CoChat
Sign Up
Cited by 1Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsPharmaceutical Practices and Patient Outcomes

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index; 21 of the 46 sources its claims cite were checked for support.

Critical evaluation of real‐world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation

Open access
Tonegawa‐Kuji, Reina, Karavani, Ehud, Danziger, Michael, Zhang, Pengyue, Hou, Yuan, Zhou, Yadi, Bykova, Marina, Pieper, Andrew A., Rosen‐Zvi, Michal, Cummings, Jeffrey, Cheng, Feixiong·2026·Alzheimer's & Dementia: Translational Research & Clinical Interventions
DOI 10.1002/trc2.70193PMC PMC12746425
Open this paper in CoChat — free accountOpen PDF

Abstract

INTRODUCTION: Repurposing Food and Drug Administration (FDA)‐approved drugs could accelerate treatment development for Alzheimer's disease (AD). METHODS: Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over‐70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same‐class or active comparators. Covariate‐adjusted hazard ratios (HRs) were estimated using inverse‐probability‐weighted Cox models. RESULTS: A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over‐70 cohort were associated with a lower AD incidence versus same‐class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over‐70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]). DISCUSSION: This is the first comprehensive set of trial emulations for FDA‐approved drugs that are represented in AD trials. Findings may inform future trial designs. Highlights: Repurposing FDA‐approved drugs originally developed for other diseases could accelerate treatment development for AD. We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large‐scale insurance claims‐based database. Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over‐70 cohort were associated with reduced AD incidence versus same‐class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over‐70 cohort. A minority of repurposed table drugs that are in current or completed clinical trials for AD and meet criteria for inclusion in this study showed no effect in our trial emulation studies. This is the first comprehensive set of trial emulations for FDA‐approved drugs that are represented in AD trials. Building on our findings, integrating real‐world evidence can inform future trials and accelerate drug development for AD.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This target trial emulation used MarketScan claims (2011–2020) to evaluate FDA-approved repurposable drugs in AD trials across MCI and over-70 cohorts. It found bupropion, trazodone, venlafaxine, and zolpidem associated with lower AD incidence/progression in active-comparator analyses, with liraglutide also associated with lower AD dementia incidence in the over-70 cohort.

Key findings

  • In same-class ATC comparisons, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with lower AD incidence versus same-class comparators; 37/54 (69%) drugs showed no statistically significant association across three models.
  • Active comparator analyses in the MCI cohort: bupropion vs escitalopram HR 0.57 (95% CI 0.49–0.66); trazodone vs sertraline HR 0.82 (0.74–0.91); venlafaxine vs escitalopram HR 0.72 (0.62–0.84); zolpidem vs lorazepam HR 0.69 (0.56–0.85).
  • In the over-70 cohort, these four plus liraglutide were associated with lower AD dementia incidence versus metformin (HR 0.74, 95% CI 0.59–0.93); zolpidem vs lorazepam HR 0.65 (0.60–0.70) and vs ramelteon HR 0.57 (0.43–0.76).
  • A sample size calculation for bupropion vs escitalopram in the MCI cohort estimated approximately 385 participants per group (about 770 total) for a randomized trial.

Methods

  • Target trial emulation using the MarketScan Research Databases (2011–2020; >171 million individuals), with two base cohorts: MCI regardless of age and individuals aged ≥70 years.
  • Drugs were identified from ClinicalTrials.gov active/completed AD trials; comparators were same ATC second-level class drugs or active comparators. Index date was first prescription; follow-up was up to 3 years for first AD dementia diagnosis.
  • Inverse-probability-weighted Cox models adjusted for >600 potential confounders; balance required weighted |SMD| < 0.20 and IP-weighted AUROC near 0.50; Benjamini–Hochberg q < 0.1. The study conducted 49 studies for 38 drugs in the MCI cohort and 73 studies for 53 drugs in the over-70 cohort.

