Frailty Trajectories Preceding Dementia in the US and UK

Importance: An accessible marker of both biological age and dementia risk is crucial to advancing dementia prevention and treatment strategies. Although frailty is a candidate for that role, the nature of the relationship between frailty and dementia is not well understood. Objective: To clarify the temporal relationship between frailty and incident dementia by investigating frailty trajectories in the years preceding dementia onset. Design, Setting, and Participants: Participant data came from 4 prospective cohort studies: the English Longitudinal Study of Ageing, the Health and Retirement Study, the Rush Memory and Aging Project, and the National Alzheimer Coordinating Center. Data were collected between 1997 and 2024 and were analyzed from July 2023 to August 2024. The settings were retirement communities, national-level surveys, and a multiclinic-based cohort. Included individuals were 60 years or older and without cognitive impairment at baseline. Included individuals also had data on age, sex, education level, and ethnicity and a frailty index score calculated at baseline. Exposure: Frailty was the main exposure, with participants' degrees of frailty quantified using retrospectively calculated frailty index scores. Main Outcomes and Measures: Incident all-cause dementia ascertained through physician-derived diagnoses, self- and informant-report, and estimated classifications based on combinations of cognitive tests. Results: The participant number before exclusions was 87 737. After exclusions, data from 29 849 participants (mean [SD] age, 71.6 [7.7] years; 18 369 female [62%]; 257 963 person-years of follow-up; 3154 cases of incident dementia) were analyzed. Bayesian generalized linear mixed regression models revealed accelerations in frailty trajectories 4 to 9 years before incident dementia. Overall, frailty was positively associated with dementia risk (adjusted hazard ratios [aHRs] ranged from 1.18; 95% CI, 1.13-1.24 to 1.73; 95% CI, 1.57-1.92). This association held among participants whose time between frailty measurement and incident dementia exceeded the identified acceleration period (aHRs ranged from 1.18; 95% CI, 1.12-1.23 to 1.43; 95% CI, 1.14-1.80). Conclusions and Relevance: These findings suggest that frailty measurements may be used to identify high-risk population groups for preferential enrolment into clinical trials for dementia prevention and treatment. Frailty itself may represent a useful upstream target for behavioral and societal approaches to dementia prevention.