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Objective: To optimise dementia prevention strategies, we must understand the complex relationships between lifestyle behaviours, frailty and genetics.Methods: We explored relationships between frailty index, healthy lifestyle and polygenic risk scores (all assessed at study entry) and incident all-cause dementia as recorded on hospital admission records and death register data.Results: The analytical sample had a mean age of 64.1 years at baseline (SD=2.9) and 53% were women. Incident dementia was detected in 1762 participants (median follow-up time=8.0 years). High frailty was associated with increased dementia risk independently of genetic risk (HR 3.68, 95% CI 3.11 to 4.35). Frailty mediated 44% of the relationship between healthy lifestyle behaviours and dementia risk (indirect effect HR 0.95, 95% CI 0.95 to 0.96). Participants at high genetic risk and with high frailty had 5.8 times greater risk of incident dementia compared with those at low genetic risk and with low frailty (HR 5.81, 95% CI 4.01 to 8.42). Higher genetic risk was most influential in those with low frailty (HR 1.31, 95% CI 1.22 to 1.40) but not influential in those with high frailty (HR 1.09, 95% CI 0.92 to 1.28).Conclusion: Frailty is strongly associated with dementia risk and affects the risk attributable to genetic factors. Frailty should be considered an important modifiable risk factor for dementia and a target for dementia prevention strategies, even among people at high genetic risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., Competing Interests: 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., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)