Limitations

  • The paper states residual biases may remain despite robust adjustment; over-the-counter drugs are not captured; drug vs no-drug effects and neuropsychiatric symptom severity could not be estimated; the design cannot distinguish slowing disease progression from delaying symptom onset.
  • The paper states AD dementia diagnosis was clinical and not biomarker-confirmed, post-diagnosis progression was not assessed, and the intention-to-treat estimand by first prescription did not model adherence or duration.
  • The paper states some drugs were not evaluable across both cohorts or comparator groups due to inadequate covariate balance, no direct comparison was made with FDA-approved AD agents, and replication in independent EHR data is needed; the text also makes evident that findings are hypothesis-generating and do not replace RCTs.

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

Integrity signals

Registry

Crossref · 10.1002/trc2.70193

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

21 of 46 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    None of the repurposed agents has been approved for AD aside from brexpiprazole for agitation.

    “none has been approved aside from brexpiprazole for agitation.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [4] Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2025. Alzheimers Dement (NY). 2025; 11(2): e70098. PMC12131090 40463637 source

      The Results (Overview; Repurposed agents) describe drugs being repurposed for AD and say they are approved for non-AD indications, but do not establish whether any have also been approved for AD. Searches for brexpiprazole and approval for agitation found no passage in our copy identifying that exception or establishing the claimed exclusivity. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
    • cites [5] Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer's disease. J Prev Alzheimers Dis. 2022; 9(2): 197‐ 210. 35542991 source

      The Discussion addresses aducanumab’s trial results, and the Clinical study patients section describes medications permitted during those trials. Neither addresses approvals of repurposed agents or brexpiprazole for agitation. Searches for brexpiprazole, agitation, and drug approval found no passage supporting the claim. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [6] Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER‐ALZ 2 randomized clinical trial. JAMA. 2023; 330(6): 512‐ 527. 37459141 PMC10352931 source

      The trial’s Outcomes section describes donanemab assessments, while the supplied References passages list other Alzheimer disease studies and imaging agents. Searches for brexpiprazole, agitation, repurposed agents, and approval found no passage in our copy addressing which repurposed agents have been approved. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Interpretationreasoning

    Previous trials evaluating bupropion or related compounds were likely underpowered to detect effects on cognitive function.

    “Nevertheless, given that previous trials evaluating bupropion or related compounds enrolled fewer participants and had shorter follow‐up periods, it is likely that these studies were underpowered to detect effects on cognitive function. 26 , 27 , 28 , 29”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [26] Axsome Therapeutics Announces AXS‐05 Achieves Primary Endpoint in the ADVANCE‐1 Pivotal Phase 2/3 Trial in Alzheimer's Disease Agitation 2020. Accessed September 24th, 2025. Available from: https://axsometherapeuticsinc.gcs‐web.com/news‐releases/news‐release‐details/axsome‐therapeutics‐announces‐axs‐05‐achieves‐primary‐endpoint‐2

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

    • cites [27] Axsome Therapeutics Announces AXS‐05 Achieves Primary Endpoint in the ACCORD Phase 3 Trial in Alzheimer's Disease Agitation 2022. Accessed September 24th, 2025. Available from: https://axsometherapeuticsinc.gcs‐web.com/news‐releases/news‐release‐details/axsome‐therapeutics‐announces‐axs‐05‐achieves‐primary‐endpoint‐3

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

    • cites [28] Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS‐05 in Alzheimer's Disease Agitation. Accessed September 24th, 2025. Available from: https://www.biospace.com/press‐releases/axsome‐therapeutics‐announces‐successful‐completion‐and‐results‐of‐phase‐3‐clinical‐program‐of‐axs‐05‐in‐alzheimers‐disease‐agitation

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

    • cites [29] Maier F, Spottke A, Bach JP, et al. Bupropion for the treatment of apathy in Alzheimer disease: a randomized clinical trial. JAMA Netw Open. 2020; 3(5): e206027. 32463470 PMC7256670 source

      The Methods (Statistical Analysis; page unavailable) describe a 108-participant bupropion trial with a 12-week outcome, and the Discussion (Strengths and Limitations; page unavailable) says early termination caused a relevant loss of statistical power. That power assessment concerns apathy, not cognitive function; the paper does not establish that previous trials were underpowered to detect cognitive effects or compare their follow-up periods. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
  • Premisecitation

    Liraglutide demonstrates favorable effects in humans.

    “Liraglutide can cross the blood–brain barrier 38 and demonstrates favorable effects in mouse models of AD 39 , 40 or in humans. 41 , 42 , 43”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [41] Gejl M, Gjedde A, Egefjord L, et al. In Alzheimer's disease, 6‐month treatment with GLP‐1 analog prevents decline of brain glucose metabolism: randomized, placebo‐controlled, double‐blind clinical trial. Front Aging Neurosci. 2016; 8: 108. 27252647 PMC4877513 source
    • cites [42] Edison P, Femminella GD, Ritchie CW, et al. Evaluation of liraglutide in the treatment of Alzheimer's disease. Alzheimers Dement. 2021; 17(S9): e057848. source
    • cites [43] GLP‐1 drug liraglutide may protect against dementia. News provided by Alzheimer's Association. 2024. Accessed September 25th, 2025. Available from: https://prnmedia.prnewswire.com/news‐releases/glp‐1‐drug‐liraglutide‐may‐protect‐against‐dementia‐302209255.html

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

  • Premisecitation

    Several trials have not demonstrated significant benefits of these agents on cognitive function.

    “Several trials have not demonstrated significant benefits of these agents on cognitive function, possibly due to inadequate sample sizes not specifically calculated to detect cognitive outcomes.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [26] Axsome Therapeutics Announces AXS‐05 Achieves Primary Endpoint in the ADVANCE‐1 Pivotal Phase 2/3 Trial in Alzheimer's Disease Agitation 2020. Accessed September 24th, 2025. Available from: https://axsometherapeuticsinc.gcs‐web.com/news‐releases/news‐release‐details/axsome‐therapeutics‐announces‐axs‐05‐achieves‐primary‐endpoint‐2

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

    • cites [27] Axsome Therapeutics Announces AXS‐05 Achieves Primary Endpoint in the ACCORD Phase 3 Trial in Alzheimer's Disease Agitation 2022. Accessed September 24th, 2025. Available from: https://axsometherapeuticsinc.gcs‐web.com/news‐releases/news‐release‐details/axsome‐therapeutics‐announces‐axs‐05‐achieves‐primary‐endpoint‐3

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

    • cites [28] Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS‐05 in Alzheimer's Disease Agitation. Accessed September 24th, 2025. Available from: https://www.biospace.com/press‐releases/axsome‐therapeutics‐announces‐successful‐completion‐and‐results‐of‐phase‐3‐clinical‐program‐of‐axs‐05‐in‐alzheimers‐disease‐agitation

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

    • cites [29] Maier F, Spottke A, Bach JP, et al. Bupropion for the treatment of apathy in Alzheimer disease: a randomized clinical trial. JAMA Netw Open. 2020; 3(5): e206027. 32463470 PMC7256670 source

      The Results table reports no significant difference between bupropion and placebo on two cognitive measures (ADAS-Cog, P = .86; MMSE, P = .53). But this paper reports one bupropion trial, not several trials of multiple agents. The Methods also say its sample size was calculated for apathy, not cognitive outcomes, without establishing that sample size explains the cognitive results. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Liraglutide can cross the blood-brain barrier.

    “Liraglutide can cross the blood–brain barrier 38 and demonstrates favorable effects in mouse models of AD 39 , 40 or in humans. 41 , 42 , 43”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012; 13: 33. 22443187 PMC3352246 source
  • It may state two separate claims as one. 17
  • Probably not a substantial claim. 24

  • It may state two separate claims as one.

    Premisecitation

    There are 46 repurposed agents in the 2025 AD drug development pipeline, comprising 33% of drugs in trials.

