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Cited by 539Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Alzheimer’s disease drug development pipeline: 2021

Open access
Cummings, Jeffrey, Lee, Garam, Zhong, Kate, Fonseca, Jorge, Taghva, Kazem·2021·Alzheimer's & Dementia: Translational Research & Clinical Interventions
DOI 10.1002/trc2.12179PMC PMC8145448
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Abstract

Introduction: The number of individuals worldwide with Alzheimer's disease (AD) is growing at a rapid rate. New treatments are urgently needed. We review the current pipeline of drugs in clinical trials for the treatment of AD. Methods: We interrogated ClinicalTrials.gov, the federal registry of clinical trials to identify drugs in trials. Results: There are 126 agents in 152 trials assessing new therapies for AD: 28 treatments in Phase 3 trials, 74 in Phase 2, and 24 in Phase 1. The majority of drugs in trials (82.5%) target the underlying biology of AD with the intent of disease modification; 10.3% are putative cognitive enhancing agents; and 7.1% are drugs being developed to reduce neuropsychiatric symptoms. Discussion: This pipeline analysis shows that target biological processes are more diversified, biomarkers are more regularly used, and repurposed agents are being explored to determine their utility for the treatment of AD.

AI snapshot

Written from the paper’s full text.

TL;DR

This annual pipeline review identified 126 agents in 152 ongoing Alzheimer’s disease clinical trials as of January 5, 2021, with most agents intended as disease-modifying therapies. The pipeline showed continued target diversification, frequent biomarker use in later-phase disease-modifying trials, and substantial participant burden.

Key findings

  • There were 126 agents in 152 trials: 28 agents in 41 Phase 3 trials, 74 agents in 87 Phase 2 trials, and 24 agents in 24 Phase 1 trials.
  • Disease-modifying therapies made up 104 agents (82.5%); 13 (10.3%) were cognitive enhancers and 9 (7.1%) targeted neuropsychiatric/behavioral symptoms.
  • Repurposed agents numbered 50, or 39.6% of candidate agents; they were more likely to have academic medical center/NIH sponsors (59%) than industry sponsors (16%).
  • Currently active trials required 38,826 participants, contributing 2,540,014 participant-weeks; biopharma sponsored 49% of all trials, academic centers/NIH 29%, public–private partnerships 14%, and others 7%.

Methods

  • The authors interrogated ClinicalTrials.gov as of January 5, 2021, including Phase 1, 2, and 3 trials listed as recruiting, active but not recruiting, enrolling by invitation, or not yet recruiting.
  • They excluded completed, terminated, suspended, unknown, or withdrawn trials, non-pharmacologic therapeutic approaches, and biomarker trials; stem cell therapies were included.
  • Agents were classified by mechanism using the Common Alzheimer’s Disease Research Ontology (CADRO), and trials were categorized as disease-modifying, cognitive-enhancing, or neuropsychiatric-symptom treatments based on trial features and stated intent.

Limitations

  • The paper states that ClinicalTrials.gov includes the majority of AD agents in trials, making the review “comprehensive but not exhaustive”; Phase 1 trials conducted outside the United States may be under-represented.
  • The authors state that not all trial descriptions on ClinicalTrials.gov note whether biomarkers are included, and they recognize that definitions of “disease-modifying” versus “symptomatic” are arbitrary.
  • Evident from the design: this is a registry-based descriptive analysis without efficacy outcomes, and it excludes completed, terminated, suspended, unknown, or withdrawn trials, so it does not assess whether agents work.

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

Integrity signals

Registry

Crossref · 10.1002/trc2.12179

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 36 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Of the DMTs, 16 (15.4%) have amyloid as the primary target or as one of several potential effects.

    “Of the DMTs 16 (15.4%) have amyloid and 11 (10.6%) have tau as the primary target or as one of several potential effects.”
    Quote in the paperNot a substantial claim
  • Findingown data

    There were five Phase 3 prevention trials enrolling cognitively normal participants known to be at risk for AD (preclinical AD).

