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We aimed to identify whole-brain connectivity patterns associated with transdiagnostic psychiatric dimensions and their links to mental health trajectories and mortality. We analyzed resting-state functional connectivity from the UK Biobank (N = 6529) using multivariate partial least squares analysis to identify latent variables linking brain networks with mental health symptoms. Associations with longitudinal mental health outcomes and mortality risk were examined. Validation of the psychopathology-linked connectome constructs was conducted in HCP-Aging (N = 697) and a Singapore-based community dwelling elderly cohort known as the SG70 Study (N = 943). Two robust latent variables emerged. The first represented a general psychopathology factor (p = 0.0006, 28.0% of the overall covariance), marked by altered connectivity in the somatomotor and default mode networks. The second (p &amp;lt; 0.0001, 17.2% of the overall covariance) distinguished affective disorders from alcohol use disorder via attentional and subcortical network patterns. Importantly, the general psychopathology brain scores differentiated groups with varying future depression trajectories (F(3) = 16.47, p &amp;lt; 0.0001) and were linked to elevated mortality risk (HR = 1.31, CI [1.06\u20131.62], p = 0.014). This same connectivity signature was also associated with general mental health outcomes in HCP-Aging (rho = 0.13, p = 0.015) and depression in SG70 (rho = 0.07, p = 0.031), demonstrating cross-country and multiethnic robustness. Our findings reveal a stable, interpretable brain connectome-based signature of general psychopathology in later life. This work provides insight into mechanisms of vulnerability and suggests that brain-based markers may help indicate risk and differentiate patterns of symptom persistence, transition, and remission across disorders in aging populations.<\/jats:p>","DOI":"10.1162\/imag.a.1308","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T20:02:12Z","timestamp":1783022532000},"update-policy":"https:\/\/doi.org\/10.1162\/mitpressjournals.corrections.policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional connectome signature of general psychopathology in middle-aged and older adults: Evidence from multi-cohort, multi-ethnic analyses"],"prefix":"10.1162","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1216-7747","authenticated-orcid":false,"given":"Thuan Tinh","family":"Nguyen","sequence":"first","affiliation":[{"name":"Centre for Sleep and Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwun Kei","family":"Ng","sequence":"additional","affiliation":[{"name":"Centre for Sleep and Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Voon Hao","family":"Lew","sequence":"additional","affiliation":[{"name":"Centre for Sleep and Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice Jue Xin","family":"Koi","sequence":"additional","affiliation":[{"name":"Centre for Sleep and Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Liang","family":"Loh","sequence":"additional","affiliation":[{"name":"Centre for Sleep and Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woon-Puay","family":"Koh","sequence":"additional","affiliation":[{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"},{"name":"Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0180-8648","authenticated-orcid":false,"given":"Juan Helen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Centre for Sleep and Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Healthy Longevity & Human Potential Translational Research Program and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"},{"name":"Department of Electrical and Computer Engineering & Integrative Sciences and Engineering Programme (ISEP), NUS Graduate School, National University of Singapore, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"281","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"2026072015555261700_IMAG.a.1308-b1","article-title":"Manual for the ASEBA adult forms & profiles","author":"Achenbach","year":"2003"},{"key":"2026072015555261700_IMAG.a.1308-b2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.neuroimage.2017.10.034","article-title":"Image processing and quality control for the first 10,000 brain imaging datasets from UK 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