    “There are 46 repurposed agents in the 2025 AD drug development pipeline, comprising 33% of drugs in trials. 4”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2025. Alzheimers Dement (NY). 2025; 11(2): e70098. PMC12131090 40463637 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The target trial emulation approach also informs pragmatic randomized controlled trial redesigns and sample size estimations.

    “This approach also informs pragmatic randomized controlled trial (RCT) redesigns and sample size estimations. 11”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Cook JA, Julious SA, Sones W, et al. DELTA(2) guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial. BMJ. 2018; 363: k3750. 30560792 PMC6216070 source

      The Abstract and Discussion describe guidance for estimating sample size when designing a randomized controlled trial. They do not describe target trial emulation or say that it informs pragmatic RCT redesigns or sample size estimates; the claim is supported only on the general topic of sample size calculation. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Sleep accelerates the removal of amyloid beta protein and tau protein from the brain.

    “Therapies such as zolpidem and suvorexant may improve sleep, and it is increasingly recognized that sleep accelerates the removal of amyloid beta protein and tau protein from the brain. 46”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [46] Wang C, Holtzman DM. Bidirectional relationship between sleep and Alzheimer's disease: role of amyloid, tau, and other factors. Neuropsychopharmacology. 2020; 45(1): 104‐ 120. 31408876 PMC6879647 source

      The Sleep and Aβ section says sleep facilitates Aβ clearance from brain interstitial fluid. The Conclusion reports that sleep disturbance changes extracellular levels of both Aβ and tau, but says further studies are needed to determine whether their production and clearance follow similar mechanisms. Thus, the claim that sleep accelerates tau removal is not established by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Pharmacologic treatments for insomnia are generally given reduced recommendations in clinical guidelines due to concerns about dependence and cognitive side effects.

    “While pharmacologic treatments for insomnia are generally given reduced recommendations in clinical guidelines due to concerns about dependence and cognitive side effects, 47 , 48 , 49 , 50 our findings suggest possible differences in associations with cognitive outcomes across hypnotics, and further investigation is warranted.”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [47] Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2021; 17(2): 255‐ 262. 33164742 PMC7853203 source

      The Discussion identifies CBT-I as the treatment of choice, and the Methods say it may reduce the need for medication and the risk of drug-related adverse events. But this guideline addresses behavioral and psychological treatments; it does not assign reduced recommendations to pharmacologic treatments or attribute such recommendations to dependence and cognitive side effects. The cognitive difficulties it discusses are potential short-term effects of CBT-I. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [48] Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017; 13(2): 307‐ 349. 27998379 PMC5263087 source

      The guideline says all its drug-specific recommendations are weak and, in Clinical Application, identifies dependency and cognitive impairment as potential harms. But its Recommendations section attributes downgraded evidence quality chiefly to publication bias, few eligible trials, and heterogeneous data; it does not say the weak recommendations are generally due to dependence and cognitive side effects. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [49] Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta‐analysis of risks and benefits. BMJ. 2005; 331(7526): 1169. 16284208 PMC1285093 source

      The Limitations section identifies dependence as a major concern, and the Conclusions say that modest benefits and adverse-event risks should be considered when prescribing sedative hypnotics to older people. The paper does not establish that clinical guidelines generally give pharmacologic insomnia treatments reduced recommendations, and its analysis concerns older people rather than insomnia patients generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [50] Hauglund NL, Andersen M, Tokarska K, et al. Norepinephrine‐mediated slow vasomotion drives glymphatic clearance during sleep. Cell. 2025; 188(3): 606‐ 622. 39788123 PMC12340670 source

      The Discussion section on zolpidem and glymphatic flow says the American Geriatric Society does not recommend zolpidem for people over 65 and mentions a reported risk of reversible dementia. It does not address dependence or establish that clinical guidelines generally give reduced recommendations to pharmacologic insomnia treatments as a class. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Liraglutide demonstrates favorable effects in mouse models of AD.

