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. 2022 Apr;93(4):343-350.
doi: 10.1136/jnnp-2021-327396. Epub 2021 Dec 21.

Frailty, lifestyle, genetics and dementia risk

David D Ward  1   2 , Janice M Ranson  3 , Lindsay M K Wallace  1   4 , David J Llewellyn  3   5 , Kenneth Rockwood  6   7   8   9
Affiliations

Frailty, lifestyle, genetics and dementia risk

David D Ward et al. J Neurol Neurosurg Psychiatry. 2022 Apr.

Abstract

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.

Keywords: clinical neurology; dementia; genetics; geriatrics.

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Conflict of interest statement

Competing interests: DDW, JMR, LMKW and DJL have nothing to report. 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 commercialise the scale. In addition to academic and hospital appointments, KR is cofounder of DGI Clinical, which in the last five years has contracts with pharma and device manufacturers (Biogen, Shire, Hollister, Novartis, Nutricia, Roche, Takeda) on individualiSed 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 organiSers, for presentations on frailty. He is Associate Director of the Canadian Consortium on Neurodegeneration in Aging, which is funded by the Canadian Institutes for Health Research, the Alzheimer Society of Canada and several other funding partners.

Figures

Figure 1
Figure 1
Analytical sample flow chart.
Figure 2
Figure 2
Frailty and incident dementia. (A) Distributions of unadjusted baseline frailty index scores in those who developed dementia (N=1762) and in those who remained free from dementia (N=194 361). (B) Associations of frailty index scores and dementia risk. HRs and 95% CIs were calculated from Cox proportional hazards models adjusted for all covariates for the total sample (N=196 123) and for men (N=92 838) and women (N=103 285), separately. (C) Cumulative dementia incidence within low (N=128 150), intermediate (N=61 931) and high frailty (N=6042) groups as calculated from a Cox proportional hazards model adjusted for all covariates. Analyses in (B, C) were adjusted for age at baseline, sex, education level, socioeconomic status, the polygenic risk score, the number of alleles included in the polygenic risk score, third-degree relatedness and the first 20 principal components of ancestry.
Figure 3
Figure 3
Frailty, lifestyle and incident dementia. (A) The hypothesised mediation model in which a proportion of the protective effect of higher healthy lifestyle scores on dementia development is mediated by lower frailty index scores. (B) The association of healthy lifestyle scores and dementia risk. HRs and 95% CIs were calculated from Cox proportional hazards models adjusted for all covariates (but not frailty index scores) for the total sample (N=196 123) and for men (N=92 838) and women (N=103 285), separately. (C) Relationship between healthy lifestyle scores and frailty index scores. Values represent mean frailty index scores (95% CI) for participants with 0 (N=2091), 1 (N=16 941), 2 (N=54 126), 3 (N=77 347) and four healthy lifestyle behaviours (N=45 618) and were calculated from multiple linear regression models adjusted for all covariates. Analyses in (B, C) were adjusted for age at baseline, sex, education level, socioeconomic status, the polygenic risk score, the number of alleles included in the polygenic risk score, third-degree relatedness and the first 20 principal components of ancestry.
Figure 4
Figure 4
Frailty, polygenic risk and incident dementia. (A) Cumulative dementia incidence within low (N=39 224), intermediate (N=117 674) and high polygenic risk (N=39 225) groups calculated from a Cox proportional hazards model adjusted for all covariates. (B) Difference in dementia risk between combined frailty score/polygenic risk groups as compared with a low frailty score/low polygenic risk reference group. HRs and 95% CIs were calculated from a Cox proportional hazards model adjusted for all covariates in the total sample (N=196 123). (C) Associations of polygenic risk scores and dementia risk within different frailty groups. HRs and 95% CIs were calculated from Cox proportional hazards models adjusted for all covariates for the total sample (N=196 123) and for men (N=92 838) and women (N=103 285), separately. Analyses in (A–C) were adjusted for age at baseline, sex, education level, socioeconomic status, the number of alleles included in the polygenic risk score, third-degree relatedness and the first 20 principal components of ancestry; analyses in (A) were additionally adjusted for frailty index scores.
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