    “There were five Phase 3 prevention trials enrolling cognitively normal participants known to be at risk for AD (preclinical AD).”
    Quote in the paperNot a substantial claim
  • Findingown data

    There are 10 repurposed agents in Phase 3 trials.

    “There are 10 repurposed agents in Phase 3 trials.”
    Quote in the paperNot a substantial claim
  • Findingown data

    13 agents (10.3%) in trials target cognitive enhancement.

    “13 (10.3%) agents in trials target cognitive enhancement”
    • Also stated in: § Results · hedged
      “10.3% are putative cognitive enhancing agents”
    Quote in the paperNot a substantial claim
  • Findingown data

    There were 126 agents in 152 trials of treatments for Alzheimer's disease as of January 5, 2021.

    “There were 126 agents in 152 trials of treatments for AD (as of the index date of January 5, 2021).”
    • Also stated in: § Results · plain
      “There are 126 agents in 152 trials assessing new therapies for AD”
    Quote in the paperSubstantial claim
  • May combine two claims. 44
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    Phase 3 trials include one trial enrolling both preclinical patients and patients with MCI to mild AD dementia (DIAN‐TU trial), 13 trials in patients with prodromal AD/MCI or prodromal/mild AD dementia, 11 trials of patients with mild to moderate AD, and 11 trials of patients with mild-to-severe AD.

    “There is one Phase 3 trial enrolling both preclinical patients and patients with MCI to mild AD dementia (DIAN‐TU trial); 13 trials in patients with prodromal AD/MCI or prodromal/mild AD dementia; 11 trials of patients with mild to moderate AD; and 11 trials of patients with mild‐to‐severe AD (most of the neuropsychiatric agents).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The mean treatment exposure period was 154 weeks for prevention trials, 87 weeks for prodromal AD or prodromal AD/mild AD dementia trials, and 31 weeks for mild-to-moderate AD dementia trials.

    “The mean treatment exposure period was 154 weeks for prevention trials, 87 weeks for prodromal AD or prodromal AD/mild AD dementia trials, and 31 weeks for mild‐to‐moderate AD dementia trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two of the Phase 3 prevention trials are assessing monoclonal antibodies (solanezumab, gantenerumab), one is a vaccine trial (CAD106), and two are trials of small molecules (icosapent ethyl and a combination of losartan, amlodipine, and atorvastatin).

    “Two of these trials are assessing monoclonal antibodies (solanezumab, gantenerumab), there is one vaccine trial (CAD106), and two trials of small molecules (icosapent ethyl and a combination of losartan, amlodipine, and atorvastatin).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Phase 3 trials included a mean of 619 participants per trial and a total of 25,373 participants were needed for enrollment.

    “Phase 3 trials included a mean of 619 participants per trial and a total of 25,373 participants were needed for enrollment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Phase 3 DMTs, the CADRO mechanisms represented include tau (one agent; 5.9%), inflammation/infection (two; 11.8%), oxidative stress (two; 11.8%), metabolism and bioenergetics (two; 11.8%), vascular factors (one; 5.9%), synaptic plasticity/neuroprotection (three; 17.6%), and gut-brain axis (one; 5.9%).

    “Other CADRO mechanisms represented among Phase 3 DMT therapies include tau (one agent; 5.9% of Phase 3 DMTs), inflammation/infection (two agents; 11.8%), oxidative stress (two agents; 11.8%), metabolism and bioenergetics (two agents; 11.8%), vascular factors (one agent; 5.9%), synaptic plasticity/neuroprotection (three agents; 17.6%), and gut–brain axis (one agent; 5.9%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Across all phases, DMTs comprise 31 (29.8%) biological therapies and 73 (70.2%) small-molecule drugs.

    “Across all phases, DMTs comprise 31 (29.8%) biological therapies and 73 (70.2%) small‐molecule drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There are 50 repurposed agents in the pipeline-39.6% of the candidate agents.

