Hippocampal volume mediates the association between depression and cognitive function differently by sex

Abstract

AbstractBackgroundSex differences are prominent features of both depression and Alzheimer’s disease, with women showing an increased lifetime risk relative to men. However, the neural mechanisms that explain sex differences in the relationship between depression and cognition are poorly understood. The goal of this study was to evaluate whether smaller brain volumes mediate the relationship between higher depression symptom severity and poorer cognition, and whether this association differed by sex.MethodUK Biobank participants were included in the sample based on availability of demographic variables, mental health assessments, structural MRI scans, and four cognitive measures (Fluid Intelligence, Numeric Function, Pairs Matching, and Symbol Digit Substitution). Depression symptom severity was evaluated using the Patient Health Questionnaire (PHQ‐9). The indirect effect of depression symptom severity on cognition via hippocampal volumes was evaluated using causal mediation analyses. Models were adjusted for age, sex, APOE‐e4 status, and Townsend Deprivation Index, a measure of material deprivation (Fig.1). A priori sex‐stratified models evaluated sex differences. Exploratory analyses assessed the indirect effect of depressive symptom severity on cognition with amygdalar and total brain volumes as separate mediators. The significance of indirect effects was evaluated using bootstrapping procedures.ResultThe study sample consisted of 39,692 middle‐aged and older adults (53% women, mean age±SD = 64.1±7.6 years, 28% APOE‐e4 carriers). Hippocampal and amygdalar volumes mediated the effect of depression symptom severity on cognition, for Fluid Intelligence, Numeric Function, and Symbol Digit Substitution, but not Pairs Matching. Total brain volume mediated the effect of depression symptom severity on Symbol Digit Substitution performance (Fig.1, Table1). In sex‐stratified analyses, the effect of depression symptom severity on Fluid Intelligence, Numeric Function, and Symbol Digit Substitution was mediated by hippocampal and amygdalar volumes in women. In men, the effect of depression symptom severity on Symbol Digit Substitution was mediated by total brain volume (Table2).ConclusionDepression symptom severity influences cognition via hippocampal and amygdalar volumes in women, while in men, total brain volume mediated the relationship with cognition. These data suggest sex‐specific neural pathways for the relationship between depression and cognition.