Article Text

Original research
Cumulative health deficits, APOE genotype, and risk for later-life mild cognitive impairment and dementia
  1. David D Ward1,2,
  2. Lindsay M K Wallace3,
  3. Kenneth Rockwood1,2
  1. 1 Geriatric Medicine Research, Centre for Health Care of the Elderly, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada
  2. 2 Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  3. 3 Faculty of Graduate Studies, Dalhousie University, Halifax, Nova Scotia, Canada
  1. Correspondence to Professor Kenneth Rockwood, Geriatric Medicine Research, Centre for Health Care of the Elderly, Nova Scotia Health Authority, Halifax, Canada; kenneth.rockwood{at}


Objective To determine whether health-deficit accumulation is associated with the risks of mild cognitive impairment (MCI) and dementia independently of APOE genotype.

Methods A frailty index was calculated using the deficit-accumulation approach in participants aged 50 years and older from the National Alzheimer’s Coordinating Center. Cognitive status was determined by clinical evaluation. Using multistate transition models, we assessed the extent to which an increasing degree of frailty affected the probabilities of transitioning between not cognitively impaired (NCI), MCI, and dementia.

Results Participants (n=14 490) had a mean age of 72.2 years (SD=8.9 years; range=50–103 years). Among those NCI at baseline (n=9773), each 0.1 increment increase in the frailty index was associated with a higher risk of developing MCI and a higher risk of progressing to dementia. Among those with MCI at baseline (n=4717), higher frailty was associated with a higher risk of progressing to dementia, a lower probability of being reclassified as NCI, and a higher likelihood of returning to MCI in those that were reclassified as NCI. These risk effects were present and similar in both carriers and non-carriers of the APOE ε4 allele.

Conclusion Among older Americans, health-deficit accumulation affects the likelihood of progressive cognitive impairment and the likelihood of cognitive improvement independently of a strong genetic risk factor for dementia. Frailty represents an important risk factor for cognitive dysfunction and a marker of potential prognostic value.

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  • Twitter @David_D_Ward, @WallaceLindsay, @Krockdoc

  • Contributors DDW and KR designed and conceptualised the study; DDW analysed the data, wrote the first draft, and revised all drafts; DDW, LMKW, and KR interpreted the data; LMKR and KR reviewed all drafts; KR supervised the project.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests KR has asserted copyright of the Clinical Frailty Scale through Dalhousie University’s Industry, Liaison, and Innovation Office. Use is free for education, research, and not-for-profit health care. Users agree not to change or commercialize the scale. In addition to academic and hospital appointments, KR is co-founder of DGI Clinical, which in the last five years has contracts with pharma and device manufacturers (Biogen, Shire, Hollister, Novartis, Nutricia, Roche, Takeda) on individualized outcome measurement. In 2017 he attended an advisory board meeting with Lundbeck on dementia, and in 2020 chaired a Scientific Workshop & Technical Review Panel on frailty for the Singapore National Research Foundation. Otherwise any personal fees are for invited guest lectures, rounds and academic symposia, received directly from event organizers, for presentations on frailty. He is Associate Director of the Canadian Consortium on Neurodegenerataion in Aging, which is funded by the Canadian Institutes for Health Research, the Alzheimer Society of Canada, and several other charities.

  • Patient consent for publication Not required.

  • Ethics approval The NACC is approved by the University of Washington Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. Data from the National Alzheimer’s Coordinating Center (NACC) are available from the publicly available NACC Uniform Data Set database (

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.