Brain structure and connectivity mediate the association of lifestyle and cognition: the Maastricht study

Abstract Life-course exposure to risk and protective factors impacts brain macro- and micro-structure, which in turn affects cognition. The concept of Brain Age Gap (BAG) assesses brain health by comparing an individual’s neuroimaging-based predicted age with their calendar age. Higher BAG implies accelerated brain aging and is expected to be associated with worse cognition. In this study, we comprehensively modelled mutual associations between brain-health and lifestyle factors, brain age, and cognition in a large, middle-aged population. For this study, cognitive test scores, lifestyle, and 3T MRI data for n=4881 participants (mean age (±SD) = 59.2 (±8.6), 50.1% male) were available from The Maastricht Study, a population-based cohort study with extensive phenotyping. Whole brain volumes (grey matter (GM), cerebrospinal fluid (CSF), white matter hyperintensity (WMH)), cerebral microbleeds (CMB), and structural white matter connectivity were calculated. Lifestyle factors were combined into an adapted LIfestyle for BRAin health (LIBRA) weighted sum score, with higher score indicating greater dementia risk. Cognition was calculated by averaging z-scores across three cognitive domains (memory, information processing speed, executive function and attention). BAG was calculated by comparing calendar age to predictions from a neuroimaging-based multivariable regression model. Paths between LIBRA tertiles, BAG and cognitive function were tested using linear regression and structural equation modelling, adjusting for sociodemographic and clinical confounders. Results show that CSF, GM, WMH and CMB best predicted BAG (R2 = 0.455, RMSE = 6.44). In regression analysis, higher LIBRA scores (greater dementia risk) were associated with higher BAG (standardized regression coefficient ß = 0.126, p < 0.001) and worse cognition (ß = -0.046, p = 0.013), while higher BAG was associated with worse cognition (ß=-0.163, p<0.001). In mediation analysis, 24.7% of the total difference in cognition between the highest and lowest LIBRA tertile was mediated by BAG (ßindirect = -0.049, p < 0.001; ßtotal = -0.198, p < 0.001), and an additional 3.8% was mediated via connectivity (ßindirect = -0.006, p < 0.001; ßtotal = -0.150, p < 0.001). Findings suggest that associations between health- and lifestyle-based risk/protective factors (LIBRA) and cognition can be partially explained by structural brain health markers (BAG) and white matter connectivity markers. Lifestyle interventions targeted at high-risk individuals in mid to late life may be effective in promoting and preserving cognitive function in the general public.