Association of Platelet Aggregation With Markers of Alzheimer Disease Pathology in Middle-Aged Participants of the Framingham Heart Study.

BACKGROUND AND OBJECTIVES: Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS: In a cross-sectional study, we evaluated associations between platelet aggregation, measured by light transmission aggregometry, and amyloid (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS: Platelet aggregation response was evaluated in 382 participants (mean age 56 ± 8 years, 53% female) approximately 1.2-1.5 years before amyloid and tau PET imaging. MRI data used for the AD signature were acquired together with PET imaging or within several months. The aggregation response exhibited a nonlinear association with AD pathology. Among those in the lowest tertile of adenosine diphosphate (ADP) response, platelet aggregation response was positively associated with increased amyloid in the precuneus (β = 0.047, p = 0.020) and tau in the rhinal (β = 0.077, p = 0.012), entorhinal (β = 0.066, p < 0.020), temporal global (β = 0.063, p = 0.031), and cortical (β = 0.064, p = 0.028) regions. For the secondary outcome analysis (n = 256), platelet aggregation response was negatively associated with the MRI-based cortical thickness signature of AD risk (β = -0.002, p < 0.035), consistent with a neurodegenerative pattern. DISCUSSION: Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.