Platelet count polygenic scores may modify the effect of aspirin in primary prevention of dementia.

INTRODUCTION

Aspirin is not recommended for dementia prevention due to limited benefit. We investigated whether genetic subgroups may benefit.

METHODS

In the ASPirin in Reducing Events in the Elderly (ASPREE) trial (n = 13,541), we screened 5182 polygenic risk scores (PGSs) for aspirin interactions on dementia and major bleeding. After quality control, 1848 PGSs were analyzed using Cox models for aspirin×PGS interaction, adjusted for age, sex, apolipoprotein Estatus, and ancestry. Interactions were Bonferroni-corrected and examined by quintiles.

RESULTS

Platelet-related PGS accounted for 18/112 nominally significant interactions (enrichment_OR = 54.7, p = 3.1 × 10- 1 8). Three highly correlated platelet-count PGSs passed multiple testing. For participants in the highest quintile of the platelet-count PGS003548, aspirin allocation was associated with a 3.5-fold reduction in incident dementia versus placebo (hazard ratio [HR]: 0.28, 95% confidence interval [CI]: 0.15 to 0.52). Major bleeding was also increased (HR: 2.13, 95% CI: 1.36 to 3.34). Similar interactions were observed using the highest PGS003548 tertile, decile, and 5%.

DISCUSSION: Platelet count-related genetic variation may modify aspirin effects on dementia. These hypothesis-generating findings require validation.