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cognitive impairment (MCI cohort) and (2) individuals aged \u226570 years (over\u201070 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same\u2010class or active comparators. Covariate\u2010adjusted hazard ratios (HRs) were estimated using inverse\u2010probability\u2010weighted Cox models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over\u201070 cohort were associated with a lower AD incidence versus same\u2010class 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\u201070 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>This is the first comprehensive set of trial emulations for FDA\u2010approved drugs that are represented in AD trials. Findings may inform future trial designs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Repurposing FDA\u2010approved drugs originally developed for other diseases could accelerate treatment development for AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large\u2010scale insurance claims\u2010based database.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Among 54 drugs evaluated, 6\/38 (16%) drugs in the MCI cohort and 10\/53 (19%) in the over\u201070 cohort were associated with reduced AD incidence versus same\u2010class 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\u201070 cohort.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>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.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This is the first comprehensive set of trial emulations for FDA\u2010approved drugs that are represented in AD trials. Building on our findings, integrating real\u2010world evidence can inform future trials and accelerate drug development for AD.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70193","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T11:25:11Z","timestamp":1767007511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Critical evaluation of real\u2010world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation"],"prefix":"10.1002","volume":"12","author":[{"given":"Reina","family":"Tonegawa\u2010Kuji","sequence":"first","affiliation":[{"name":"Cleveland Clinic Genome Center Cleveland Clinic Research Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Genomic Sciences and Systems 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