Life-course leisure-time physical activity benefits cognitive health through decelerating epigenetic ageing acceleration: results from a large prospective cohort study

Abstract Background Leisure-time physical activity (LTPA) in mid-to-old life is recommended for cognitive management, but evidence linking life-course LTPA to cognitive health remains underexplored. Objective To integrate life-course LTPA, epigenetic ageing acceleration (EAA) and longitudinal cognitive outcomes. Design Prospective cohort study. Setting Health and Retirement Study (HRS) 2016/2017–2022/2023. Subjects 9131 participants aged 69.4 ± 9.6. Methods LTPA in 18–29y, 30–39y, 40–49y and ≥50y were quantified. Cognitive impairment no dementia (CIND) and dementia were defined using the Langa-Weir algorithm. Multi-domain cognitive function was assessed. Acceleration of 13 DNAm clocks was computed. Results Over 6 years, 474 (5.2%) participants developed dementia. We found L-shaped associations between LTPA of all age groups and incident dementia. Trajectory analysis identified four life-course LTPA groups, characterised by late emerging after age 50y (20.1%), intensified (21.7%) since one’s 20s, weakened (21.9%) and persistently active (36.3%). Intensified or persistently active (vs. late emerging) LTPA trajectories exhibited 31% and 28% lower dementia risks, particularly amongst those aged <65y or obese. The persistently active LTPA trajectory was associated with 21% fewer progressions from normal cognition to CIND, whereas 49% more frequent reversals. Additionally, engaging in life-course LTPA was linked to better episodic memory, quantitative reasoning, mental status and semantic verbal fluency in later life, which was partially mediated by GrimAge and Zhang Accel. For instance, decelerated GrimAge Accel mediated 16.0% and 5.8% of the impacts of intensified and persistently active LTPA on global cognition. Conclusions LTPA since early life can help decelerate EAA, thereby preserving cognitive health, particularly before the prodromal dementia stage.