    “There are 50 repurposed agents in the pipeline—39.6% of the candidate agents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There are 11 (39.3%) symptomatic agents in Phase 3: six (21.4%) cognitive enhancers and five (17.9%) targeting behavioral symptoms.

    “There are 11 (39.3%) symptomatic agents in Phase 3: six (21.4%) cognitive enhancers and five (17.9%) targeting behavioral symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the 17 Phase 3 DMTs there are four biological therapies and 13 oral agents/small molecule therapies.

    “Among the 17 DMTs there are four biological therapies and 13 oral agents/small molecule therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Since the 2020 review, seven Phase 3 trials have been completed or terminated and there are five new agents in this phase.

    “Since the 2020 review, seven Phase 3 trials have been completed or terminated and there are five new agents in this phase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among DMTs, there are 17 in Phase 3, 64 in Phase 2, and 23 in Phase 1.

    “Considering DMTs only, there are 17 in Phase 3, 64 in Phase 2, 23 in Phase 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two Phase 2 trials are prevention trials involving participants with preclinical AD, assessing crenezumab and levetiracetam.

    “Two Phase 2 trials are prevention trials involving participants with preclinical AD (assessing crenezumab and levetiracetam)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Across all trials, biopharmaceutical companies sponsor 49% of trials and collaborate in another 14% of trials sponsored by public-private partnerships.

    “Across all trials, biopharmaceutical companies sponsor 49% of trials and collaborate in another 14% of trials sponsored by public–private partnerships.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of Phase 2 candidate treatments, there are 64 potential DMTs, six cognitive enhancing agents, and four drugs targeting behavioral symptoms.

    “Of Phase 2 candidate treatments, there are 64 potential DMTs, six cognitive enhancing agents, and four drugs targeting behavioral symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Since the 2020 review, 16 trials have been completed or terminated and there are 22 new agents in the Phase 2 pipeline.

    “Since the 2020 review, 16 trials have been completed or terminated and there are 22 new agents in the Phase 2 pipeline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among DMTs in Phase 2 there are 21 biologics and 43 small molecules.

    “Among DMTs in Phase 2 there are 21 biologics and 43 small molecules.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Using the CADRO approach, four of the small molecules and seven of the biologics in Phase 2 have amyloid reduction as one of the mechanisms (17.2% of DMTs).

    “Using the CADRO approach, four of the small molecules and seven of the biologics in Phase 2 have amyloid reduction as one of the mechanisms (17.2% of DMTs).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In Phase 2 DMTs, the CADRO mechanisms represented include tau (nine agents; 14.1%), inflammation/infection/immunity (12; 18.8%), transmitter systems and receptors (two; 3.1%), oxidative stress (one; 1.6%), cell death (2; 3.1%), proteostasis (four; 6.3%), metabolism and bioenergetics (four; 6.3%), vascular factors (three; 4.7%), growth factors and hormones (1; 1.6%), synaptic plasticity/neuroprotet

    “Other CADRO mechanisms represented among Phase 2 DMT therapies include tau (nine agents; 14.1% of Phase 2 DMTs), inflammation/infection/immunity (12 agents; 18.8%), transmitter systems and receptors (two agents; 3.1%), oxidative stress (one agent; 1.6%), cell death (2 agents; 3.1%), proteostasis (four agents; 6.3%), metabolism and bioenergetics (four agents; 6.3%), vascular factors (three agents;”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Trial participants make an enormous contribution to clinical trials (calculated to be ≈2.5 million participant‐weeks for currently ongoing trials).

    “Trial participants make an enormous contribution to clinical trials (calculated to be ≈2.5 million participant‐weeks for currently ongoing trials)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Repurposed agents are more likely to have academic medical centers/NIH sponsors (59%) and less likely to have industry sponsors (16%).

    “Repurposed agents are more likely to have academic medical centers/NIH sponsors (59%) and less likely to have industry sponsors (16%; Table 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Across all phases, 54% of trials are conducted in North America only, 25% only outside North America, and 21% with both North American and non-North American sites.

