Associations of physical frailty, depression and their interaction with incident all-cause dementia among older adults: evidence from three prospective cohorts.

Background: Physical frailty and depression may share common pathophysiological pathways associated with dementia and thus interact with each other. However, previous studies have primarily focused on the individual impact of these factors on dementia. Aims: To examine the joint effect and interaction of physical frailty and depression on the risk of all-cause dementia. Methods: We conducted prospective analyses among participants aged ≥60 years from three cohorts: the UK Biobank (UKB), the English Longitudinal Study of Ageing (ELSA) and the Health and Retirement Study (HRS). Physical frailty was assessed using modified versions of the Fried frailty phenotype. Depression was evaluated through mental health questionnaires or combined with hospital admission records. The primary outcome was incident all-cause dementia, identified via active follow-up and passive surveillance. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A total of 220 947 participants (mean age: 64.5 years; 53.3% female) were included. Over 2 832 696 person-years of follow-up, 9088 participants (7605 in UKB, 1207 in HRS and 276 in ELSA) developed incident all-cause dementia. Compared with robust individuals, frail participants faced a 155% increased risk of dementia (pooled HR: 2.55, 95% CI 2.36 to 2.76; I2=72.3%). Depression conferred a 1.59-fold excess risk for dementia (pooled HR: 1.59, 95% CI 1.50 to 1.69; I2=56.8%). Adding physical frailty and depression to a traditional dementia risk model significantly improved prediction accuracy (all p-Δarea under the curve<0.05). Jointly, participants with both physical frailty and depression exhibited the highest dementia risk (pooled HR: 3.23, 95% CI 2.86 to 3.65; I2=41.6%) compared with those without physical frailty and depression. Moreover, a significant additive interaction between physical frailty and depression was observed (pooled relative excess risk due to interaction: 0.38, 95% CI 0.13 to 0.63), with 17.1% (95% CI 6.0% to 28.3%) of dementia risk attributed to their interactive effects. Conclusions: Individuals with both physical frailty and depression had the highest risk of dementia. More importantly, these two factors interact in an additive manner, further amplifying dementia risk.