Antihypertensive Medication Class and Incident Alzheimers Disease and Related Dementias: External Replication Across Two Independent Healthcare Data Sources-the Vanderbilt EHR Synthetic Derivative and US Medicare Claims

Importance. Hypertension is among the most important modifiable risk factors for Alzheimers disease and related dementias (ADRD), but whether different antihypertensive drug classes confer different cognitive risk, particularly through differential modulation of angiotensin II receptor signaling, remains uncertain. Prior pharmacoepidemiologic evidence is based largely on a single Medicare cohort, and external validation across distinct healthcare data environments is needed. Objective. To externally replicate and extend prior findings across two structurally independent healthcare data sources, evaluating whether predominant use of antihypertensive medications that stimulate versus inhibit angiotensin II type 2 and type 4 receptor signaling is associated with risk of incident ADRD. Design, Setting, and Participants. Retrospective new user, active comparator cohort study with propensity score matching, conducted in parallel across two independent data sources: the Vanderbilt University Medical Center Synthetic Derivative (VUMC SD; deidentified academic medical center electronic health record through February 2025) and the Merative MarketScan Medicare Database (2015 to 2023). Adults aged 65 years or older with hypertension and at least 365 cumulative days of antihypertensive exposure were included after a 365-day blanking period. Exposures. Predominant use ([&ge;]80% of cumulative exposure days) of receptor-stimulating antihypertensive medications (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, thiazide diuretics) vs receptor-inhibiting antihypertensive medications (angiotensin-converting enzyme inhibitors, {beta}blockers, nondihydropyridine calcium channel blockers); a third group of nonusers comprised participants without predominant use of either class. Main Outcomes and Measures. Time to first incident ADRD diagnosis was identified using ICD9 and ICD10 codes consistent with the CMS Chronic Conditions Data Warehouse definition. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models with time-dependent covariates. Results. The Medicare cohort included 1,596,034 beneficiaries (mean [SD] age, 75.0 [8.0] years; 55% female), and the VUMC SD cohort included 80,267 patients (mean [SD] age, 72.3 [5.8] years; 57% female). Over approximately 7 years of follow-up, ADRD incidence was lower among predominant users of stimulating vs. inhibiting medications in both cohorts (Medicare: 6.7% vs. 8.2%; VUMC SD: 4.9% vs. 5.7%). After adjustment, predominant use of stimulating medications was associated with lower ADRD risk versus inhibiting medications in both cohorts (Medicare: HR, 0.92; 95% CI, 0.90,0.93; P < .001; VUMC SD: HR, 0.92; 95% CI, 0.85,0.99; P = .03). Established cardiovascular and neuropsychiatric risk factors (atrial fibrillation, heart failure, chronic kidney disease, depression) showed expected associations with ADRD risk in both cohorts, supporting internal validity. Conclusions and Relevance. Across two structurally independent data sources, the predominant use of antihypertensive medications that stimulate angiotensin II type 2 and type 4 receptor signaling was associated with a modestly lower risk of incident ADRD compared with predominantly inhibiting agents. By replicating in two distinct data environments, these findings extend prior single-source pharmacoepidemiologic evidence and support evaluation of receptor targeted antihypertensive strategies for cognitive outcomes in randomized comparative-effectiveness trials.