    “Across all phases, 54% of trials are conducted in North America only, 25% are conducted only outside North America, and 21% are conducted with both North American and non–North American sites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the total participants needed, 25,373 are in Phase 3 trials, 12,414 in Phase 2 trials, and 1039 in Phase 1 trials.

    “Of these, 25,373 are in Phase 3 trials; 12,414 in Phase 2 trials; and 1039 in Phase 1 trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There are 28 agents in Phase 3, 74 in Phase 2, and 24 in Phase 1.

    “There are 28 agents in Phase 3, 74 in Phase 2, and 24 in Phase 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There are five prevention trials in Phase 3 and two prevention trials in Phase 2.

    “There are five prevention trials in Phase 3 and two prevention trials in Phase 2; the number of prevention trials in Phase 3 has remained constant over the past 6 years, while the number of Phase 2 prevention trials has varied (0 to 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Phase 2 has both more agents in trials and a greater diversity of targets than other phases.

    “Phase 2 has both more agents in trials and a greater diversity of targets than other phases; this may reflect a more diversified approach to treatment targets in Phase 2 or a reduction of targets in Phase 3 because of the lack of success in Phase 2 outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to the 2020 pipeline, there is one less agent in Phase 3, nine additional agents in Phase 2, and three less agents in Phase 1.

    “The 126 agents in the pipeline compares to 121 in the pipeline in 2020; 13 with one less agent in Phase 3, nine additional agents in Phase 2, and three less agents in Phase 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    66.7% of Phase 3 trials and 78.6% of Phase 2 trials took longer to complete than originally anticipated as recorded on ClinicalTrials.gov.

    “Although sponsors plan for slow recruitment, 66.7% of Phase 3 trials and 78.6% of Phase 2 trials took longer to complete than originally anticipated as recorded on ClinicalTrials.gov.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There are 13 cognitive enhancers and nine drugs targeting neuropsychiatric symptoms in the pipeline.

    “There are 13 cognitive enhancers and nine drugs targeting neuropsychiatric symptoms in the pipeline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Since the 2020 pipeline, 7 trials in Phase 3, 18 trials in Phase 2, and 9 trials in Phase 1 have been either completed, terminated, suspended, or the status is unknown.

    “Since the 2020 pipeline, 7 trials in Phase 3, 18 trials in Phase 2, and 9 trials in Phase 1 have been either completed, terminated, suspended, or the status is unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Repurposed agents are more common in trials in Phase 2 and more likely to be in trials sponsored by NIH/academic medical centers.

    “Repurposed agents are more common in trials in Phase 2 and more likely to be in trials sponsored by NIH/academic medical centers (Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Phase 1 trials are often conducted outside of the United States, may not be registered on ClinicalTrials.gov, and may be under-represented in this analysis.

    “Phase 1 trials are often conducted outside of the United States, may not be registered on ClinicalTrials.gov, and may be under‐represented in our analysis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Alzheimer's disease has preclinical, prodromal, and dementia phases.

    “AD has preclinical, prodromal, and dementia phases”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG‐2 criteria. Lancet Neurol. 2014; 13: 614‐ 629. 24849862 source

      Not checked in the free run.

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

    Premisecitation

    The reporting of results of clinical trials is required, but trial sponsors are less adherent to this expectation.

    “The reporting of results of clinical trials is required, but trial sponsors are less adherent to this expectation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] DeVito NJ, Bacon S, Goldacre B. Compliance with legal requirement to report clinical trial results on clinicaltrials.gov: a cohort study. Lancet. 2020; 395: 361‐ 369. 31958402 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    There are 126 agents in clinical trials in 2021; the total number of treatments in trials is similar in 2021 and 2020.

    “There are 126 agents in clinical trials in 2021; the total number of treatments in trials is similar in 2021 and 2020.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The United States has more clinical trials than any other country.

