglia with an immature phenotype, blunted inflammatory response, and defective immune response to infection.

    “Germ-free mice develop microglia with an immature phenotype, blunted response to inflammatory stimuli and defective immune response to infection (Erny et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Erny et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysfunctional microglia are less able to sequester Aβ within compact plaques and to inhibit amyloid and tau seeding near plaques, resulting in neuronal damage.

    “These data in models of Aβ deposition would suggest that dysfunctional microglia are less able to sequester Aβ pathology within compact plaques and less able to inhibit amyloid and tau seeding near plaques, resulting in neuronal damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    5xFAD mice survived longer with less severe disease than wild-type mice, while APP knockout mice had slightly increased mortality.

    “5xFAD mice survived longer with less severe disease than WT mice, while APP KO mice had slightly increased mortality compared to WT mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kumar et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD33 knockout decreases amyloid pathology and improves cognition in 5xFAD mice.

    “CD33 KO results in decreased amyloid pathology and improved cognition in 5xFAD mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Griciuc et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Synthetic and AD-brain-derived Aβ fibrils inhibit growth of gram-positive and gram-negative bacteria, fungus, and herpesvirus, and inhibit herpesvirus entry into cells.

    “Synthetic and AD-brain derived Aβ peptide fibrils significantly inhibit the growth of gram positive and gram negative bacteria, fungus (Soscia et al., 2010) and herpesvirus, and inhibits the entry of herpesvirus into cells (Bourgade et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Soscia et al., 2010; Bourgade et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated microglia can secrete toxic proinflammatory cytokines or mediators that stimulate astrocytes to secrete neurotoxic substances.

    “Activated microglia can directly secrete toxic proinflammatory cytokines (Colonna and Butovsky, 2017; Kinney et al., 2018) or secrete indirect mediators that stimulate astrocytes to secrete a neurotoxic substance (Liddelow et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Colonna and Butovsky, 2017; Kinney et al., 2018; Liddelow et al., 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    The current Alzheimer disease clinical pipeline contains over 100 compounds in various trial phases.

    “The current AD clinical pipeline has over 100 different compounds currently being tested in various phases of clinical trials (Hara et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hara et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After Aβ plaque formation, the sleep-wake cycle is impaired and diurnal fluctuation in ISF/CSF Aβ levels is lost.

    “However, after Aβ plaque formation, there is an impaired sleep-wake cycle and loss of diurnal fluctuation in ISF/CSF Aβ levels (Roh et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Roh et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral Porphyromonas gingivalis infection in wild-type mice elevates intraparenchymal Aβ, and gingipain inhibition reduces bacterial burden, Aβ levels, and neuroinflammation.

    “Oral infection of WT mice with Porphyromsonas gingivalis resulted in elevated intraparenchymal Aβ levels, and inhibition of gingipain activity led to reduced intracerebral bacterial burden, decreased Aβ levels and reduced neuroinflammation (Dominy et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dominy et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Memantine is an uncompetitive NMDA receptor modulator that may inhibit glutamate-mediated neurotoxicity, though its precise mechanism is unclear.

    “Memantine is a uncompetitive NMDA receptor modulator that may act to inhibit glutamate-mediated neurotoxicity that develops as neurons die during AD progression, although the precise mechanism of its effect is unclear (Greenamyre et al., 1988; Livingston et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Greenamyre et al., 1988; Livingston et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Memantine effect size is small and it has no effect on long-term disease progression.

    “However, as with ChEI, the effect size is quite small and the medication has no effect on long-term disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Sleep deprivation increases Aβ and tau levels in human CSF and animal brains and enhances intracerebral pathology.

    “In summary, these studies provide compelling evidence that sleep deprivation stimulates increased levels of Aβ and tau in human CSF and animal model brains and enhances intracerebral pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Cholinesterase inhibitor effect size is modest (MMSE mean difference 1.37 points at 6 months) and there is no effect on long-term progression.