    “Liraglutide can cross the blood–brain barrier 38 and demonstrates favorable effects in mouse models of AD 39 , 40 or in humans. 41 , 42 , 43”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [39] Vargas‐Soria M, Carranza‐Naval MJ, Del Marco A, Garcia‐Alloza M. Role of liraglutide in Alzheimer's disease pathology. Alzheimers Res Ther. 2021; 13(1): 112. 34118986 PMC8199799 source
    • cites [40] Salles GN, Calió ML, Hölscher C, Pacheco‐Soares C, Porcionatto M, Lobo AO. Neuroprotective and restorative properties of the GLP‐1/GIP dual agonist DA‐JC1 compared with a GLP‐1 single agonist in Alzheimer's disease. Neuropharmacology. 2020; 162: 107813. 31628935 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Two phase III clinical trials of semaglutide are ongoing.

    “Two phase III clinical trials are ongoing, 45 and re‐evaluation with more recent data is warranted.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Cummings JL, Atri A, Feldman HH, et al. Evoke and evoke+: design of two large‐scale, double‐blind, placebo‐controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early‐stage symptomatic Alzheimer's disease. Alzheimers Res Ther. 2025; 17(1): 14. 39780249 PMC11708093 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    The discrepancy between our semaglutide finding and a prior analysis in a larger EHR network may reflect a smaller available sample as well as differences in population and comparator definitions.

    “The discrepancy with a prior analysis in a larger electronic health record (EHR) network that reported an association among patients with type 2 diabetes 44 may reflect a smaller available sample as well as differences in population and comparator definitions.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Wang W, Wang Q, Qi X, et al. Associations of semaglutide with first‐time diagnosis of Alzheimer's disease in patients with type 2 diabetes: target trial emulation using nationwide real‐world data in the US. Alzheimers Dement. 2024; 20: 8661‐ 8672. 39445596 PMC11667504 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    GLP-1 analogs are being investigated as disease-targeted therapies with the potential to slow the progression of cognitive decline.

    “Glucagon‐like peptide 1 (GLP‐1) analogs are being investigated as disease‐targeted therapies with the potential to slow the progression of cognitive decline. 34 , 35 , 36 , 37”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [34] Nørgaard CH, Friedrich S, Hansen CT, et al. Treatment with glucagon‐like peptide‐1 receptor agonists and incidence of dementia: data from pooled double‐blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (NY). 2022; 8(1): e12268. PMC8864443 35229024 source
    • cites [35] Akimoto H, Negishi A, Oshima S, et al. Antidiabetic drugs for the risk of Alzheimer disease in patients with Type 2 DM using FAERS. Am J Alzheimers Dis Other Demen. 2020; 35: 1533317519899546. 32162525 PMC11005324 source

      The Discussion says GLP-1 receptor agonists may have neuroprotective activity, and the Conclusion reports a lower associated risk of developing Alzheimer disease in patients with type 2 diabetes. Neither section establishes that these drugs are being investigated as disease-targeted therapies to slow the progression of existing cognitive decline; the study examined reported adverse events, not cognitive progression. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [36] Wium‐Andersen IK, Osler M, Jørgensen MB, Rungby J, Wium‐Andersen MK. Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case‐control study. Eur J Endocrinol. 2019; 181(5): 499‐ 507. 31437816 source
    • cites [37] Seminer A, Mulihano A, O'Brien C, et al. Cardioprotective glucose‐lowering agents and dementia risk: a systematic review and meta‐analysis. JAMA Neurol. 2025; 82(5): 450‐ 460. 40193122 PMC11976645 source

  • It may state two separate claims as one.

    Findingown data

    In the over-70 cohort, trazodone showed a slightly more favorable association than venlafaxine in two of the three models (difference: -0.01 [-0.02, 0.000], p = 0.03; HR: 0.97 [0.90, 1.04], p = 0.39).

    “Although trazodone showed a slightly more favorable association than venlafaxine in two of the three models (difference: −0.01 [−0.02, 0.000], p = 0.03; HR: 0.97 [0.90, 1.04], p = 0.39)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • It may state two separate claims as one.

    Findingown data

    Bupropion, trazodone, and venlafaxine showed favorable associations in this study.

