Population‐based Discovery and Ethnically Mixed Mendelian Randomization Validation Identifies Telmisartan as a Candidate Drug for Alzheimer’s Disease in African Americans

Abstract

AbstractBackgroundElevated incidences of Alzheimer’s disease (AD) and disease progression may be associated with African American (AA)‐specific disease comorbidities, such as hypertension, diabetes, and chronic kidney disease. Treatments and management of these comorbidities — such as antihypertensive angiotensin‐II receptor blockers (ARBs) — may reduce risk of AD in AA people, while conferring additional beneficial effects on renal function and diabetes control.MethodWe conducted a race‐specific pharmacoepidemiologic study to investigate the association between telmisartan (an ARB having PPAR‐gamma (PPARG) agonistic properties and beneficial anti‐diabetic effects) use and AD using Cox analysis, Kaplan‐Meier analysis, and propensity score‐matched log‐rank test. We further conducted ethnically mixed Mendelian randomization analysis to identify likely causal relationships between telmisartan use and AD in AA people. All models were adjusted for age, sex, underlying health, and comorbidities.ResultIn Cox analyses of ARB users in insurance claim data, telmisartan use was significantly associated with reduced risks of AD in AA people (Hazard ratio [HR] = 0.77, P‐value = 0.002), but was not associated with AD reduction in non‐Hispanic White Americans (HR = 0.97, P‐value = 0.411). Compared to lisinopril (an angiotensin‐converting‐enzyme inhibitor) use, telmisartan use was associated with stronger reduced risk of AD in AA people (HR = 0.68, P‐value < 0.001). In all sensitivity and secondary analyses, telmisartan use was associated with stronger protective effects (including AD and dementia) in AA people. Using ethnically mixed Mendelian randomization analysis from large genome‐wide association studies (over 2 million individuals) across AD, hypertension, and diabetes, we demonstrated that telmisartan has greater beneficial effect on AD in AA people compared to European populations.ConclusionWe identified that telmisartan is a candidate drug for potential prevention and treatment of AD in AA people, but not in non‐Hispanic White Americans. Our findings indicate that early comorbidity management (hypertension, diabetes, and kidney dysfunction) by telmisartan will significantly reduce AD incidence for aged individuals, in particular for aged AA people. The association between telmisartan use and decreased incidence of AD in AAs will require a randomized controlled trial with an ethnically diverse population to establish causality and explore therapeutic outcomes.