    “However, the overall effect size is modest (mean difference in MiniMental State Examination (MMSE) of 1.37 points after 6 months treatment), and there is no effect on long-term disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Memantine effects in mild-to-moderate Alzheimer disease are marginal, and it is not recommended for mild Alzheimer disease.

    “Effects in mild-to-moderate stage disease were marginal and therefore, it is not recommended that this medication be prescribed to patients with mild AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    At the mild-to-moderate stage of Alzheimer disease, significant irreversible synaptic and neuronal loss has occurred and the pathological cascade is likely difficult to reverse.

    “At this stage of disease pathogenesis, significant and irreversible synaptic and neuronal loss has occurred and the pathological cascade would likely be very difficult to reverse (Gómez-Isla et al., 1996).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gómez-Isla et al., 1996 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Available data do not support cholinesterase inhibitor use in very mild Alzheimer disease or mild cognitive impairment, and they may worsen cognition at this stage.

    “Available data does not support the use of ChEI in very mild AD (i.e. mild cognitive impairment), and in fact ChEI may worsen cognition at this early clinical stage (Han et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Han et al., 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The underlying evidence for the amyloid cascade hypothesis remains solid.

    “While the underlying evidence for the amyloid cascade hypothesis remains solid, new discoveries should continually inform and update our understanding of disease pathobiology, eventually leading to the development of novel treatment approaches.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In humans, sleep deprivation increases CSF Aβ levels without changing the rate of Aβ clearance.

    “In a recent study of amyloid kinetics in human CSF using stable isotope labeling, there was an increase in Aβ levels following sleep deprivation but no change in rate of Aβ clearance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lucey et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, interstitial fluid Aβ levels correlate with wakefulness and increase after acute sleep deprivation or orexin infusion.

    “In animal microdialysis experiments, interstitial fluid (ISF) Aβ levels correlate with wakefulness and significantly increase following acute sleep deprivation or orexin infusion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kang et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Partial sleep deprivation lasting 5-8 days did not change AD CSF biomarkers, but the study did not alter slow-wave sleep quantity.

    “However, in a recent study of partial sleep deprivation lasting 5-8 days, no changes in AD CSF biomarkers were noted although that study did not alter the quantity of slow-wave sleep (Olsson et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Olsson et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Cholinesterase inhibitors differ in pharmacokinetics and formulation but not overall efficacy.

    “They differ primarily in their pharmacokinetic profiles (donepezil has a much longer half-life than the others and is dosed once daily) and formulation (rivastigmine is available as a continuous release transdermal patch) but not in overall efficacy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    More than 20 compounds completed phase 3 trials in Alzheimer disease and none slowed cognitive decline or improved global functioning.

    “More than 20 compounds have completed large phase 3 double-blind randomized control trials in cohorts of patients at various stages of AD and none has demonstrated any efficacy in slowing cognitive decline or improving global functioning (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aducanumab binds a conformational Aβ epitope and clears amyloid plaques in transgenic APP models and in humans with prodromal or mild Alzheimer disease.

    “Aducanumab is a fully human IgG1 antibody that binds a specific conformational epitope of Aβ. There was initial excitement for this antibody, as it was demonstrated to actively engage and clear amyloid plaques both in transgenic APP models and in human participants with prodromal or mild AD based on florbetapir-PET imaging.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sevigny et al., 2016 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    BACE1 inhibition would be preferred for primary prevention because blocking Aβ production before pathology could prevent its development.

    “Ideally, BACE1 inhibition would be the preferred target for primary prevention studies, as blocking Aβ production prior to onset of pathology would be sufficient to prevent the development of pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mouse amyloidosis models, BACE1 inhibition limits initiation of new plaques but does not prevent growth of established plaques.

    “In mouse amyloidosis model, BACE1 inhibition limits initiation of new plaque formation but does not prevent growth of established plaques (Peters et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Peters et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Gantenerumab binds aggregated Aβ fibrils in plaques and triggers Fc-mediated microglial phagocytosis.