    “Bupropion, trazodone, and venlafaxine, generally classified as atypical antidepressants due to mechanisms of action beyond serotonin reuptake inhibition, showed favorable associations in this study (Figure 6E).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The clinical diagnosis of AD dementia in the database is a valid proxy for AD dementia.
    • Rests on an assumption: Prescription records accurately reflect drug exposure.
    • Rests on an assumption: Residual biases after adjustment do not materially affect the reported associations.
    • Rests on an assumption: The first prescription exposure definition captures the relevant exposure for the associations.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    The drugs investigated spanned 25 pharmacological/therapeutic subgroups in the MCI cohort and 36 second-level ATC classifications in the over-70 cohort.

    “The drugs investigated in this study spanned 25 pharmacological/therapeutic subgroups (ATC second level) in the MCI cohort and 36 second‐level ATC classifications in the over‐70 cohort.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The study emulated 49 trials in a cohort of individuals diagnosed with MCI and 72 trials in a general insured population aged 70 years or older, covering 54 FDA-approved drugs previously tested for AD dementia across 37 ATC second-level categories.

    “We emulated 49 trials in a cohort of individuals diagnosed with MCI and 72 trials in a general insured population aged 70 years or older, covering 54 FDA‐approved drugs previously tested for AD dementia across 37 ATC second‐level categories.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • It may state two separate claims as one.

    Findingown data

    Bupropion was associated with a lower rate of both AD progression and incidence, followed by trazodone and venlafaxine.

    “Bupropion was associated with a lower rate of both AD progression and incidence, followed by trazodone and venlafaxine.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • It may state two separate claims as one.

    Findingown data

    After applying filters based on data availability and covariate balance, the study conducted 49 studies in 38 drugs in the MCI cohort and 73 studies for 53 drugs in the over-70 cohort.

    “After applying filters based on data availability and covariate balance, we conducted 49 studies in 38 drugs in the MCI cohort and 73 studies for 53 drugs in the over‐70 cohort”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    Adequate balance required all weighted absolute standardized mean differences below 0.20 and the difference from IP-weighted AUROC within 0.01 of 0.50.

    “Adequate balance required all weighted |SMD| < 0.20 and the difference from IP‐weighted AUROC within 0.01 of 0.50”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.

    Interpretationown data

    Building on the findings, integrating real-world evidence can inform future trials and accelerate drug development for AD.

    “Building on our findings, integrating real‐world evidence can inform future trials and accelerate drug development for AD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationnone given

    The findings may inform future trial designs.

    “Findings may inform future trial designs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductcitation

    Multiplicity was controlled using the Benjamini-Hochberg method for ATC level-2 comparisons, with q values below 0.1 considered statistically significant.

    “Multiplicity was controlled using the Benjamini–Hochberg method 23 for ATC level‐2 comparisons, with q values < 0.1 considered statistically significant.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Methodol. 2018; 57(1): 289‐ 300. source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials.

    “This is the first comprehensive set of trial emulations for FDA‐approved drugs that are represented in AD trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Covariate balance after weighting was evaluated using standardized mean difference and the difference from the IP-weighted AUROC.

    “Covariate balance after weighting was evaluated using standardized mean difference (SMD) and the difference from the IP‐weighted area under the receiver operating characteristic curve (AUROC).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    To the authors' knowledge, no prior study systematically conducted trial emulations for all FDA-approved drugs previously included in trials for AD.

    “To our knowledge, no prior study systematically conducted trial emulations for all FDA‐approved drugs previously included in trials for AD.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The study's findings provide real-world evidence that supports or complements the rationale for conducting such trials and informs the redesign of future clinical trials, including setting realistic target differences and sample size estimations.

    “our findings provide real‐world evidence that not only supports or complements the rationale for conducting such trials but also informs the redesign of future clinical trials, including setting realistic target differences and sample size estimations.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • It may state two separate claims as one.

    Premisenone given

    Many trials have tested repurposable agents, but few have meaningfully modified cognitive function.