    “The United States has more clinical trials than any other country”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Studies of ClinicalTrials.gov suggest that compliance with the common rule is high.

    “Studies of ClinicalTrials.gov suggest that compliance with the common rule is high.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Lassman SM, Shopshear OM, Jazic I, Ulrich J, Francer J. Clinical trial transparency: a reassessment of industry compliance with clinical trial registration and reporting requirements in the United States. BMJ Open. 2017; 7: e015110. PMC5623439 28942418

      Not checked in the free run.

    • cites [16] Phillips AT, Desai NR, Krumholz HM, Zou CX, Miller JE, Ross JS. Association of the FDA Amendment Act with trial registration, publication, and outcome reporting. Trials. 2017; 18: 333. 28720112 PMC5516301

      Not checked in the free run.

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

    Premisecitation

    The Common Alzheimer's Disease Research Ontology (CADRO) provides a means of classifying targets for drug development relevant to Alzheimer's disease.

    “The Common Alzheimer's Disease Research Ontology (CADRO) provides a means of classifying targets for drug development relevant to AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] International Alzheimer's and Related Dementia Research Portfolio; Accessed January 4, 2021; https://iadrp.nia.nih.gov/about/cadro

      Not checked in the free run.

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

    Interpretationreasoning

    This review is comprehensive but not exhaustive.

    “this review is therefore comprehensive but not exhaustive”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Phase 1 trials are often conducted outside of the United States, may not be registered on ClinicalTrials.gov, and may be under-represented in this analysis.
    • Rests on an assumption: ClinicalTrials.gov includes the majority of agents currently in clinical trials for Alzheimer's disease.

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

    Premisecitation

    In 2020, the FDA approved 53 new drugs across all therapeutic categories.

    “In 2020, the FDA approved 53 new drugs across all therapeutic categories.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Food and Drug Administration. Advancing Health Through Innovation: New Drug Therapy Approvals 2020. US Food and Drug Administration. Silver Spring, MD. 2020.

      Not checked in the free run.

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

    Study design and conductnone given

    The total participant-weeks sum does not include time devoted to screening prior to randomization or the number of participant-weeks consumed in screen fails of individuals who do not progress to randomization.

    “This sum does not include time devoted to screening prior to randomization or the number of participant‐weeks consumed in screen fails of individuals who do not progress to randomization.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Some Phase 1 trials conducted outside the United States may not be registered on ClinicalTrials.gov and may have gone undetected in this review.

    “Some Phase 1 trials conducted outside the United States may not be registered on ClinicalTrials.gov and may have gone undetected in this review.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    DMT-related targets, biomarkers, and trial designs are progressing.

    “Thirty‐six percent of the CNS approvals were for DMTs, suggesting that DMT‐related targets, biomarkers, and trial designs are progressing.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The greater diversity of targets in Phase 2 may reflect a more diversified approach to treatment targets in Phase 2 or a reduction of targets in Phase 3 because of the lack of success in Phase 2 outcomes.

    “Phase 2 has both more agents in trials and a greater diversity of targets than other phases; this may reflect a more diversified approach to treatment targets in Phase 2 or a reduction of targets in Phase 3 because of the lack of success in Phase 2 outcomes.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Stem cell interventions may promote nerve cell regeneration, adding a dimension to therapeutic response beyond the slowing of cognitive decline targeted by DMTs in current trials.

    “Stem cell interventions may promote nerve cell regeneration, adding a dimension to therapeutic response beyond the slowing of cognitive decline targeted by DMTs in current trials. 36 , 37”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Vasic V, Barth K, Schmidt MHH. Neurodegeneration and neuro‐regeneration‐Alzheimer's disease and stem cell therapy. Int J Mol Sci. 2019: 20. PMC6747457 31480448

      Not checked in the free run.

    • cites [37] Han F, Bi J, Qiao L, Arancio O. Stem cell therapy for Alzheimer's disease. Adv Exp Med Biol. 2020; 1266: 39‐ 55. 33105494

      Not checked in the free run.