    “Gantenerumab is a fully human IgG1 antibody that binds to a conformational epitope on aggregated Aβ fibrils within plaques and triggers Fc-mediated microglial phagocytosis of Aβ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Many clinical trials were inadequately designed to robustly test the amyloid hypothesis, so negative results cannot necessarily be interpreted as rejecting it.

    “Unfortunately, many clinical trials have been inadequately designed to robustly test the amyloid hypothesis, such that negative trial results cannot be necessarily interpreted as a rejection of the amyloid hypothesis (Karran and Hardy, 2014; Karran et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Karran and Hardy, 2014; Karran et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two phase 3 solanezumab trials in mild-to-moderate Alzheimer disease failed to show marked cognitive or ADL benefit and did not reduce cerebral amyloid deposition.

    “Two phase 3 trials of solanezumab in mild-to-moderate AD failed to demonstrate a marked benefit on cognition or ADL and did not reduce cerebral amyloid deposition (Doody et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Doody et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Elenbecestat is the only BACE1 inhibitor left in clinical trials, in phase 3 for biomarker-positive MCI/prodromal Alzheimer disease, without safety, tolerability, or outcome futility issues to date.

    “Only one BACE1 inhibitor is now left standing in clinical trials. Elenbecestat is currently engaged in phase 3 clinical trials in biomarker positive MCI/prodromal AD and has not had issues with safety, tolerability or outcome futility to-date.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Active immunization of PDAPP mice with full-length human Aβ42 decreased existing amyloid deposits in older animals and almost completely prevented amyloid deposition in younger animals.

    “The first successful demonstration of antibody-mediated clearance of Aβ was in 1999, when active immunization of PDAPP mice using full length human Aβ42 peptide resulted in a significant decrease in existing amyloid deposits in animals vaccinated at an older age and almost completely prevented the development of amyloid deposition in animals vaccinated at a younger age (Schenk et al., 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schenk et al., 1999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    The peripheral sink hypothesis proposes that solanezumab alters plasma-CNS Aβ equilibrium and may also bind soluble Aβ in the CNS.

    “It was hypothesized that the antibody might alter the equilibrium between plasma and CNS Aβ, the so-called “peripheral sink” hypothesis (DeMattos et al., 2001) as well as directly binding soluble Aβ in the CNS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites DeMattos et al., 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Verubecestat failed to slow cognitive decline in a phase 3 trial of mild-to-moderate Alzheimer disease and worsened some cognition measures.

    “Verubecestat failed to slow cognitive decline in a phase 3 trial of mild to moderate AD and resulted in worse cognition on some measures. (Egan et al., 2018, 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Egan et al., 2018, 2019

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Several antibodies are being used in prevention studies where earlier dosing may better modify disease.

    “Though the data for Aβ-directed monoclonal antibodies in symptomatic AD have been discouraging, several antibodies are currently being used in primary and secondary prevention studies, where dose administration at an earlier disease stage might provide a better opportunity for disease modification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    No integrated Alzheimer disease animal model exists to definitively test the amyloid cascade hypothesis, so human Aβ-directed trials are considered a direct test.

    “Since no integrated AD animal model exists in which to definitively test the validity of the amyloid cascade hypothesis, clinical trials using Aβ-directed therapies in humans have been considered one of the most direct ways to test this.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: No integrated animal model exists that can definitively test the amyloid cascade hypothesis.

  • May combine two claims.

    Premisenone given

    Donanemab targets plaque-specific pyroglutamate Aβ(p3-42) and is in phase 2.

    “Donanemab is a monoclonal antibody developed by Lilly that uniquely targets Aβ(p3-42), a pyroglutamate form of Aβ exclusively found in plaques, in which the goal is to directly engage plaque-based Aβ for clearance and is currently in a phase 2 trial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BAN2401 binds large soluble Aβ protofibrils; phase 2 showed amyloid clearance and possible cognitive benefit, and it is now in phase 3.

