Differential associations of engagement in physical activity and estimated cardiorespiratory fitness with brain volume in middle-aged to older adults

Previous work has confirmed the benefits of aerobic exercise for brain aging, however mechanisms underlying these effects remain unclear. Two measures of exercise, time spent in moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF), may reflect different pathways linking activity to brain health. Using data from the UK Biobank, the largest sample combining neuroimaging and objectively measured MVPA available to date (n = 7148, n_male = 3062, n_female = 4086; age = 62.14 ± 7.40 years), we found that, when adjusted for covariates including MVPA, CRF was positively associated with overall gray matter volume (FDR p = 1.28E-05). In contrast, when adjusted for covariates including CRF, MVPA was positively associated with left and right hippocampal (FDR p_left = 0.01; FDR p_right = 0.02) volumes, but not overall gray matter volume. Both CRF and MVPA were inversely associated with white matter hyperintensity lesion loads (FDR p_CRF = 0.002; p_MVPA = 0.02). Our results suggest separable effects of engagement in exercise behaviors (MVPA) and the physiological effects of exercise (CRF) on structural brain volumes, which may have implications for differential pathways linking exercise and brain benefits.