Functional connectome signature of general psychopathology in middle-aged and older adults: Evidence from multi-cohort, multi-ethnic analyses

Mental health disorders are increasingly prevalent in middle-aged and older adults, a population undergoing substantial brain network reorganization. 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 < 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 < 0.0001) and were linked to elevated mortality risk (HR = 1.31, CI [1.06-1.62], 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.