Sex influences whether hippocampal volumes mediate the relationship between depression and cognition in older adults without dementia: A UK Biobank study

Depression is a modifiable risk factor for dementia; however, it remains unclear whether there are sex differences in how depression affects dementia risk. To better understand sex-specific differences in how depression confers risk of dementia, the link between depression, hippocampal volumes, and cognition was evaluated in a sample of older adults without dementia from the UK Biobank cohort. A total of 18,220 participants (women n = 9,474; men n = 8,746) were selected based on completion of the Patient Health Questionnaire (PHQ-9), structural MRI, and cognitive assessments. Causal mediation analyses were used to evaluate if the relationship between depression and cognition is mediated by the hippocampus differently by sex. Women reported greater depression severity than men. Hippocampal volumes were found to mediate the relationship between depression severity and fluid intelligence only in women. Upon categorization of the depression symptoms as either cognitive/affective or somatic, the mediation effect of the hippocampus was seen for both cognitive/affective and somatic symptom severity in women for fluid intelligence. These results offer insight into the sex-specific pathways underlying the relationship between depression, hippocampal volumes, and cognition in older adults without dementia with a focus on the type of depression symptoms. This knowledge could aid in the development of sex-focused dementia prevention strategies and treatments.