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. 2025 Jan 1;82(1):61-71.
doi: 10.1001/jamaneurol.2024.3774.

Frailty Trajectories Preceding Dementia in the US and UK

David D Ward  1   2 , Jonny P Flint  3   4   5 , Thomas J Littlejohns  6 , Isabelle F Foote  7 , Marco Canevelli  8   9   10 , Lindsay M K Wallace  11 , Emily H Gordon  1   2 , David J Llewellyn  12   13 , Janice M Ranson  12 , Ruth E Hubbard  1   2 , Kenneth Rockwood  14   15 , Erwin Stolz  16
Affiliations

Frailty Trajectories Preceding Dementia in the US and UK

David D Ward et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Foote reported receiving grants from National Institute on Aging (RF1AG073593) during the conduct of the study. Dr Rockwood reported holding copyright over the Clinical Frailty Scale and Pictorial Fit-Frail Scale, which are made freely available for noncommercial education and research, as well as nonprofit health care with completion of a permission agreement stipulating that users will not change or charge for or commercialize the scales; in addition, for-profit entities (including pharma) pay a licensing fee, 15% of which is retained by the Dalhousie University Office of Commercialization and Innovation Engagement, and all remaining license fees are donated to the Dalhousie Faculty of Medicine Advancement Fund. In the past 3 years, licenses have been negotiated with Rebibus Therapeutics Inc, Cook Research Incorporated, W.L. Gore Associates Inc, Pfizer Inc, Cellcolabs AB, AstraZeneca UK Limited, Qu Biologics Inc, Biotest AG, BioAge Labs Inc, Congenica, Icosavax Inc outside the submitted work; in addition, Dr Rockwood reported having a patent for Electronic Goal Attainment Scaling pending Application made and in the past 3 years Dr Rockwood reported receiving honoraria for invited lectures, rounds and academic symposia on frailty from: Burnaby Family Practice, Chinese Medical Association, University of Nebraska-Omaha, the Australia New Zealand Society of Geriatric Medicine, the Atria Institute, University of British Columbia, McMaster University, and the Fraser Health Authority. Dr Rockwood reported currently serving on a data safety monitoring board for EIP Pharma Inc and being a member for the past 3 years of the ADMET-2 advisory board (Johns Hopkins), and the Wake Forest University Medical School Centre advisory board. No other disclosures were reported.

Update of

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