    “Despite the fact that many trials have tested repurposable agents, few have meaningfully modified cognitive function, and none has been approved aside from brexpiprazole for agitation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    Only well-balanced analyses were considered.

    “Only well‐balanced analyses were considered.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.

    Interpretationreasoning

    These findings should be interpreted as hypothesis-generating and do not replace the need for fully powered and well-designed randomized controlled trials.

    “These findings should, however, be interpreted as hypothesis‐generating and do not replace the need for fully powered and well‐designed RCTs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Trazodone acts by inhibiting serotonin reuptake, blocking 5-HT2A/2C receptors, and antagonizing histamine and alpha-1-adrenergic receptors, contributing to its sedative effects.

    “Trazodone acts by inhibiting serotonin reuptake, blocking 5‐HT2A/2C receptors, and antagonizing histamine and alpha‐1‐adrenergic receptors, contributing to its sedative effects. 30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009; 14(10): 536‐ 546. 20095366

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    New onset depression in elderly patients can precede memory impairment in AD.

    “As new onset depression in elderly patients can precede memory impairment in AD, these insights might help guide selection of antidepressant treatment in elderly patients. 25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002; 288(12): 1475‐ 1483. 12243634 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In older patients with major depressive disorder, SSRIs are the most commonly recommended pharmacological treatments.

    “In older patients with major depressive disorder, SSRIs are the most commonly recommended pharmacological treatments. 33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] McQuaid JRLE, Barber JP, Breland‐Noble AM, et al. APA clinical practice guideline for the treatment of depression across three age cohorts: American psychological association; 2019. Accessed September 25th, 2025. Available from: https://www.apa.org/depression‐guideline

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

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    We were unable to evaluate the severity of neuropsychiatric symptoms due to database constraints.

    “Third, we were unable to estimate the effects of taking the drug versus not taking the drug, nor evaluate the severity of neuropsychiatric symptoms due to database constraints.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Although we performed robust adjustments, there might have been residual biases.

    “First, although we performed robust adjustments, there might have been residual biases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductreasoning

    Our analyses targeted an intention-to-treat framework defining exposure by the first prescription and not modeling post-baseline adherence or duration.

    “Furthermore, our analyses targeted an intention‐to‐treat framework defining exposure by the first prescription and not modeling post‐baseline adherence or duration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    We maximized internal validation within the database using both same-class and active comparator designs and multiple effect measures.

    “Finally, while we maximized internal validation within the database using both same‐class and active comparator designs and multiple effect measures, replication in independent EHR database will be an important future direction.”
    Quote in the paperNot a substantial claim
32 of 32

  • The paper relies on this without support.

    Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for Alzheimer's disease.

    “Repurposing Food and Drug Administration (FDA)‐approved drugs could accelerate treatment development for Alzheimer's disease (AD).”
    “Repurposing FDA‐approved drugs originally developed for other diseases could accelerate treatment development for AD.”

  • The paper relies on this without support.

    Evidence informing clinical trials for drug repurposing is scattered across sources, limiting robust inference.

    “Evidence informing clinical trials for drug repurposing typically derives from observational or experimental studies but is scattered across sources, limiting robust inference.”

  • The paper relies on this without support.

    Claims-based diagnosis codes accurately identify mild cognitive impairment and Alzheimer's disease dementia in the MarketScan database.

    “International Classification of Diseases (ICD) codes used for cohort definitions are listed in Table S2.”

  • The paper relies on this without support.

    Most repurposable drugs in current or completed AD trials that showed no effect in our trial emulation studies have failed to demonstrate a drug-placebo difference in clinical trials.

    “Most of these drugs have failed to demonstrate a drug‐placebo difference in clinical trials.”

  • The paper relies on this without support.

    The clinical diagnosis of AD dementia in the database is a valid proxy for AD dementia.

    “The diagnosis of AD in this study was based on clinical assessment and was not confirmed by amyloid‐related biomarkers.”

  • The paper relies on this without support.

