Late-life depression (LLD) is highly recurrent and associated with disability and increased mortality. In this study, we aim to identify neurobiological factors that are prospectively associated with relapse risk in late-life depression. We recruited 145 older adults (age ≥ 60): 102 recently remitted LLD participants and 43 healthy comparisons. Participants underwent baseline MRI and evaluation of depression symptoms/status for up to 2 years. We evaluated intrinsic network connectivity for 111 participants (39 healthy comparisons, 47 stable remitted, 25 relapsed). Compared to healthy comparisons, LLD participants had lower connectivity within the somatomotor network and greater connectivity between the executive control and default mode networks (DMN). Lower connectivity of DMN to somatomotor and salience networks was associated with relapse. Overall, connectivity of relapse participants was more similar to healthy comparisons than connectivity of stable remitted participants was. We found robust differences in network functional connectivity between stable remitted and relapsed participants. We also found evidence of neural "scarring," or persistent functional network differences at baseline in all participants with a history of depression. Alterations in DMN connectivity were observed most prominently. Notably, the network structure of relapsed participants was more similar to healthy comparisons than stable remitted participants. These findings indicate that remission is associated with persistent functional network alterations while vulnerability to relapse is associated with a failure to establish a new stable homeostatic functional network structure.
© 2025. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.