Cognitive Reserve as a Stratification Factor for Cognitive Impairment and Disease Progression in Major Depressive Disorder.

BACKGROUND: Cognitive deficits in Major Depressive Disorder (MDD) are clinically debilitating, persist after remission, and predict worse long-term outcomes, yet factors determining which patients are most at risk remain poorly understood. Cognitive reserve (CR) - the brain's capacity to buffer negative effects of structural alterations on cognitive functioning - is assessable through brief, clinically applicable proxy measures and may serve as a practical stratification factor in MDD. METHODS: CR of 539 MDD patients (65% female) and 549 healthy controls (65% female) from the Marburg-Münster Affective Disorders Cohort Study was estimated from educational years, occupational attainment, and verbal IQ. We examined the association of CR with cognitive impairment, tested whether CR moderates the relationship between MRI-based connectome alterations and cognitive performance, and predicted two-year disease course characteristics from baseline CR, benchmarked against polygenic risk and childhood maltreatment. RESULTS: Low CR was associated with increased cognitive impairment, especially in MDD patients (OR=6.24, p=0.003). CR moderated the association between cognitive performance and white matter network connectivity (t=2.780, pFWE=0.006). Low baseline CR predicted increased episode duration and symptom severity (psFDR<0.001) over two years, with effect sizes statistically indistinguishable from those of polygenic risk and childhood maltreatment. CONCLUSIONS: CR identifies MDD patients at risk for cognitive impairment and worse disease progression, with prognostic utility comparable to polygenic risk and childhood maltreatment. The moderating effect of CR on the brain network-cognition association provides a neurobiological rationale for this vulnerability. These findings support incorporating CR into routine clinical assessment to guide risk stratification and personalized treatment planning.