Depressive symptoms as a risk factor or prodrome of dementia: multi-state cognitive transitions modified by age and...

Whether depressive symptoms signal a risk factor or a prodromal symptom of dementia, and how this depends on age, genetic susceptibility, and cognitive stages, remains controversial.

To examine the association between depressive symptoms and incident dementia and cognitive transitions, and to test effect modification by age and AD genetic susceptibility (APOE and AD polygenic risk score [PRS]).

Longitudinal cohort study (1998-2020) using repeated assessments; incident dementia was modeled using Fine-Gray competing-risk models, and cognitive transitions were modeled with multi-state Markov models.

The U.S. Health and Retirement Study.

For the main incident dementia analysis, 13,225 dementia-free participants were included at baseline; genetic and repeated-measures analyses were restricted to 12,089 participants with complete PRS/APOE data.

Depressive symptoms were assessed with the 8-item CES-D. Cognitive status was classified as normal cognition, subjective memory complaint (SMC), cognitive impairment no dementia (CIND), or dementia. AD genetic susceptibility was indexed by APOE and AD PRS. Outcomes included incident dementia and transitions across cognitive states.

Baseline depressive symptoms (prevalence 11.3%) were associated with a higher incidence of dementia (sHR 1.24, 95% CI 1.10-1.39), with stronger associations in late midlife (50-59y: sHR 1.65) than ≥60y (sHR 1.19; P for interaction=0.001). After excluding dementia occurring within 5-10y, the associations for late midlife (but not ≥60y) remained significant (sHR for 5y=1.57; for 10y=1.55, both P for interaction≤0.030). AD PRS modified this association: depressive symptoms predicted dementia only among individuals with lower AD PRS, whereas APOE ε4 showed no modification. Multi-state analyses showed depressive symptoms accelerated progression across the cognitive continuum (e.g., normal cognition → SMC, HR=1.49; SMC → CIND, HR=1.33; CIND → dementia, HR=1.17) and reduced reversion to normal cognition. Furthermore, AD genetic susceptibility was positively associated with depressive symptom burden, specifically at the SMC stage.

Depressive symptoms in late midlife, especially with lower AD PRS, are more consistent with a potentially modifiable risk marker for dementia, whereas depressive symptoms emerging at SMC in genetically susceptible adults may more often reflect prodromal disease activity.