Brain-predicted age difference is associated with the progression of subthreshold depression: evidence from the UK Biobank

Background: Previous studies have reported accelerated brain aging in individuals with major depressive disorder (MDD) compared to healthy controls. However, these findings are based primarily on cross-sectional data, limiting dynamic association between brain aging and MDD. Here, we examined the relationship between brain aging and MDD progression by focusing on subthreshold depression, a prodromal stage of MDD, and aimed to determine whether quantitative markers of brain aging exhibit a stable association with disease progression. Methods: Using neuroimaging data from the UK Biobank and a support vector regression (SVR) model, we predicted brain age in individuals who exhibited subthreshold depressive symptoms at baseline but showed divergent mental status at follow-up, and then conducted between-group comparisons. Logistic regression was then applied to assess whether brain-predicted age difference (Brain-PAD) stably associates with the progression of subthreshold depression after adjusting for covariates. Results: Individuals with subthreshold depression showed a higher risk of progression to MDD compared to healthy controls. Those whose condition worsened from subthreshold depression to MDD exhibited greater brain aging than those who remained subthreshold or recovered. Importantly, Brain-PAD remained significantly and stably associated with this progression after controlling for sex, ethnicity, lifestyle, and socioeconomic factors. Conclusions: This study supports an association between brain aging and MDD progression and demonstrates a robust association between an increased Brain-PAD and the conversion from subthreshold depression to MDD. These findings enhance our understanding of MDD's developmental trajectory and suggest that Brain-PAD may facilitate early detection and intervention targeting brain aging.