    Prescription records accurately reflect drug exposure.

    “since the database captures prescribed drugs, results of the drugs that are available over the counter are not reflected in the data.”

  • The paper relies on this without support.

    Residual biases after adjustment do not materially affect the reported associations.

    “although we performed robust adjustments, there might have been residual biases.”

  • The paper relies on this without support.

    The first prescription exposure definition captures the relevant exposure for the associations.

    “our analyses targeted an intention‐to‐treat framework defining exposure by the first prescription and not modeling post‐baseline adherence or duration.”

  • The paper relies on this without support.

    FDA-approved AD agents are preferentially used in more symptomatic patients.

    “as these are preferentially used in more symptomatic patients”
9 of 9

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.

  • Over-70 study count differs between text and figure

    Minor

    The Results report 73 studies in the over-70 cohort, while the Figure 2 caption reports 72 comparisons for that cohort. The Discussion also gives 72 trials.

  • Figure 6 caption assigns an over-70 panel to the MCI cohort

    Minor

    The caption says panels A-D show curves in the MCI cohort, but identifies panel D as a comparison in the over-70 cohort.

  • Liraglutide-metformin hazard ratio differs between Abstract and Results

    Minor

    For the same over-70 comparison, the Abstract reports an HR of 0.74 and the Results report 0.75; both give the same confidence interval.

  • Over-70 cohort is described as measuring progression rather than incidence

    Minor

    The Methods assign AD progression to the MCI cohort and AD dementia incidence to the over-70 cohort, but the Results describe the ten over-70 drug associations as lower AD progression.

4 of 4

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS‐05 in Alzheimer's Disease Agitation. Accessed September 24th 2025. Available from:https://www.biospace.com/press‐releases/axsome‐therapeutics‐announces‐successful‐completion‐and‐results‐of‐phase‐3‐clinical‐program‐of‐axs‐05‐in‐alzheimers‐disease‐agitation

Cited by

Sorted by citations

Related

Metadata

Authors
Tonegawa‐Kuji, R., Karavani, E., Danziger, M., Zhang, P., Hou, Y., Zhou, Y., Bykova, M., Pieper, A. A., Rosen‐Zvi, M., Cummings, J., & Cheng, F.
Affiliations
  • Cleveland Clinic (US)
  • IBM Research - Haifa (IL)
  • Indiana University Indianapolis (US)
  • University Hospitals of Cleveland (US)
  • Hebrew University of Jerusalem (IL)
  • University of Nevada, Las Vegas (US)
Corresponding author
Cheng, Feixiong
ORCID
Venue
Alzheimer's & Dementia: Translational Research & Clinical Interventions
Publisher
Wiley
Published
2025-12-29
Volume
12
Issue
1
Pages
e70193-e70193
ISSN
2352-8737 (ISSN-L)
DOI
10.1002/trc2.70193
PMC
PMC12746425
OpenAlex
W7117468243
Semantic Scholar
cd01fb8cc017116bfe5c80a056c87d07df7081e3
Cited by
1
References
42
Citations by year
2026: 1
FWCI
0.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc)
Funders
  • National Institute on Aging (U01AG073323, R01AG053798, R01AG066707, R01AG084250, R01AG076448, R01AG082118, R01AG092462, R01AG092591, RF1AG082211, R33AG083003, R35AG071476)
  • National Institute of Neurological Disorders and Stroke (RF1NS133812, U01NS093334)
  • Alzheimer's Association (ALZDISCOVERY‐1051936)
  • National Institute of General Medical Sciences (P20GM109025)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
Keywords
Alzheimer's disease, drug repurposing, FDA-approved drugs, target trial emulation, mild cognitive impairment, older adults, antidepressants, bupropion, trazodone, venlafaxine, zolpidem, liraglutide, metformin, dementia prevention, real-world evidence, health insurance claims, clinical trial design

About these checks

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

A language model drew the claims from the paper on 2026-11-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

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

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

Are you an author, or do you see a problem with this page? Request a review