AbstractBackgroundCortical thinning occurs with brain ageing and is a hallmark of neurodegenerative diseases, especially Alzheimer’s disease. While there is growing evidence that physical activity facilitates neuroplasticity and has neuroprotective effects, its influence on cortical thickness remains largely unexplored. We therefore aimed to elucidate 1) whether objectively‐assessed physical activity is associated with cortical thickness, and 2) which molecular mechanisms could underlie this association.MethodOur source population consisted of the first 5,000 participants of the Rhineland Study, a prospective cohort study in Bonn (Germany), from which we included data of 2,649 participants (57.6% female, mean age: 54.7 years (range: 30 – 94 years)) with valid physical activity and MRI measurements. Free‐living physical activity was measured continuously over seven days using activPAL3 accelerometers. Physical activity measures included average daily metabolic equivalent (MET)‐hours, total step count and minutes spent stepping as well as average daily percentage of time (%) spent performing sedentary, light‐intensity and moderate‐to‐vigorous physical activities. We obtained cortical thickness estimates from 3T MRI scans using FreeSurfer. The association of physical activity and cortical thickness was examined using multivariable regression, with physical activity as independent and cortical thickness as dependent variables, while adjusting for age, sex, education and smoking status. Using gene expression profiles from the Allen Brain Atlas, we subsequently assessed which molecular signatures were associated with vertex‐wise effects of physical activity on cortical thickness.ResultMore daily MET‐hours and step minutes were associated with higher mean precentral thickness (standardised effects: MET‐hours, ß=0.01 mm2/hour, 95% CI: 0.001–0.019; step counts, ß=0.01 mm2/3145 steps, 95% CI: 0.001–0.019). However, mean lateral‐occipital thickness decreased by 0.018 mm2 (95% CI: ‐0.027 – ‐0.01) for each standard deviation increase in %time spent in light‐intensity activities. Whole brain vertex‐wise analysis demonstrated that higher physical activity levels were related to larger cortical thickness in frontal and temporal areas, but lower cortical thickness in parietal and occipital areas. The largest positive effects were observed in regions enriched for genes involved in mitochondrial respiration.ConclusionPhysical activity is associated with cortical thickness, but its effect is not uniform across the brain. Physical activity may particularly benefit cortical regions with a relatively high oxidative demand.