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

Apolipoprotein E ( APOE ) ε4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE ε4 carrier status remains unknown. This is among the first randomized evaluations of intensive SBP control on all-cause dementia by APOE ε4 status in US adults without diabetes.

To compare effects of intensive vs standard SBP control on incident all-cause probable dementia between APOE ε4 carriers and non-carriers.

Secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized trial of adults >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.

Intensive SBP control (goal <120 mm Hg) vs standard SBP control (goal <140 mm Hg).

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 ε4 status was the primary effect modifier.

Of 9,361 randomized participants, 8,390 (89.6%) had APOE genotyping (29% ε4 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 ε4 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 ε4 subgroups.

Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute risk reduction in dementia among APOE ε4 carriers than non-carriers; relative effects were similar. These findings may inform APOE ε4-stratified blood pressure management for dementia prevention.

Question: What is the effect of intensive vs standard systolic blood pressure (SBP) control on incident dementia by APOE ε4 status? Findings: In SPRINT, intensive vs standard SBP control yielded a significantly larger 4-year absolute risk reduction in dementia among APOE ε4 carriers (-1.7%) than non-carriers (0.2%; P-interaction = .045); the relative-scale interactions were directionally consistent but not significant. Meaning: Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute benefit among APOE ε4 carriers than non-carriers; relative benefits were similar. APOE ε4 status may inform risk-stratified blood pressure management for dementia prevention.