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

    Premisecitation

    Cell senescence occurs throughout the lifespan but plays a larger role with aging and is postulated to contribute to many diseases of aging including vascular disease, arthritis, and neurodegeneration.

    “Cell senescence occurs throughout the lifespan but plays a larger role with aging and is postulated to contribute to many diseases of aging including vascular disease, arthritis, and neurodegeneration. 38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017; 16: 718‐ 735. 28729727 PMC5942225 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The increased focus of biopharmaceutical companies on late-stage development and outsourcing larger portions of the early-stage drug development enterprise explains the sponsorship pattern.

    “This reflects the increased focus of biopharmaceutical companies on late‐stage development and outsourcing larger portions of the early‐stage drug development enterprise. 31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Dierks RML, Bruyere O, Reginster JY. Critical analysis of valuation and strategical orientation of merger and acquisition deals in the pharmaceutical industry. Expert Rev Pharmacoecon Outcomes Res. 2018; 18: 147‐ 160. 29243501

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The COVID-19 pandemic further exacerbated recruitment struggles with many clinics suspending research at least temporarily, delaying visits during this time, and experiencing attrition due to SARS-CoV-2 infections in patients and family members or an unwillingness to attend medical facilities.

    “The COVID‐19 pandemic further exacerbated recruitment struggles with many clinics suspending research at least temporarily, delaying visits during this time, and experiencing attrition due to SARS‐CoV‐2 infections in patients and family members or an unwillingness to attend medical facilities. 33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Ousset PJ, Vellas B. Viewpoint: impact of the Covid‐19 outbreak on the clinical and research activities of memory clinics: an Alzheimer's disease center facing the Covid‐19 crisis. J Prev Alzheimer's Dis. 2020; 7: 197‐ 198. 32463074 PMC7147199

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There are at least an equivalent number of weeks contributed by research partners, doubling the total participant-partner weeks to 5,080,028 weeks.

    “There are at least an equivalent number of weeks contributed by research partners, doubling the total participant‐partner weeks to 5,080,028 weeks.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Research partners contribute at least an equivalent number of weeks as trial participants.

  • May combine two claims.

    Premisecitation

    Metformin, rapamycin, and dasatinib plus quercetin have shown benefit in non-clinical models of aging and AD.

    “Three senolytics in current AD trials are metformin, rapamycin, and dasatinib plus quercetin; these therapies have shown benefit in non‐clinical models of aging and AD. 39 , 40 , 41”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015; 14: 644‐ 658. 25754370 PMC4531078 source

      Not checked in the free run.

    • cites [40] Farr SA, Roesler E, Niehoff ML, Roby DA, McKee A, Morley JE. Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer's disease. J Alzheimers Dis. 2019; 68: 1699‐ 1710. 30958364

      Not checked in the free run.

    • cites [41] Partridge L, Fuentealba M, Kennedy BK. The quest to slow ageing through drug discovery. Nat Rev Drug Discov. 2020; 19: 513‐ 532. 32467649 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biomarkers play an increasing role in drug development and use the amyloid (A), tau (T), neurodegeneration (N)-A/T/N-biomarker framework.

    “Biomarkers play an increasing role in drug development and use the amyloid (A), tau (T), neurodegeneration (N)—A/T/N—biomarker framework. 22 , 23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Cummings J. The role of biomarkers in Alzheimer's disease drug development. Adv Exp Med Biol. 2019; 1118: 29‐ 61. 30747416 PMC6750734

      Not checked in the free run.

    • cites [23] Jack CR Jr, Bennett DA, Blennow K, et al. NIA‐AA research framework: toward a biological definition of Alzheimer's disease. Alzheimer's Dement. 2018; 14: 535‐ 562. 29653606 PMC5958625 source

      Not checked in the free run.

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

    Premisecitation

    Many questions remain unresolved concerning the relationship of cellular senescence and neurodegeneration/AD.

