Frailty transitions, depressive symptoms, and incident dementia: findings from four longitudinal studies.

BACKGROUND: Frailty is a potentially reversible risk factor for dementia. Whether frailty reversal actively reduces dementia risk across diverse populations, and the extent to which depressive symptoms mediate this pathway, remains unclear. METHODS: We included 59,331 adults aged ≥50 from the Health and Retirement Study (HRS), the China Health and Retirement Longitudinal Study (CHARLS), the Survey of Health, Ageing and Retirement in Europe (SHARE), and the English Longitudinal Study of Ageing (ELSA). A harmonized 25-item FI defined frailty (FI ≥ 0.25). Primary exposures were baseline frailty status and frailty transitions between the first two waves, evaluated within baseline strata as worsening versus stable non-frail status and improvement versus stable frail status. Mean FI and FI change were also examined. RESULTS: Over 7.51 ± 2.09 years, 5629 participants (9.49%) developed dementia. Baseline frailty was associated with higher risk (HRs, 1.35-2.23), as was frailty worsening (HRs, 1.43-2.53). Frailty reversal was associated with lower risk in SHARE (HR, 0.55) and CHARLS (HR, 0.70); associations in ELSA and HRS were not statistically significant. Estimated mediation proportions for depressive symptoms ranged from 29.29% to 44.78%. CLPN analyses showed cross-lagged associations in three cohorts for walking limitations, difficulty managing finances, and psychiatric problems. CONCLUSION: Frailty worsening was associated with higher dementia risk, whereas frailty improvement was associated with lower risk in some cohorts. Depressive symptoms showed indirect associations with incident dementia for both baseline frailty and frailty worsening. However, whether interventions targeting frailty and depressive symptoms can reduce dementia incidence remains to be determined in future interventional studies.