    “BAN2401 is a humanized version of murine antibody mAb158 that binds large soluble Aβ protofibrils in vitro. Phase 2 trials demonstrated significant engagement and clearance of cerebral amyloid deposits and possible reduction in cognitive decline. It has now entered a phase 3 clinical trial in very mild to mild AD patients (Logovinsky et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Logovinsky et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Bapineuzumab targets N-terminal Aβ, binds soluble and fibrillar Aβ, and triggers microglial phagocytosis of Aβ deposits.

    “This is a humanized version of mouse 3D6 antibody that targets N-terminal Aβ peptide and binds to soluble and fibrillar Aβ, triggering microglial phagocytosis of Aβ deposits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Preclinical studies showed that peripheral solanezumab administration sequestered peripheral Aβ and caused a rapid rise in peripheral Aβ levels.

    “Preclinical studies demonstrated that peripheral administration sequestered peripheral Aβ and led to a dramatic and rapid rise in peripheral Aβ levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    Gantenerumab's phase 3 trial in mild Alzheimer disease stopped enrolling early due to futility and continued as an open-label high-dose extension.

    “Gantenerumab entered a phase 3 clinical trial for mild AD in 2014 that ultimately stopped enrolling early due to futility. The study was continued as an open label extension at high dose for two years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Post-mortem AN-1792 evaluation found variable amyloid clearance, with some patients showing nearly complete clearance, but most still had prominent tau pathology and severe dementia at death.

    “Post-mortem evaluation determined that there was significant variability in degree of amyloid clearance but that some vaccinated patients had long-lasting nearly complete clearance of Aβ deposits. However, they still had prominent tau pathology with advanced Braak staging and most had severe dementia at time of death, even despite plaque clearance (Nicoll et al., 2019; Vellas et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nicoll et al., 2019; Vellas et al., 2009

      Not checked in the free run.

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

    Premisecitation

    Aβ-directed immunotherapy has been explored as a disease-modifying therapy in Alzheimer disease for about 20 years.

    “Aβ-directed immunotherapy has been explored as a disease-modifying therapy in AD for the last 20 years (Gallardo and Holtzman, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gallardo and Holtzman, 2017

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Lilly BACE1 inhibitors LY2886721 and LY3202626 failed phase 2 trials due to hepatotoxicity and impaired cognitive performance, respectively.

    “Lilly inhibitors LY2886721 and LY3202626 failed in phase 2 trials due to hepatotoxicity and impaired cognitive performance, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Open-label gantenerumab produced a dramatic decline in Aβ deposition, with some participants becoming amyloid negative on imaging.

    “Follow-up analyses demonstrated a dramatic decline in Aβ deposition in participants in the open extension, such that some became amyloid negative on imaging.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ostrowitzki et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Active vaccination with CAD106 is in phase 3 and ABVac40 is in phase 2.

    “Active vaccination strategies using Aβ peptides as immunogens are still being pursued, with CAD106 in a phase 3 trial (Table 2) and ABVac40 currently in phase 2 trials (Lacosta et al., 2018; Vandenberghe et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lacosta et al., 2018; Vandenberghe et al., 2017

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    The amyloid cascade hypothesis proposes that Aβ accumulation triggers Alzheimer disease pathogenesis, so lowering parenchymal Aβ might slow progression.

    “The amyloid cascade hypothesis suggests that Aβ accumulation triggers disease pathogenesis, so therapies that lower parenchymal Aβ might be expected to slow disease progression.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Aβ accumulation triggers Alzheimer disease pathogenesis, as proposed by the amyloid cascade hypothesis.

  • May combine two claims.

    Premisenone given

    In the AN-1792 phase 2a trial, four patients developed aseptic meningoencephalitis, leading to trial discontinuation.

    “In a phase 2a trial, four patients developed aseptic meningoencephalitis leading to the discontinuation of the trial, although ongoing neuroimaging and neuropathologic follow-up allowed for assessment of long-term treatment response.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CAD106 and ABVac40 are claimed to avoid meningoencephalitis risk by excluding Aβ portions that induce Th1 immune responses.

