PLATELET count polygenic scores modify low-dose aspirin therapy to reduce incident dementia risk in older adults. While large randomized controlled trials established that daily aspirin provides no broad cognitive protection, secondary pharmacogenomic data indicate profound inter-individual variation. Investigating whether inherited biological traits alter clinical outcomes, investigators screened thousands of genomic scores using adjudicated endpoints from 13,541 initially healthy individuals aged 70 years or older.
Rigorous screening revealed that genetic variations influencing thrombocyte volume and count significantly interact with aspirin therapy. Among participants situated in the highest quintile of the platelet polygenic score, daily low-dose aspirin administration achieved a 3.5-fold lower incidence of dementia relative to placebo. This association remained statistically robust after adjusting for age, sex, lifestyle behaviors, cardiovascular comorbidities, and competing risk of death. By contrast, individuals in lower genetic quintiles derived no preventive cognitive benefit, exhibiting neutral or potentially unfavorable trend estimates.
The neuroprotective advantages observed in the top genetic strata carry substantial clinical tradeoffs. Within that same fifth quintile, aspirin allocation resulted in a 2.1-fold elevated risk of major bleeding events compared to placebo. From an epidemiological standpoint, the absolute reduction in dementia risk matched the absolute increase in bleeding events, producing an identical number needed to treat and number needed to harm of approximately 44. Crucially, standard susceptibility benchmarks including apolipoprotein E genotype showed zero interaction with aspirin, underscoring that the observed modification stems specifically from platelet biological pathways rather than classic neurodegenerative risk profiles.
These findings suggest a potential precision medicine framework for selecting older adults who might benefit from targeted aspirin prophylaxis. However, the exploratory post hoc design necessitates external validation in diverse prospective cohorts prior to altering routine clinical protocols. Clinicians must continue following established guidelines discouraging empiric aspirin use for dementia prevention until validated genomic testing panels become standard practice.
Reference
Fransquet PD et al. Platelet count polygenic scores may modify the effect of aspirin in primary prevention of dementia. Alzheimer’s Dement. 2026;22:e71817.
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