A platelet-related genetic profile may identify older people who respond differently to aspirin, but bleeding risk remains a concern.
Low-dose aspirin was associated with a 70% lower dementia risk among older people with a particular platelet-related genetic profile, although the apparent benefit came with a similar absolute increase in major bleeding, Australian researchers have reported.
The post hoc analysis of the ASPREE trial screened more than 5000 polygenic risk scores (PGSs) to identify genetic profiles that might modify the effects of aspirin on dementia and major bleeding.
Among participants in the highest fifth of a platelet-count PGS, those assigned to aspirin had a 3.5-fold lower risk of incident dementia than those assigned to placebo (HR 0.28, 95% CI 0.15–0.52).
However, major bleeding was also more common among people with the high platelet-related genetic score who received aspirin (HR 2.13, 95% CI 1.36–3.34).
Dementia developed in 1.0% of participants receiving aspirin compared with 3.3% of those receiving placebo, and major bleeding occurred in 4.4% of aspirin recipients compared with 2.1% of those given placebo – meaning this particular genetic profile was associated with both an absolute reduction in dementia and absolute increase in major bleeding of 2.3 percentage points.
Per 1000 person-years, aspirin was associated with about five fewer dementia cases but five additional major bleeding events in this subgroup.
Lead author Dr Peter Fransquet, a research fellow at Monash University’s School of Public Health and Preventive Medicine, said previous trials had found no dementia-prevention benefit from aspirin when participants were considered as a whole.
“Our findings suggest there may be more to the story,” he told media. “It raises the possibility that genetics could one day help us identify who may benefit from a preventive treatment, rather than taking a one-size-fits-all approach.”
The study used genetic data from 13,541 participants in the ASPREE (Aspirin in Reducing Events in the Elderly) trial of daily low-dose (100mg) aspirin in healthy older adults.
Participants were aged at least 70 years in Australia and the US, or 65 years for US minorities, and had no previous cardiovascular disease, dementia, or physical disability. Their mean age was 75 years and 54.8% were female.
Over a median 4.6 years of follow-up, 345 participants developed dementia.
Researchers screened 5182 PGSs for interactions with aspirin, with 1848 scores remaining after quality control. Of these, 112 showed a nominally significant interaction with aspirin, but only three highly correlated platelet-count scores remained significant after correction for multiple testing.
The three scores appeared to capture a common platelet-related genetic signal and were derived from genetic studies of platelet count rather than directly measured platelet activation or aggregation.
The analysis found no significant interaction between aspirin and APOE genotype or genetic scores associated with Alzheimer’s disease and dementia risk.
“What’s particularly interesting is that the signal wasn’t linked to the established genetic risk factors for Alzheimer’s disease and dementia,” Dr Fransquet said.
Instead of genetic susceptibility to dementia itself, the findings point research towards platelet biology as a new avenue of investigation.
Platelet count is highly heritable, with estimates suggesting that 30% to 80% of variation may be genetically determined. Previous research has linked platelet-related processes with dementia, although most of that work has focused on platelet activation, reactivity, or aggregation rather than platelet count.
This latest study found no difference in all-cause mortality between aspirin and placebo in the highest-score group.
Researchers also noted that participants receiving placebo in this group had a higher incidence of dementia than the overall cohort, raising the possibility that very high genetically predicted platelet counts could themselves be associated with dementia risk.
However, a continuous platelet PGS was not significantly associated with dementia in the overall cohort or placebo group, suggesting any relationship might be confined to the extreme upper end of the genetic score distribution rather than following a linear pattern.
The study authors stressed that the findings were exploratory and the mechanism underlying the aspirin interaction remains uncertain. They cautioned against using the findings to guide aspirin treatment.
“People shouldn’t start taking aspirin to prevent dementia on the basis of this study without consulting with their doctor, particularly given the increased risk of serious bleeding,” Dr Fransquet said.
“We now need to confirm the finding in other studies and ultimately test it in a trial designed specifically for people with this genetic profile.”
There are currently no medications approved specifically for the primary prevention of dementia. Dementia Australia estimates that 446,500 Australians are living with dementia in 2026, with this number projected to exceed one million by 2065.
Dr Fransquet said confirmation of the genetic signal could eventually support a more targeted approach to prevention.
“If it holds up, the fact that aspirin is already cheap and widely available could make personalised dementia prevention a real possibility.”
Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 24 September 2026