    “Both claim to avoid the risk of meningoencephalitis by excluding portions of the Aβ peptide responsible for inducing Th1 immune responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    The API Generation CNP520 arm was discontinued in July 2019 after interim analysis showed worse cognition, increased brain atrophy, and more weight loss versus placebo.

    “Unfortunately study sponsors announced discontinuation of this arm in July 2019 when interim analysis demonstrated worse cognition, increased brain atrophy and more weight loss in the treatment group relative to placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Passive immunotherapy has less efficacy variability and lower adverse event risk because antibody titers can be tightly controlled.

    “With infusions of a monoclonal antibody, there is less variability in efficacy from patient to patient, and since titer levels can be more tightly controlled, there is less risk of adverse events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Crenezumab binds oligomeric, fibrillar, and plaque-based Aβ, and two phase 3 trials were terminated early for futility.

    “Crenezumab is a fully human IgG4 antibody that binds oligomeric, fibrillar and plaque-based Aβ. Two phase 3 trials were terminated early in January 2019 for futility after interim analysis failed to demonstrate any benefit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ABBV-8E12 was safe in a phase 1 trial and advanced to two phase 2 trials including patients with early Alzheimer disease and progressive supranuclear palsy.

    “The humanized version of HJ8.5 (ABBV-8E12) has been tested in a phase 1 trial and found to be safe and has now advanced to two phase 2 trials including patients with early AD and PSP (West et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites West et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-ApoE ASO delivered intracerebroventricularly in ApoE-TR/APPPS1-21 mice dramatically reduced Aβ plaque deposition if given before plaque seeding but not after.

    “Use of anti-ApoE ASO delivered via intracerebroventricular injection in ApoE-TR/APPPS1-21 mice demonstrated dramatically reduced Aβ plaque deposition if administered prior to plaque seeding but not after.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huynh et al., 2017b

      Not checked in the free run.

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

    Premisecitation

    A proposed strategy is to overexpress ApoE2 in APOE ε4/ε4 carriers to overcome loss of function associated with ApoE4.

    “Another proposed strategy is to utilize gene therapy methods to overexpress ApoE2 in APOE ε4/ε4 carriers as means to overcome loss of function associated with ApoE4 (Rosenberg et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rosenberg et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ApoE2 gene therapy would only be effective if ApoE4-mediated disease mechanisms are due to loss of function, or if due to toxic gain of function, ApoE2 can act dominantly to inhibit ApoE4 toxicity.

    “This strategy would only be effective if ApoE4-mediated disease mechanisms are truly due to loss of function or, if secondary to ApoE4 toxic gain of function, that ApoE2 is able to act in dominant protective fashion to inhibit ApoE4 toxic effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Conditional adult BACE1 knockout mitigates many side effects but axon guidance defects remain.

    “Conditional BACE1 KO in adulthood mitigates many of these side effects but there remains impaired axon guidance defects (Ou-Yang et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ou-Yang et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AADvac-1 completed phase 1 testing and is currently undergoing phase 2 trials.

    “AADvac-1 recently completed phase 1 testing and is currently undergoing phase 2 trials (Novak et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Novak et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other promising gamma-secretase modulators are in development and may enter human trials in the near future.

    “Indeed, there are other promising GSMs now in development that may enter human trials in the near future (Wagner et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wagner et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HJ8.5 in PS19 mice reduced tau seeding, hyperphosphorylation, thioflavin S staining, detergent-insoluble tau, brain atrophy, and cognitive deficits when given before significant tau pathology, whether intraventricularly or peripherally.

    “In preclinical studies, mouse anti-human tau monoclonal antibody HJ8.5 demonstrated reduced tau seeding, hyperphosphorylation and thioflavin S staining, reduced levels of detergent insoluble tau, and reduced brain atrophy and cognitive deficits in PS19 (P301S) mice, whether administered via intraventricular infusion (Yanamandra et al., 2013) or peripherally (Yanamandra et al., 2015) when administ”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Yanamandra et al., 2013 source

      Not checked in the free run.

