Key result
Aspirin cuts incident dementia ~72% in older adults with high platelet-count polygenic scores.
Why the study?
Aspirin is not recommended for dementia prevention due to limited benefit, but genetic subgroups that may benefit have not been investigated.
Does aspirin reduce incident dementia in healthy older adults stratified by platelet count polygenic scores?
RCT (n=13,541)
Placebo-controlled
Randomized
Yes
Does aspirin reduce incident dementia in healthy older adults stratified by platelet count polygenic scores?
Aspirin may substantially reduce dementia risk in a specific genetic subgroup with high genetically predicted platelet counts, though this benefit is offset by increased bleeding risk.
Aspirin may reduce dementia risk in highest platelet PGS quintile despite bleeding increase; extends ASPREE RCT to this genetic subgroup.
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. 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.
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Fransquet et al. (2026) conducted an RCT in Healthy older adults (primary prevention of dementia) (n=13,541). Aspirin vs. Placebo was evaluated on Incident dementia in the highest quintile of platelet-count PGS003548 (HR 0.28, 95% CI 0.15-0.52, p=0.00012). In older adults in the highest quintile of a platelet-count polygenic score, aspirin reduced incident dementia by 72% (HR 0.28) but increased major bleeding compared to placebo.
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