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BACKGROUND: Age-related cholinergic dysfunction within the basal forebrain (BF) is associated with cognitive decline and Alzheimer’s disease (AD) in older adults. Accumulating evidence suggests that higher cardiorespiratory fitness (CRF) is linked to neuroprotective effects. However, we have yet to understand the associations between CRF, BF cholinergic function, and cognitive function in older adults. In humans, resting state functional connectivity (rsFC) using functional MRI (fMRI) is useful to characterize the functional aspect of the BF cholinergic connectivity. PURPOSE: 1) To investigate the relationships between CRF-BF rsFC, CRF-cognitive performance, and BF rsFC-cognitive performance in older adults; 2) To investigate the moderating effects of CRF in the relationship between BF rsFC and cognitive function; 3) To investigate the possibility of BF rsFC as a neurophysiological mechanism underpinning the association between CRF and cognitive function in older adults. METHODS: We utilized a publicly available dataset from the Nathan Kline Institute Rockland Sample in which CRF, cognitive test scores (e.g., Rey Auditory Verbal Learning Test, Delis-Kaplan color-word Interference test, and D Delis-Kaplan trail making test), and fMRI data are available in a large sample of older adults. Resting-state fMRI were preprocessed using a rigorous method and valid image processing software. Linear regression models were used to assess the associations between CRF, BF rsFC, and cognitive performance in Specific Aim 1. Sex-dependent differences in the BF rsFC were also investigated as a post-hoc analysis. The interaction between CRF and BF rsFC on cognitive performance was tested using linear regression and analysis of covariance (ANCOVA) for Specific Aim 2. Mediation analysis was administered to examine the possible mediating role of BF rsFC in the relationship between CRF and cognitive function (Specific Aim 3). RESULTS: There was an association between higher CRF and greater NBM rsFC in older adults. There were significant correlations between CRF, CRF-related NBM rsFC, and trail making test performance only in women. Importantly, higher CRF was associated with better Trail Making performance through greater NBM rsFC in females. Lastly, higher CRF was associated with a greater positive association between NBM rsFC and Color-Word Interference performance in older women. CONCLUSION: Higher CRF is associated with greater NBM rsFC in older adults. The association between higher CRF and better executive function performance, however, was evident only in females. Our results further provide evidence that the NBM rsFC may be an underlying neural mechanism in the relationship between CRF and executive function specifically in older women. Hence, sex differences may exist within the CRF-related neuroprotective effects on the NBM functional network and executive function.