Cognitive Reserve and Depression Vulnerability: Prospective Evidence from the UK Biobank

Cognitive reserve (CR) may contribute to individual differences in vulnerability to depression, but prospective evidence remains limited. We aimed to investigate the prospective association between a constructed CR proxy and incident depression, and to explore its inflammatory and neuroanatomical correlates. We included 309,137 participants with 14.08-year follow-up from UK Biobank, among whom 14,853 (4.8%) incident depression cases occurred. CR was constructed by averaging z-scores of educational attainment and occupational status into tertile groups. This construction was supported by principal component analysis and restricted cubic splines confirmed a nonlinear association. Under restricted mean survival time analysis (τ = 10), medium and high CR were respectively associated with 0.166 and 0.183 additional depression-free years. Compared with low CR, depression risk was lower in the medium (medium CR: HR = 0.61, 95% CI [0.58, 0.64]) and high (HR = 0.54, 95% CI [0.52, 0.57]) CR groups (both FDR-corrected P < 2 × 10⁻¹⁶). These findings remained robust across multiple sensitivity analyses. Exploratory analyses suggested that neutrophil count and seven additional markers partly accounted for the CR–depression association. Further, higher CR was associated with larger grey matter volumes (GMVs) in 85 regions, most prominently in the hippocampus and thalamus regions. In an external Chinese cross-sectional sample, high CR showed directionally consistent association with lower odds of depressive symptoms (OR = 0.433, 95% CI [0.214, 0.864], P = 0.033). These findings suggest that CR should be considered as a reserve-related background when evaluating depression vulnerability, alongside symptoms, inflammatory markers, and neuroimaging features.