Cognitive reserve (CR) measured by proxies of life experiences is thought to account for the heterogeneity in cognitive ageing. One hypothesis is that cognitively enriched environments acting on the noradrenergic system strengthen the right fronto-parietal networks to facilitate cognitive reserve and maintain cognition throughout the lifetime. We used machine learning and mediation analysis to model interactions between neurobiological features (genetic variants in noradrenergic signalling, structural and functional fronto-parietal connectivity) and CR (by proxy of education) on cognitive outcomes (general cognitive ability score) in the UK Biobank cohort. We show that: (1) interactions between CR and neurobiological variables more fully explain cognitive outcomes than either factor alone; (2) among the neurobiological features selected using variable importance testing, measures of fronto-parietal connectivity are the strongest mediators of the effect of CR on cognitive outcomes. Our findings offer novel insights into neurobiological basis of CR by pointing to two between-networks connectivity measures, representing connections linking the default mode network with the right fronto-parietal network, and with the executive control network, as the key facilitators of CR.

Modelling cognitive outcomes in the UK Biobank: education, noradrenaline and frontoparietal networks