Sex‐specific neuropsychological correlates of apathy and depression across neurodegenerative disorders

Abstract Background Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. Objectives We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. Design, Setting and Participants We conducted a cohort analysis of participants in the COMPASS‐ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. Measurements Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. Results Groups included depressive symptoms only ( n = 70), apathy symptoms only ( n = 52), both ( n = 68), or neither ( n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory ( t (312) = −2.4, p = 0.02 and t (328) = −3.8, p = 0.001, respectively) and visuospatial reasoning ( t (301) = −2.3, p = 0.02 and t (321) = −2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex‐stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function ( t (166) = 2.4, p = 0.01) and verbal learning ( t (167) = −4.3, p = 0.001) compared to the female neither group. Conclusions This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes.