The Impact of Cognitive Reserve on Cognitive Impairment, Brain Network Pathology and Disease Trajectory in Major Depressive Disorder

Background: Cognitive reserve (CR) describes the brain's ability to buffer negative effects of disease-related structural brain alterations on cognitive functioning. Here, we analyze CR in major depressive disorder (MDD) by determining its effects on cognitive impairment, its ability to moderate the association between brain network pathology and cognitive performance, and its utility in predicting future disease progression in a two-year follow-up.Methods: CR of 539 MDD patients and 549 healthy controls was estimated from educational years, occupational attainment, and verbal IQ. We examined the effect of CR on cognitive impairment using logistic regression. We tested whether CR moderates the association of magnetic resonance imaging-based structural connectome alterations and cognitive impairment. Disease course characteristics from a two-year follow-up were predicted from baseline CR, which was benchmarked against predictive effects of environmental (childhood maltreatment) and genetic (polygenetic risk for MDD) determinants of disease course.Results: Low CR was associated with increased cognitive impairment, especially in MDD patients. CR moderated the association of mean cognitive performance with connectivity strength in a network of white matter connections. Low baseline CR predicted increased duration of depressive episodes and symptom severity after two years with predictive effect sizes on par with genetic and environmental risk factors.Conclusions: CR helps to identify MDD patients at risk for debilitating cognitive impairment and worse future disease trajectory. The moderating effect of CR on the cognition-connectome association suggests CR buffers neuropathological effects in MDD. These results call for a greater appreciation of CR in personalized treatment decisions and demand research agendas dedicated to investigating potential treatments focusing on CR.