AbstractBackgroundPlatelets are key mediators of inflammation and vascular dysfunction. Prior work highlighted a role of platelet function in Ab and tau dynamics, and dementia risk. We hypothesized that platelet aggregation may associate with amyloid and tau brain levels in middled age people at risk of cardiovascular disease.MethodWe examined cross sectional associations of platelet aggregation with brain amyloid and tau PET levels (11C‐labeled Pittsburgh Compound‐B (PiB) and tau (18F‐Flortaucipir (FTP)) in middle aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3 Cohort. Platelet aggregation was measured by light transmission aggregometry. The response to 0.98uM ADP stimulation was primarily evaluated followed by additional agonists and stimulation doses for sensitivity analysis. The associations were explored in multivariate regression models adjusted for age, age squared, sex, the time from blood to PET examination, and PET camera used.ResultThe final study sample included 356 participants (median [Q1,Q3] age, 55 [49, 61]; 51% women) of which 82 (23%) were on preventive platelet modifying treatments (PPT) (Table 1). We found significant interaction between PPT and platelet aggregation in their association with amyloid and tau PET levels, motivating a stratified analysis by the use or not of PPT. The platelet aggregation response was not associated with PiB or FTP retention in non‐PPT users (n = 274) (Table 2). In PPT users, the platelet aggregation response was positively associated with amyloid levels in the precuneus (β±SE: 0.36±0.14, P<0.05), and tau levels in the rhinal (β±SE: 0.49±0.15, P<0.01) and temporal regions (β±SE: 0.39±0.17, P<0.05).ConclusionOur results indicate that platelet aggregation is not associated with amyloid and tau PET levels in the general population. In people who are on PPT for primary prevention of CVD, platelet aggregation associates with amyloid and tau PET in Alzheimer’s disease (AD) relevant brain regions. This result reinforces the need for further examining the mediator role of platelet aggregation in the association of cardiovascular risk and AD.