Abstract
BACKGROUND: Late-life depression (LLD) is associated with cognitive impairment and an elevated risk of dementia, yet the influence of age at depression onset on cognitive prognosis remains unclear. Emerging evidence suggests that late-onset depression, defined as first depressive episode in later adulthood, may reflect distinct neuropathological mechanisms and predict more severe cognitive decline and greater dementia risk than early-onset depression. AIMS: This study aimed to investigate whether late-onset depression is linked to domain-specific cognitive impairment and higher risk of incident dementia among older adults with major depressive disorder. METHOD: We analysed UK Biobank data from older adults (aged ≥60 years) with primary care linkage, classifying participants into depression-free controls, early-life depression, late-life depression with early onset (LLD-EO) and late-life depression with late onset (LLD-LO). Cognitive performance across these five domains was assessed cross-sectionally at baseline using touchscreen tasks. Incident dementia was evaluated prospectively using clinical records up to 2022. Multi-level models with inverse-probability weighting and survey-adjusted mixed modelling were applied to assess group differences in cognitive function, controlling for demographic covariates, lifestyle factors and physical and mental health conditions. A Cox regression model was employed to estimate dementia risk among groups. RESULTS: Among 75 064 participants aged ≥60 years, the LLD-LO group (n = 4858) showed significantly worse cognitive performance than healthy controls, particularly on fluid intelligence and visuospatial memory. The LLD-LO group performed worse than LLD-EO on fluid intelligence. During follow-up, LLD-LO was associated with a higher risk of incident dementia (hazard ratio 1.42-1.52) across all adjusted models. Deficits in fluid intelligence and visuospatial memory partially mediated the link between LLD-LO and subsequent dementia. CONCLUSIONS: Late-onset depression showed more severe impairment in fluid intelligence compared with LLD-EO. Late-onset depression was associated with increased incident dementia compared with depression-free individuals.