Sex differences in the impact of BDNF genotype on the longitudinal relationship between physical activity and cognitive performance

Background: Physical activity may preserve cognitive function in older adults, but benefits vary by sex and genetic factors. Objective: We tested the longitudinal association between physical activity and cognitive performance to de termine whether a common genetic polymorphism for brain-derived neurotrophic factor (BDNF Val66Met) moderated this effect. Methods: In a 12-year longitudinal population-based sample of older adults (n = 2,218), we used growth curve modeling to investigate whether the benefits of physical activity on cognitive preservation differed by BDNF genotype and sex across multiple cognitive domains including processing speed, attention, working memory, and episodic verbal memory. Results: The relationship between physical activity and cognitive performance was dependent on BDNF carrier status in males (Δχ² [Δdf] = 12.94 [4], p = 0.01), but not in females (Δχ² [Δdf] = 4.38 [4], p = 0.36). Cognition benefited from physical activity in male BDNF met noncarriers, but not met carriers, whereas cognition was not statistically significantly related to physical activity in females regardless of genotype. Conclusion: We observed longitudinal, but not cross-sectional, effects of physical activity on cognitive performance. Our study highlights the importance of longitudinal follow-up and consideration of sex differences in the relationships between physical activity, BDNF genotype, and cognitive decline. The findings contribute to understanding gene-lifestyle interactions in promoting cognitive health.