OBJECTIVES: The objective was to test the hypothesis that antihypertensive drugs have a differential effect on cognition in carriers and noncarriers of the apolipoprotein epsilon4 (APOE4) polymorphism. DESIGN: Prospective population-based cohort, France. SETTING AND PARTICIPANTS: A total of 3359 persons using antihypertensive drugs (median age 74 years, 62% women) were serially assessed up to 10 years follow-up. MEASURES: Exposure to antihypertensive drug use was established in the first 2 years. Cognitive function was assessed at baseline, 2, 4, 7, and 10 years with a validated test battery covering global cognition, verbal fluency, immediate visual recognition memory, processing speed, and executive function. Clinically significant change in cognitive function was determined using reliable change indices represented as z scores and analyzed with linear mixed-models. RESULTS: From 3359 persons exposed to antihypertensive drugs, 653 were APOE4 carriers (5.1% homozygous, 94.9% heterozygous) and median follow-up was 5.2 years (interquartile range 3.7-8.0). In APOE4 carriers, improved general cognitive function over time was associated with exposure to angiotensin converting enzyme inhibitors [beta = .14; 95% confidence interval (CI) .06-.23, P = .001] and angiotensin receptor blockers (beta = .11; 95% CI .02-.21, P = .019). Improved verbal fluency was associated with angiotensin converting enzyme inhibitors (beta = .11; 95% CI .03-.20, P = .012). CONCLUSIONS: Renin-angiotensin-system blockade was associated with improved general cognitive function in APOE4 carriers. Findings did not support renin-angiotensin-system drugs' lipophilicity or ability to cross the blood-brain barrier as potential mechanisms. The findings have implications for selecting the optimal antihypertensive drug in older populations at risk of cognitive decline and dementia.Read less <