AbstractBackgroundPhysical activity is associated with a reduced risk of dementia. Although physical activity induces potent neuroprotective effects in animals, human studies assessing its effects on brain structure are sparse and inconclusive. The discrepancies in human studies may have been due to application of subjective physical activity measures, low spatial‐resolution imaging or small sample sizes. Therefore, we aimed to assess whether objectively quantified physical activity levels are associated with detailed measures of brain structure in a large cohort study.MethodOur analyses were based on data of the first 4,000 participants (56.6% female, mean age: 55.2 years (range 30 – 95 years)) of the Rhineland Study, a population‐based prospective cohort study in Bonn, Germany. Free‐living physical activity over seven days was continuously measured using the ActivPAL™ accelerometer. Average daily physical activity measures included metabolic equivalent (MET)‐hours, total step count, as well as minutes spent stepping or performing light and moderate‐to‐vigorous physical activities. Grey matter (GM), white matter (WM) and total brain volume (TBV) estimates were obtained from 3T MRI scans using FreeSurfer. Multivariable regression models were used to examine the association between physical activity and brain structure, with physical activity levels as independent and brain structure measures as dependent variables, while adjusting for age, sex, intracranial volume, education and smoking status.ResultDaily MET‐hours were associated with all volumetric measures of brain structure (effect estimates [in cm3/hour] for TBV: ß=2.36, 95% CI: 1.05 – 3.67; GM: ß=0.82, 95% CI: 0.15 – 1.50; WM: ß=0.97, 95% CI: 0.08 – 1.85). Importantly, we found a significant interaction between the effects of MET‐hours and age on TBV: in participants below median age the effect of MET‐hours on TBV was 0.28 cm3/hour (95% CI: ‐1.40 – 1.97), while in those above median age the effect was 2.01 cm3/hour (95% CI: 0.08–3.94). Overall, we obtained comparable findings for other physical activity measures as well (data not shown).ConclusionPhysical activity was consistently associated with grey matter, white matter and total brain volumes in a large cohort of individuals from the general population. These findings suggest that promoting physical activity could be critical in the prevention of age‐associated brain atrophy.