Physical Activity, Alzheimer Plasma Biomarkers, and Cognition.

Importance: Physical activity (PA) is a nonpharmacological intervention for dementia prevention. The association between PA and Alzheimer disease (AD) plasma biomarkers remains underexplored. Objective: To investigate the associations among PA; plasma biomarkers, including β-amyloid 42/40 (Aβ42/40), phosphorylated-tau217 (ptau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL); and cognition. Design, Setting, and Participants: This cross-sectional study included participants with and without cognitive impairment recruited from multiple memory clinics in South Korea between May 2019 and May 2022. Data were analyzed from June to December 2024. Exposures: PA was assessed as metabolic equivalent task minutes per week using the International Physical Activity Questionnaire and categorized into quartiles from the lowest (Q1) to the highest (Q4). Main Outcomes and Measures: Plasma Aβ42/40, ptau217, GFAP, and NfL were measured. Cognition was assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Results: Among 1144 participants (mean [SD] age 70.9 [8.7] years; 744 [65.0%] female), the highest PA quartile showed significantly lower ptau217 (estimate [SE], -0.14 [0.06]; P = .01) and NfL (estimate [SE], -0.12 [0.05]; P = .01) compared with the lowest quartile. Higher PA quartiles were associated with higher MMSE scores (estimate [SE]: Q2, 0.93 [0.31]; P = .003; Q3, 0.82 [0.32]; P = .009; Q4, 0.94 [0.32]; P = .004) and lower CDR-SB scores (estimate [SE]: Q2, -0.33 [0.16]; P = .04; Q3, -0.37 [0.16]; P = .02; Q4, -0.55 [0.16]; P = .001) after adjusting for age, sex, education years, and β-amyloid uptake. In subgroup analyses according to age and cognitive status, the associations of PA and plasma biomarkers with cognition were more pronounced in the older (age ≥65 years) and cognitively impaired groups compared with the younger and cognitively unimpaired groups. Conclusions and Relevance: These findings suggest that PA may help delay cognitive decline by modulating neurodegeneration and AD-specific tau pathologies. However, the cross-sectional design limits causal inference, and longitudinal studies are needed to confirm and clarify these associations.