Effect of Intensive vs Standard Blood Pressure Control According to APOE ε4 Genotype: A Secondary Analysis of SPRINT

Importance: Apolipoprotein E (APOE) {varepsilon}4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE {varepsilon}4 carrier status remains unknown. This is among the first randomized evaluations of intensive SBP control on all-cause dementia by APOE {varepsilon}4 status in US adults without diabetes. Objective: To compare effects of intensive vs standard SBP control on incident all-cause probable dementia between APOE {varepsilon}4 carriers and non-carriers. Design, Setting, and Participants: Secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized trial of adults [&ge;]50 years with hypertension and increased cardiovascular risk, but without diabetes, prior stroke, or dementia. Primary cognitive follow-up ended July 2018. Participants were further followed with telephone-based outcome assessment from 2019 through 2023. Interventions: Intensive SBP control (goal <120 mm Hg) vs standard SBP control (goal <140 mm Hg). Main Outcomes and Measures: The primary outcome was all-cause probable dementia. Secondary outcomes were mild cognitive impairment (MCI); MCI or dementia; MCI, dementia, or death; and all-cause mortality. APOE {varepsilon}4 status was the primary effect modifier. Results: Of 9,361 randomized participants, 8,390 (89.6%) had APOE genotyping (29% {varepsilon}4 carriers); 7,733 (82.6%) had both genotype and outcome data (mean age, 68 years; 36% female; 28% Non-Hispanic Black). Over a median follow-up of 5.1 years, dementia rates (intensive vs standard) were 9.7 vs 13.2 per 1,000 person-years among {varepsilon}4 carriers (hazard ratio [HR], 0.73; 95% CI, 0.51-1.04) and 6.1 vs 6.7 among non-carriers (HR, 0.91; 95% CI, 0.67-1.23; P-interaction = .35). Four-year risk differences were -1.7% (95% CI, -3.4% to 0%; number needed to treat, 59) among carriers and 0.2% (95% CI, -0.6% to 1%) among non-carriers (P-interaction = .045). Patterns were similar for the composite of MCI or dementia; effects on MCI were similar between APOE {varepsilon}4 subgroups. Conclusions and Relevance: Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute risk reduction in dementia among APOE {varepsilon}4 carriers than non-carriers; relative effects were similar. These findings may inform APOE {varepsilon}4-stratified blood pressure management for dementia prevention.