    “Many questions remain unresolved concerning the relationship of cellular senescence and neurodegeneration/AD; 43 trials of senolytics will provide key insights into the value of these agents as treatments for AD and late‐life cognitive decline.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Saez‐Atienzar S, Masliah E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat Rev Neurosci. 2020; 21: 433‐ 444. 32601397 PMC12548380 source

      Not checked in the free run.

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

    Interpretationnone given

    Global trials allow diversified participant exposures and improved understanding of effects of ethnicity, standard of care, body size, nutrition, and educational level on trial outcomes.

    “Global trials allow diversified participant exposures and improved understanding of effects of ethnicity, standard of care, body size, nutrition, and educational level on trial outcomes.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    There is a gap in the trial system that requires remedy to accelerate trials and drug development.

    “These observations identify a gap in the trial system that requires remedy to accelerate trials and drug development.”
    Quote in the paperNot a substantial claim
53 of 53

  • The paper relies on this without support.

    Phase 1 trials are often conducted outside of the United States, may not be registered on ClinicalTrials.gov, and may be under-represented in this analysis.

    “Phase 1 trials are often conducted outside of the United States, may not be registered on ClinicalTrials.gov, and may be under‐represented in our analysis.”

  • The paper relies on this without support.

    ClinicalTrials.gov includes the majority of agents currently in clinical trials for Alzheimer's disease.

    “ClinicalTrials.gov includes the majority of agents currently in clinical trials for AD”

  • The paper relies on this without support.

    Information on completed, terminated, suspended, unknown, or withdrawn trials and reasons for their current status are often not publicly revealed.

    “We did not include trials listed as completed, terminated, suspended, unknown, or withdrawn as information on these trials and reasons for their current status are often not publicly revealed.”

  • The paper relies on this without support.

    The features of trials (clinical outcomes, trial duration, use of biomarkers, number of participants) can determine whether a trial was attempting to demonstrate disease modification or symptomatic benefit.

    “We used the features of the trials (e.g., clinical outcomes, trial duration, use of biomarkers, number of participants) to determine whether a trial was attempting to demonstrate disease medication or symptomatic benefit.”

  • The paper relies on this without support.

    The available literature can identify a dominant mechanism of action for agents with multiple mechanisms of action.

    “Some agents have more than one mechanism of action and, in these cases, we noted both mechanisms and depended on the available literature to identify a dominant mechanism.”

  • The paper relies on this without support.

    The trials registered on ClinicalTrials.gov as of January 5, 2021 are representative of the AD drug development pipeline.

    “Table 6 shows the biomarkers used as entry criteria or as outcome measures in current Phase 2 and Phase 3 AD clinical trials of DMTs as described on ClinicalTrials.gov; not all trial descriptions on the website note if biomarkers are included in the trial.”

  • The paper relies on this without support.

    Research partners contribute at least an equivalent number of weeks as trial participants.

    “There are at least an equivalent number of weeks contributed by research partners, doubling the total participant‐partner weeks to 5,080,028 weeks.”

  • The paper relies on this without support.

    ClinicalTrials.gov is a US trial registry and most trials conducted by sponsors anywhere in the world are registered on ClinicalTrials.gov.

    “This is, in part, a reflection of the fact that ClinicalTrials.gov is a US trial registry (although note that most trials conducted by sponsors anywhere in the world are registered on ClinicalTrials.gov).”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The 2024 AD drug development pipeline includes 164 trials, of which 127 are exploring possible treatments or medicines.

    “The most recent list of studies was provided by the 2024 AD drug development pipeline, which includes 164 trials (of which 127 are exploring possible treatments or medicines).”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [182]

  • Of these trials, 41% look into disease-modifying small molecule medications, 34% look into biological agents that change disease, and the remaining trials focus on treatments that improve cognitive function or address neuropsychiatric symptoms linked to AD.

    “Of these trials, 41% look into disease-modifying small molecule medications, 34% look into biological agents that change disease, and the remaining trials focus on treatments that improve cognitive function or address neuropsychiatric symptoms linked to ADs [68,70,71,182,183,184].”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [182]

  • Azeliragon is an inhibitor of RAGE that can be administered orally.

