Frailty trajectories preceding dementia: an individual-level analysis of four cohort studies in the United States and United Kingdom

Abstract

Frailty may represent a modifiable risk factor for dementia, but the direction of that association remains uncertain. We investigated frailty trajectories in the years preceding dementia onset using data from 23,672 participants (242,760 person-years of follow-up, 2,906 cases of incident dementia) across four cohort studies in the United States and United Kingdom. Bayesian non-linear models revealed accelerations in frailty trajectories 4-9 years before incident dementia. Among participants whose time between frailty measurement and incident dementia exceeded that prodromal period, frailty remained positively associated with dementia risk (adjusted hazard ratios ranged from 1.20 [95% confidence interval, CI = 1.15-1.26] to 1.43 [95% CI = 1.14-1.81]). This observational evidence suggests that frailty increases dementia risk independently of any reverse causality. These findings indicate that frailty measurements can 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 behavioural and societal approaches to dementia prevention.

Figure 1. Participant exclusions and analytical samples.

ELSA, English Longitudinal Study of Ageing; HRS, Health and Retirement Study; MAP, Rush Memory and Aging Project; NACC, National Alzheimer’s Coordinating Center.

Figure 2. Frailty trajectories before dementia.

Plots used expected frailty index scores calculated from Bayesian mixed-effects gamma regression models that included fixed effects of time, time x event group, age, sex and education, as well as random participant intercepts and slopes. For the trajectory plots, the thicker lines are mean trajectories surrounded by 95% credible intervals and the thinner lines represent raw (unadjusted) data from 20 participants randomly selected from each group. For the forest plots, mean differences (95% confidence intervals) are between the censored group (reference line) and the incident dementia group, and the dashed line represents the estimated start of the pre-dementia frailty acceleration period. ELSA, English Longitudinal Study of Ageing; HRS, Health and Retirement Study; MAP, Rush Memory and Aging Project; NACC, National Alzheimer’s Coordinating Center.

Figure 3. Associations of frailty and incident dementia.

Hazard ratios were calculated from Cox proportional-hazards models that included covariates of age, sex and education. Sensitivity analysis 1, the pre-dementia frailty acceleration period was increased by two years; sensitivity analysis 2, deficits found to be independently associated with incident dementia were removed from the calculation of frailty index scores. Details regarding sizes of samples and subgroups included in these analyses are presented in Table 3. ELSA, English Longitudinal Study of Ageing, HRS, Health and Retirement Study; MAP, Rush Memory and Aging Project; NACC, National Alzheimer’s Coordinating Center.