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Population‐based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans
Author(s) -
Zhang Pengyue,
Hou Yuan,
Tu Wanzhu,
Campbell Noll,
Pieper Andrew A.,
Leverenz James B.,
Gao Sujuan,
Cummings Jeffrey,
Cheng Feixiong
Publication year - 2023
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12819
Subject(s) - telmisartan , medicine , mendelian randomization , hazard ratio , population , diabetes mellitus , blood pressure , endocrinology , confidence interval , genotype , genetics , environmental health , genetic variants , biology , gene
African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials. Methods We conducted race‐conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan–Meier analysis, and log‐rank test. We performed Mendelian randomization (MR) analysis of large ethnically diverse genetic data to test likely causal relationships between telmisartan's target and AD. Results We identified that moderate/high telmisartan exposure was significantly associated with a reduced incidence of AD in the AAs compared to low/no telmisartan exposure (hazard ratio [HR] = 0.77, 95% CI: 0.65–0.91, p ‐value = 0.0022), but not in the non‐Hispanic EAs (HR = 0.97, 95% CI: 0.89–1.05, p ‐value = 0.4110). Sensitivity and sex‐/age‐stratified patient subgroup analyses identified that telmisartan's medication possession ratio (MPR) and average hypertension daily dosage were significantly associated with a stronger reduction in the incidence of both AD and dementia in AAs. Using MR analysis from large genome‐wide association studies (GWAS) (over 2 million individuals) across AD, hypertension, and diabetes, we further identified AA‐specific beneficial effects of telmisartan for AD. Discussion Randomized controlled trials with ethnically diverse patient cohorts are warranted to establish causality and therapeutic outcomes of telmisartan and AD. HighlightsTelmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans (AAs). Telmisartan is the only angiotensin II receptor blockers having PPAR‐γ agonistic properties with beneficial anti‐diabetic and renal function effects, which mitigate AD risk in AAs. Mendelian randomization (MR) analysis demonstrates the specificity of telmisartan's protective mechanism to AAs.