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Here, we examined a cross\u2010sectional sample of the Human Connectome Project (HCP) Aging dataset (ages 36\u2013100;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009378) to test the hypothesis that functional connectivity profiles that are related to CRF are also associated with episodic memory and executive function across middle age and older adults. To test these hypotheses, we first used connectome\u2010based predictive modeling (CPM) to identify functional connections (FCs) that were separately predictive of CRF (2\u2009Minute Walk Test), episodic memory (Rey Auditory Verbal Learning Test), and executive function (Flanker task). Briefly, this involved using nine\u2010fold cross\u2010validation to identify the top 2% of FCs most correlated with the outcome measure (e.g., CRF), adjusting for age, education, and sex. We then examined the relationship between CRF (as the predictor), cognitive function (as outcome), and FCs (as mediator or moderator). First, there was a high degree of overlap between the CRF and the cognition measure functional connectivity profiles in both the ventral attentional and limbic networks. Second, although we did not observe moderation effects, we did observe that these functional connectivity profiles fully mediated the relationship between CRF and episodic memory and partially mediated the relationship between CRF and executive function. Together, these findings suggest that the connectivities within the ventral attention network (VAN), particularly with the right mid\u2010insula, right inferior frontal gyrus, and the limbic network, are neural mechanisms that underlie the associations between CRF and cognition across the lifespan from middle to older adulthood. These findings provide insight into the potential targets (CRF) and biomarkers (functional connectivity profiles) of brain health for future interventions to improve or maintain neurocognitive health in aging.\n                  <\/jats:p>","DOI":"10.1002\/hbm.70404","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T05:30:57Z","timestamp":1763357457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Functional Connectome Mediates Associations Between Fitness and Cognition Across the Adult Lifespan"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4315-6211","authenticated-orcid":false,"given":"Junaid S.","family":"Merchant","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health, University of Maryland  College Park Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4331-4467","authenticated-orcid":false,"given":"Jeremy J.","family":"Purcell","sequence":"additional","affiliation":[{"name":"Maryland Neuroimaging Center, University of Maryland  College Park Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel D.","family":"Callow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Science School of Medicine, Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyeon","family":"Won","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yash","family":"Kommula","sequence":"additional","affiliation":[{"name":"Neuroscience and Cognitive Science Program University of Maryland  College Park Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Maryland Neuroimaging Center, University of Maryland  College Park Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Wei","sequence":"additional","affiliation":[{"name":"Neuroscience and Cognitive Science Program University of Maryland  College Park Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Woodard","sequence":"additional","affiliation":[{"name":"Department of Psychology Wayne State University  Detroit Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristy A.","family":"Nielson","sequence":"additional","affiliation":[{"name":"Department of Psychology Marquette University  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen M.","family":"Rao","sequence":"additional","affiliation":[{"name":"Center for Brain Health, Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally","family":"Durgerian","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology Imaging Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-4947","authenticated-orcid":false,"given":"Shuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry University of Maryland\u2010Baltimore  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6142-0920","authenticated-orcid":false,"given":"J. 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