    “Another molecule in Phase 3 is Azeliragon (NTC03980730), an inhibitor of RAGE that can be administered orally [163].”

    From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [163]

  • Ginkgo Biloba extracts are supposed to improve mitochondrial function and brain blood flow, acting as a cognitive enhancer.

    “Ginkgo Biloba (NCT03090516) extracts are supposed to improve mitochondrial function and brain blood flow, acting as a cognitive enhancer [163].”

    From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [163]

  • Of the 18 agents in phase 3 classified as disease-modifying treatments, three have OS as mechanism of action, two have metabolism/bioenergetic, two have antioxidant properties, and among the three agents acting on synaptic plasticity/neuroprotection, Azeliragon is also meant to ameliorate OS.

    “Of the 18 agents in phase 3 classified as disease-modifying treatments, three have OS as mechanism of action, two have metabolism/bioenergetic, two have antioxidant properties, and among the three agents acting on synaptic plasticity/neuroprotection, Azeliragon is also meant to ameliorate OS (Table 2).”

    From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [163]

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.

  • DMT share of CNS approvals is miscalculated

    Major

    The paper identifies five DMTs among 11 CNS approvals. That is about 45%, not 36%; the percentage is used to support a conclusion about DMT development.

    Reported 36 · recomputed 45.454545

  • Tau PET outcome counts differ between table and text

    Minor

    Table 6 gives four Phase 3 and three Phase 2 DMT trials with tau PET as an outcome; the accompanying text instead gives three Phase 3 and nine Phase 2 trials.

  • Phase 3 trials conducted in both regions are reported as 71% rather than 34%

    Minor

    The text says 71% of Phase 3 trials included both North American and non-North American countries, whereas Table 8 assigns 34% to the "Both" category.

  • Academic/NIH sponsor total does not match phase counts

    Minor

    Table 5 lists 8, 27, and 9 academic medical center/NIH-sponsored trials in Phases 3, 2, and 1, respectively. These add to 44, not the reported all-phases total of 49.

    Reported 49 · recomputed 44

4 of 4

Cites

Flagged first, then by citations

2 of the 40 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. Food and Drug Administration, 2018, U.S. Department of Health and Human Services, Food and Drug Administration
  2. International Alzheimer's and Related Dementia Research Portfolio
  3. Food and Drug Administration, 2020, Advancing Health Through Innovation: New Drug Therapy Approvals 2020
  4. IQVIA, 2019, The Changing Landscape of Research and Development

Cited by

Sorted by citations

Related

Authors
Cummings, J., Lee, G., Zhong, K., Fonseca, J., & Taghva, K.
Affiliations
  • University of Nevada, Las Vegas (US)
  • Biogen (United States) (US)
  • Howard R. Hughes College of Engineering Department of Computer Science University of Nevada, Las Vegas (UNLV) Las Vegas Nevada USA
Corresponding author
Cummings, Jeffrey
ORCID
Venue
Alzheimer's & Dementia: Translational Research & Clinical Interventions
Publisher
Wiley
Published
2021-01
Volume
7
Issue
1
Pages
e12179-e12179
ISSN
2352-8737 (ISSN-L)
DOI
10.1002/trc2.12179
PMC
PMC8145448
OpenAlex
W3164214667
Semantic Scholar
bbab7a44a3b914a574816f1b4885797eb472650c
Cited by
539
References
40
Citations by year
2026: 48 · 2025: 95 · 2024: 81 · 2023: 102 · 2022: 156 · 2021: 54 · 2020: 3
FWCI
61.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (P20AG068053)
  • National Institute of General Medical Sciences (P20GM109025)
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
Alzheimer's disease, drug development pipeline, clinical trials, disease-modifying therapy, cognitive enhancement, neuropsychiatric symptoms, drug repurposing, biomarkers, ClinicalTrials.gov

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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