Associations of physical frailty with health outcomes and brain structure in 483 033 middle-aged and older adults: a population-based study from the UK Biobank

Abstract

Background: Physical frailty is a state of increased vulnerability to stressors and is associated with serious health issues. However, how frailty affects and is affected by numerous other factors, including mental health and brain structure, remains underexplored. We aimed to investigate the mutual effects of frailty and health using large, multidimensional data.

Methods: For this population-based study, we used data from the UK Biobank to examine the pattern and direction of association between physical frailty and 325 health-related measures across multiple domains, using linear mixed-effect models and adjusting for numerous confounders. Participants were included if complete data were available for all five indicators of frailty, all covariates, and at least one health measure. We further examined the association between frailty and brain structure and the role of this association in mediating the relationship between frailty and health outcomes.

Findings: 483 033 participants aged 38-73 years were included in the study at baseline (between Dec 19, 2006, and Oct 1, 2010); at a median follow-up of 9 years (IQR 8-10), behavioural data were available for 46 501 participants and neuroimaging data for 40 210 participants. The severity of physical frailty was significantly associated with decreased cognitive performance (Cohen's d=0·025-0·162), increased early-life risks (d=0·026-0·111), unhealthy lifestyle (d=0·013-0·394), poor physical fitness (d=0·007-0·668), increased symptoms of poor mental health (d=0·032-0·607), severe environmental pollution (d=0·013-0·064), and adverse biochemical markers (d=0·025-0·198). Some associations were bidirectional, with the strongest effects on mental health measures. The severity of frailty correlated with increased total white matter hyperintensity and lower grey matter volume, particularly in subcortical regions (d=0·027-0·082), which significantly mediated the association between frailty and health-related outcomes, although the mediated effects were small.

Interpretation: Physical frailty is associated with diverse unfavourable health-related outcomes, which can be mediated by differences in brain structure. Our findings offer a framework for guiding preventative strategies targeting both frailty and psychiatric disorders.

Funding: National Institute of Mental Health, National Science Foundation.

Figure 1:. Summary of health outcomes and four analyses performed in the present study

Top, the 325 health-related measures assessed are grouped into seven broad categories. Bottom, the number of participants with the indicated number of frailty indicators (physical frailty score) at baseline and 9-year follow-up.

Figure 2:. Associations between physical frailty and health-related measures

(A) Of 325 health measures, 283 showed significant associations (p<1·54 × 10⁻⁴; Bonferroni-corrected) with physical frailty while covarying for a set of potential confounders. Phenotypes that did not show significant associations are shown in grey. The top 20 phenotypic measures showing the numerically most significant associations with frailty are highlighted. (B) Distribution of effect sizes with and without additional control for family income, smoking status, and alcohol intake. (C) The top ten health measures exhibiting the numerically most significant associations with frailty. For ease of getting up, higher values represent better outcomes; for all other measures, higher values represent worse outcomes. Data are mean (95% CI). PHQ=patient health questionnaire. PTSD=post-traumatic stress disorder.

Figure 3:. The longitudinal association between physical frailty and health-related measures

(A) Physical frailty at baseline was significantly associated with 70 of 152 health-related outcomes examined at follow-up after controlling for the baseline level of these outcomes and numerous confounders alongside their change over time (p<3·29 × 10⁻⁴; Bonferroni-corrected). The pie charts show the number of significant and insignificant associations. Health measures not showing significant associations are shown in grey. The top ten health measures showing numerically significant associations with frailty are highlighted. (B) The reverse associations (baseline health measures predicting future frailty) reached statistical significance for 85 measures. (C) Significant bidirectional associations were observed for mental health measures, for which baseline frailty predicted 17 of 18 mental health traits at a 9-year follow-up, and the reverse was also significant in 15 of 18 measures. L=left. R=right. PHQ=patient health questionnaire.