Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer’s disease drug development pipeline using a target trial emulation
High-throughput target-trial emulations to evaluate potential drug candidates for delaying Alzheimer’s onset.
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.
Citation
@article{kuji2026critical,
author={Tonegawa-Kuji, Reina and Karavani, Ehud and Danziger, Michael and Zhang, Pengyue and Hou, Yuan and Zhou, Yadi and Bykova, Marina and Pieper, Andrew A. and Rosen-Zvi, Michal and Cummings, Jeffrey and Cheng, Feixiong},
title={Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation},
journal={Alzheimer's \& Dementia: Translational Research \& Clinical Interventions},
doi={https://doi.org/10.1002/trc2.70193},
year={2026}
}