    • cites Yanamandra et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Avagacestat phase 2 trials in mild to moderate and prodromal Alzheimer disease were terminated after no reduction in cognitive decline and after higher-dose adverse effects including nausea, vomiting, diarrhea, rash, pruritis, and increased non-melanoma skin cancer.

    “Avagacestat phase 2 trials in mild to moderate and prodromal AD were terminated after it failed to demonstrate any reduction in cognitive decline and caused adverse effects at higher doses, such as nausea, vomiting, diarrhea, rash, pruritis and increased incidence of non-melanoma skin cancer (Coric et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Coric et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tideglusib in preclinical double transgenic mice expressing human tau and APP reduced tau phosphorylation, decreased amyloid deposition, led to less neuronal loss, and improved cognition.

    “A GSK-3 inhibitor, tideglusib, was shown in a preclinical study using double transgenic mice expressing human tau and APP to reduce tau phosphorylation, decrease amyloid deposition, lead to less neuronal loss and improved cognition (Serenó et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Serenó et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Semagacestat was the first gamma-secretase inhibitor to enter a phase 3 Alzheimer disease trial, but the trial was halted early because of worsening cognition, increased skin cancers and infection, and weight loss relative to placebo.

    “Semagacestat was the first GSI to enter a phase 3 trial for AD. However, the trial was halted early due to concerns of worsening cognition, increased incidence of skin cancers and infection, and weight loss relative to placebo (Doody et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Doody et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ASO-based clinical treatments have shown dramatic success in spinal muscular atrophy and are being tested in Huntington disease.

    “ASO-based clinical treatments have demonstrated dramatic success in cases of spinal motor atrophy (Finkel et al., 2017) and are being tested in Huntington’s disease (Tabrizi et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Finkel et al., 2017

      Not checked in the free run.

    • cites Tabrizi et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HAE-4 delivered centrally or peripherally reduced fibrillary amyloid plaque load and soluble and insoluble Aβ levels without reducing cerebral or plasma ApoE levels.

    “Delivery of this antibody centrally or peripherally reduced fibrillary amyloid plaque load and soluble and insoluble Aβ levels without reducing cerebral or plasma ApoE levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liao et al., 2018

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    If a peripherally administered anti-tau antibody is to be efficacious in Alzheimer disease, extracellular tau seeding and spreading must occur and the antibody must inhibit this process.

    “It is likely that if a peripherally administered anti-tau antibody is to be efficacious in a disease such as AD, such a mechanism would need to occur and an antibody would need to inhibit this process.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Tau- and ApoE-directed therapeutics remain at an early stage of development and both hold great potential.

    “Tau- and ApoE-directed therapeutics remain at an early stage of development and both hold great potential going foward.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In one study, rheumatoid arthritis patients treated with etanercept had lower incidence of Alzheimer disease, but no effect was noted with other anti-rheumatic medications or anti-TNF agents.

    “In one study, patients with rheumatoid arthritis treated with etanercept, TNFα decoy receptor, had lower incidence of AD, but no effect was noted with use of other anti-rheumatic medications (prednisone, sulfasalazine, rituximab) or anti-TNF agents (infliximab, adalimumab) (Chou et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chou et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A phase 3 trial of intravenous immunoglobulin showed no cognitive benefits in mild Alzheimer disease despite a favorable safety profile.

    “However, a phase 3 trial of IVIg did not demonstrate any cognitive benefits in mild AD despite a favorable safety profile (Relkin et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Relkin et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heterochronic parabiosis with young blood in old mice increased neurogenesis and dendritic spine density and improved age-related cognitive impairment.

    “Recent heterochronic parabiosis experiments demonstrated that introduction of young blood in old mice led to increased neurogenesis and dendritic spine density, and improved age-related cognitive impairment, (Katsimpardi et al., 2014; Villeda et al., 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Katsimpardi et al., 2014 source

      Not checked in the free run.

    • cites Villeda et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heterochronic parabiosis and direct injection of young mouse plasma in APP amyloidosis mice increased synaptic protein levels and improved cognitive performance on spatial working memory and hippocampal-dependent associative learning tests.

