The Functional Connectome Mediates Associations Between Fitness And Cognition In Aging

Cardiorespiratory fitness (CRF) is increasingly recognized as an important factor in supporting neural and cognitive function, especially in older age. PURPOSE: This study leverages the Human Connectome Project (HCP) Aging dataset (ages 36-100 years; N = 378) to test the hypothesis that functional connectivity profiles that are related to CRF are also associated with episodic memory and executive function. METHODS: Using connectome-based predictive modeling (CPM), we separately identified functional connectivity profiles obtained from resting-state fMRI scans that were predictive of CRF (2-Minute Walk Test), episodic memory (Rey Auditory Verbal Learning Test) and executive function (Flanker task). Briefly, this involved using nine-fold cross validation to identify the top 2% of functional connections that were the most correlated to the outcome measure (e.g., CRF) adjusting for age, sex, and education. We then assessed the relationship between CRF (as the predictor), cognitive function (as outcome), and functional connectivity profiles (as mediator or moderator). RESULTS: Substantial overlap was found in the functional connectivity profiles predictive of CRF and cognitive performance within both the ventral attentional and limbic networks. While no moderation effects were observed, the connectivity profiles fully mediated the positive association between CRF and episodic memory performance (mediation proportion = .29, p = .016) and partially mediated the association between CRF and executive function performance (mediation proportion = .20, p = .001). CONCLUSION: These findings highlight the potential role of functional connectivity within the ventral attention and limbic networks, particularly the connections within and between the insular cortex, as a mechanism linking fitness to cognition in the aging brain. Both CRF and these brain connectivity profiles could serve as promising targets for interventions aimed at improving neurocognitive aging. Supported by: NIH-NIA R56AG078366