Introduction Physical inactivity and female sex are independently associated with increased Alzheimer's disease (AD) lifetime risk. This study investigates the possible interactions between sex and physical activity on neuroimaging biomarkers. Methods In 134 cognitively unimpaired older adults (≥65 years, 82 women) from the Age‐Well randomized controlled trial (baseline data), we investigated the association between physical activity and multimodal neuroimaging (gray matter volume, glucose metabolism, perfusion, and amyloid burden), and how sex modulates these associations. Results The anterior cingulate cortex volume was independently associated with sex and physical activity. Sex and physical activity interacted on perfusion and amyloid deposition in medial parietal regions, such that physical activity was related to perfusion only in women, and to amyloid burden only in men. Discussion Physical activity has both sex‐dependent and sex‐independent associations with brain integrity. Our findings highlight partly distinct reserve mechanisms in men and women, which might in turn influence their risk of AD. Highlights Sex and physical activity have been linked to Alzheimer's disease (AD) progression. The association of sex and physical activity with brain health is partly independent. Different reserve mechanisms exist in men and women.

Background Physical inactivity in older adults has been linked to an increased risk of dementia. On the other hand, increasing evidence indicates that sex is likely to influence Alzheimer’s disease (AD) pathophysiology, leading to a differential susceptibility to the disease in women versus men. We propose to investigate the interplay between sex and physical activity on brain integrity. Method We included baseline data of 134 cognitively unimpaired older adults (>65 years old, 82 women; Table) from the Age‐Well randomized control trial. They underwent multimodal neuroimaging, including structural MRI, FDG‐ and AV45‐PET, providing measures of grey matter volume (GMv), glucose metabolism, perfusion and Aβ burden. The Modifiable Activity Questionnaire was used to measure leisure time physical activity over the last 12 months. We assessed 1) the effect of sex on the amount of physical activity reported, 2) the main effects of sex and physical activity on each neuroimaging measure and 3) the interaction between sex and physical activity on the same variables. All analyses were controlled for age, education and APOE4 status. Result There was no sex differences in physical activity levels. GMv and brain perfusion in frontal medial regions were associated with both sex and physical activity, such that volume and perfusion were higher in women than in men and increased as a function of physical activity, without significant interaction between both terms. In contrast, there was an interaction between sex and physical activity on precuneus and posterior cingulate cortex perfusion and, at a trend level, on Aβ deposition (Figure). More specifically, the effect of physical activity on perfusion was stronger in women (higher activity being associated with higher perfusion), while its effect on amyloid burden was stronger in men (higher activity being associated with lower amyloid burden). Conclusion Our results suggest that physical activity has both sex‐dependent and sex‐independent effects on markers of brain integrity. Interestingly, the interaction between physical activity and biological sex suggests the existence of different reserve mechanisms in men and women, which might in turn influence their risk of AD.