Association of Early-, Middle-, and Late-Life Depression With Incident Dementia in a Danish Cohort

Importance: Late-life depressive symptoms are associated with subsequent dementia diagnosis and may be an early symptom or response to preclinical disease. Evaluating associations with early- and middle-life depression will help clarify whether depression influences dementia risk. Objective: To examine associations of early-, middle-, and late-life depression with incident dementia. Design, Setting, and Participants: This was a nationwide, population-based, cohort study conducted from April 2020 to March 2023. Participants included Danish citizens from the general population with depression diagnoses who were matched by sex and birth year to individuals with no depression diagnosis. Participants were followed up from 1977 to 2018. Excluded from analyses were individuals followed for less than 1 year, those younger than 18 years, or those with baseline dementia. Exposure: Depression was defined using diagnostic codes from the International Classification of Diseases (ICD) within the Danish National Patient Registry (DNPR) and Danish Psychiatric Central Research Register (DPCRR). Main Outcomes and Measure: Incident dementia was defined using ICD diagnostic codes within the DPCRR and DNPR. Cox proportional hazards regression was used to examine associations between depression and dementia adjusting for education, income, cardiovascular disease, chronic obstructive pulmonary disease, diabetes, anxiety disorders, stress disorders, substance use disorders, and bipolar disorder. Analyses were stratified by age at depression diagnosis, years since index date, and sex. Results: There were 246 499 individuals (median [IQR] age, 50.8 [34.7-70.7] years; 159 421 women [64.7%]) with diagnosed depression and 1 190 302 individuals (median [IQR] age, 50.4 [34.6-70.0] years; 768 876 women [64.6%]) without depression. Approximately two-thirds of those diagnosed with depression were diagnosed before the age of 60 years (684 974 [67.7%]). The hazard of dementia among those diagnosed with depression was 2.41 times that of the comparison cohort (95% CI, 2.35-2.47). This association persisted when the time elapsed from the index date was longer than 20 to 39 years (hazard ratio [HR], 1.79; 95% CI, 1.58-2.04) and among those diagnosed with depression in early, middle, or late life (18-44 years: HR, 3.08; 95% CI, 2.64-3.58; 45-59 years: HR, 2.95; 95% CI, 2.75-3.17; ≥60 years: HR, 2.31; 95% CI, 2.25-2.38). The overall HR was greater for men (HR, 2.98; 95% CI, 2.84-3.12) than for women (HR, 2.21; 95% CI, 2.15-2.27). Conclusions and Relevance: Results suggest that the risk of dementia was more than doubled for both men and women with diagnosed depression. The persistent association between dementia and depression diagnosed in early and middle life suggests that depression may increase dementia risk.