    “Heterochronic parabiosis and direct injection of young mouse plasma in APP amyloidosis mice resulted in increased levels of synaptic protein and improvement in cognitive performance on standard tests of spatial working memory and hippocampal-dependent associative learning (Middeldorp et al., 2016)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Middeldorp et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple epidemiologic studies suggest that chronic NSAID use is associated with lower incidence of Alzheimer disease, with the most pronounced effect seen with chronic ibuprofen.

    “Interest in anti-inflammatory treatments for AD were initially stoked by findings from multiple epidemiologic studies suggesting that chronic use of NSAIDs was associated with lower incidence of AD, with the most pronounced effect seen in patients taking chronic ibuprofen (in t’ Veld et al., 2001; Vlad et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites in t’ Veld et al., 2001

      Not checked in the free run.

    • cites Vlad et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Alzheimer disease pathobiology is complex, and older age increases the likelihood that other age-related diseases contribute to cognitive decline together with Alzheimer disease pathology.

    “Finally, AD pathobiology is complex and the older one is, the greater likelihood that other age-related diseases contribute to cognitive decline together with AD pathology.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation

    Intracisternal viral injection of AAVrh.10 hAPOE2-HA vector led to the widest area of cerebral transduction with only minimal surgery in non-human primates.

    “This study found that intracisternal viral injection led to the widest area of cerebral transduction with only minimal surgery (Rosenberg et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rosenberg et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transferrin receptor-fused etanercept reduced amyloid burden and improved recognition memory in APP/PS1 mice.

    “This approach demonstrated reduced amyloid burden and improvement in recognition memory in preclinical studies using APP/PS1 mice (Chang et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chang et al., 2017

      Not checked in the free run.

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

    Premisecitation

    The AMBAR phase 2b/3 trial is testing monthly plasma exchange with albumin replacement in mild to moderate Alzheimer disease.

    “The AMBAR trial, a current phase 2b/3 trial, is testing this hypothesis by assessing the effect of monthly plasma exchange with albumin replacement on mild to moderate AD (Boada et al., 2019)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boada et al., 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Therapies that modulate the neuroimmune or microglial response in Alzheimer disease have huge potential and this class of drug development is significantly underrepresented.

    “There is also huge potential for therapies that modulate the neuroimmune or microglial response in AD, and this class of drug development is significantly underrepresented.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A phase 2 trial of etanercept in mild to moderate Alzheimer disease established safety but showed no significant reduction in cognitive decline on analysis of secondary clinical outcomes.

    “A phase 2 trial of etanercept in mild to moderate AD established safety but saw no significant reduction in cognitive decline on analysis of secondary clinical outcomes (Butchart et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Butchart et al., 2015

      Not checked in the free run.

128 of 128

  • The paper relies on this without support.

    Findings from transgenic mouse and cell-culture models of AD can be extrapolated to human AD pathobiology.

    “In these studies, tau pathology and neurodegeneration is enhanced in mice with both pathologies, whereas amyloid pathology is generally unaffected”

  • The paper relies on this without support.

    No integrated animal model exists that can definitively test the amyloid cascade hypothesis.

    “Since no integrated AD animal model exists in which to definitively test the validity of the amyloid cascade hypothesis, clinical trials using Aβ-directed therapies in humans have been considered one of the most direct ways to test this.”

  • The authors state this as an assumption.

    Aβ accumulation triggers Alzheimer disease pathogenesis, as proposed by the amyloid cascade hypothesis.

    “The amyloid cascade hypothesis suggests that Aβ accumulation triggers disease pathogenesis, so therapies that lower parenchymal Aβ might be expected to slow disease progression.”

  • The paper relies on this without support.

    Tau is a critical target for developing disease-modifying therapies for Alzheimer disease.

    “Tau is considered a critical target for developing disease modifying therapies.”

  • The paper relies on this without support.

    Alzheimer disease pathobiology is multifactorial and complex.

    “Given the multifactorial nature and underlying complexity of AD pathobiology”
5 of 5

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?

  • Alzheimer's disease can affect about 5% of those under 65, termed early-onset Alzheimer's disease.

    “However, it can also affect about 5% of those under 65, termed early-onset Alzheimer’s disease [2,3].”

    From Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer’s Treatment: Systematic Review (2025) · cites this paper as [3]

    The Introduction defines early-onset Alzheimer’s disease as occurring before age 65 and says it accounts for less than 5% of all Alzheimer’s cases. The citing sentence instead says it affects about 5% of people under 65, changing the denominator and overstating the figure. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • All existing methods of AD treatment are used lifelong, since the disease has a chronic progressive course with a preclinical phase starting 10-20 years before the onset of symptoms, and an inevitable fatal outcome within 5-12 years after their onset.

    “Furthermore, all existing methods of AD treatment are used lifelong, since the disease has a chronic progressive course with a preclinical phase starting 10–20 years before the onset of symptoms, and an inevitable fatal outcome within 5–12 years after their onset [90].”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [90]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • More than 20 compounds mainly based on amyloid and tau hypotheses completed large phase 3 double-blind randomized controlled trials in AD patients at various stages, and none demonstrated satisfying efficacy in slowing cognitive decline or improving global brain function.

    “More than 20 compounds which are mainly based on amyloid and tau hypothesis have completed large phase 3, double‐blind, randomized control trials in cohorts of patients at various stages of AD. None of them has demonstrated satisfying efficacy in slowing cognitive decline or improving global brain function.[ 2 ]”

    From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [2]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Synaptic failure is considered an early molecular change followed by neuronal loss and cognitive deficits.

    “Synaptic failure is one of the major pathophysiological changes observed in patients with AD and several transgenic mouse models of AD. It is considered an early time point molecular change that is followed by neuronal loss and cognitive deficits (1, 34).”

    From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [1]

    The Neuroimmune activation section reports early synapse loss in an AD mouse model, and the Clinical and Preclinical Disease section links synaptic and neuronal loss with the onset of cognitive impairment. The paper does not establish the claimed sequence in which synaptic failure precedes neuronal loss and then cognitive deficits; it says synaptic and neuronal loss generally correlate with impairment onset. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • APOE*4 is associated with Alzheimer's disease-related proteinopathies, including amyloid-β, tau, α-synuclein, and TDP-43.

    “APOE*4 is also associated with AD-related proteinopathies, including amyloid-β, tau, α-synuclein, and TDP-43 [11, 12].”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [12]

    The Pathophysiology of AD > ApoE section links APOE ε4 to increased amyloid-β deposition and discusses ApoE4 effects in tauopathy models, while noting conflicting tau findings. The passages do not establish an APOE ε4 association with α-synuclein or TDP-43; searches for both terms found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

3 of the 333 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Long, J. M., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2019-10
Volume
179
Issue
2
Pages
312-339
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.09.001
PMC
PMC6778042
OpenAlex
W2976163884
Semantic Scholar
9231686941513e88e57650a734b2d4f1fcdbd4cb
Cited by
3,204
References
333
Citations by year
2026: 455 · 2025: 482 · 2024: 565 · 2023: 526 · 2022: 527 · 2021: 426 · 2020: 207 · 2019: 9 · 2018: 1 · 2014: 2
FWCI
34.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • JPB Foundation
  • Cure Alzheimer's Fund
  • National Institutes of Health (AG047644, NS074969, NS090934)
  • University of Washington (8,232,107, 8,591,894)
  • Alzheimer's Association (AACSF-18-564776)
  • Tau Consortium
  • AbbVie (US2013/049333)
  • Genentech
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, pathobiology, amyloid-beta, neuritic plaques, tau hyperphosphorylation, neurofibrillary tangles, disease-modifying therapy, clinical trial failure, neuropathologic diagnosis
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Clinical Trials as Topic, Humans, Amyloid beta-Peptides, tau Proteins, Alzheimer Vaccines, Mice, 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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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.

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