Physical Activity Is Associated With Age-Related Differences in Hippocampal Macrostructure and Microstructure in Middle-Aged and Older Adults.

Physical activity is found to promote healthy brain aging that is often indexed by hippocampal structure and function; however, evidence from cross-sectional studies remains limited and inconsistent, particularly for hippocampal morphology. Discrepancies in the literature may be explained by a historical focus on volumetric analyses, which obscure nuanced changes in cortical geometry, particularly in heavily folded regions of the hippocampus. In this study, we conducted a cross-sectional analysis to examine whether moderate-to-vigorous physical activity (MVPA) was associated with hippocampal macrostructure (thickness and surface area) and microstructure (T1w/T2w ratio) among 555 cognitively healthy adults (ages 36-90 years) from the Human Connectome Project-Aging cohort. Weekly MVPA was measured using the International Physical Activity Questionnaire, and participants were categorized as low-active (≥ 0-< 150 min/week), moderately active (≥ 150-< 300 min/week), or highly active (≥ 300 min/week) according to the World Health Organization 2020 guidelines on physical activity. Hippocampal thickness, surface area, and T1w/T2w ratio were derived from unfolded hippocampal surfaces using HippUnfold. Multivariate general linear models tested linear and quadratic age effects and MVPA × age interactions separately for each hemisphere, controlling for demographic and health covariates. Among the low-active group, age was associated with widespread multivariate differences in hippocampal macrostructure and microstructure, characterized by lower regionally specific thickness and surface area and by a higher T1w/T2w ratio. MVPA moderated age-related changes in the left hippocampus, with significant effects observed in the moderate- and high-MVPA groups. These effects were characterized by greater surface area and T1w/T2w ratio and were associated with lower thickness values. These results suggest that individuals who meet or exceed physical activity recommendations exhibit distinct age-related differences in hippocampus macrostructure and microstructure compared with those who do not.