The brain structure, inflammatory, and genetic mechanisms mediate the association between physical frailty and depression

Abstract

Cross-sectional studies have demonstrated strong associations between physical frailty and depression. However, the evidence from prospective studies is limited. Here, we analyze data of 352,277 participants from UK Biobank with 12.25-year follow-up. Compared with non-frail individuals, pre-frail and frail individuals have increased risk for incident depression independent of many putative confounds. Altogether, pre-frail and frail individuals account for 20.58% and 13.16% of depression cases by population attributable fraction analyses. Higher risks are observed in males and individuals younger than 65 years than their counterparts. Mendelian randomization analyses support a potential causal effect of frailty on depression. Associations are also observed between inflammatory markers, brain volumes, and incident depression. Moreover, these regional brain volumes and three inflammatory markers-C-reactive protein, neutrophils, and leukocytes-significantly mediate associations between frailty and depression. Given the scarcity of curative treatment for depression and the high disease burden, identifying potential modifiable risk factors of depression, such as frailty, is needed.

Fig. 1. Overview of analyses performed in the current study.

Leveraging data from the UK Biobank, this study investigates the prospective association of physical frailty and nine inflammatory markers with incident depression, and the mediating effects of inflammatory markers on the association between physical frailty and incident depression. These analyses are subsequently replicated based on matched frail and non-frail samples using a propensity score matching procedure to validate the main results. Then, this study uses Mendelian randomization to make causal inferences of the effect of physical frailty on depression. Finally, this study investigates how physical frailty relates to regional gray matter volume and further examines the mediating effect of these regional gray matter volumes on the association between physical frailty and depressive symptoms. CRP, C-reactive protein. Icons were made from https://www.svgrepo.com/.

Fig. 2. The prospective associations between physical frailty and incident depression.

A Compared with non-frail individuals, those with pre-frailty and frailty were at higher risk of developing depression after adjustment for covariates. When physical frailty was modeled as an ordinal variable, the depression risk increased along with the number of frailty indicators. B No evidence of non-linearity was supported. C Among all confounds, only age and sex showed significant interaction with physical frailty on depression incidence, with more pronounced effects observed in males and middle-aged people than in females and older people, respectively. The dashed vertical line indicates threshold of significance after correcting for multiple testing (−log(0.05/10) = 2.30). Frail males: n = 4391; frail females: 6850; pre-frail males: n = 62,158; pre-frail females: n = 75,953; middle-aged pre-frail: n = 108,998; middle-aged frail: n = 8476; older pre-frail: n = 29,113; older frail: n = 2765. Size of the bar represents -log10(P value). D Each of the five components of physical frailty showed independent associations with the risk of depression incidence, even in mutually adjusting models where all five components are simultaneously modeled as exposures in Cox hazard models (n = 352,277). Two-sided unadjusted P values and HRs were derived from Cox proportional hazard model (Z-tests). For all figures, the size of the bars and the internal center represent mean HRs. The error bar and horizontal lines indicate the corresponding 95% CI. All P values were two-sided, and unadjusted. HR hazard ratio. Source data are provided as a Source Data file.

Fig. 3. Prospective association of inflammatory markers with physical frailty and depression incidence.

A All nine inflammatory markers showed significant associations with physical frailty while controlling for several covariates. Analysis employed linear mixed-effects models, which tested the statistical significance of coefficients against a t-distribution. Size of the bar and the internal center represent mean Cohen’s d. The error bar represents the corresponding 95% CI. B Serum CRP showed the strongest association with physical frailty (n = 352,277). Boxplot elements were defined as follows: the center line is the median value; box limits are the upper and lower quartiles; whiskers are 1.5× the interquartile range. C Cox proportional hazards models provided evidence of linear associations between eight of the nine inflammatory markers (except monocyte percentage) and incident depression (Z-tests). Dots: mean HRs; Horizontal lines: 95% CI. D The exposure-response curve between inflammatory markers and risk of depression incidence. Significant non-linear associations were only observed for leukocytes, platelets, and neutrophils. Similar patterns of associations were observed by investigating the tertiles of each inflammatory maker (barplot in each panel). All P values were two-sided, and unadjusted. Size of the bar and the internal center represent mean HRs. The error bar and shadow indicate the corresponding 95% CI. E Eight out of the nine inflammatory markers significantly mediated the prospective association between physical frailty and depression incidence while adjusting for covariates and multiple comparisons. Path thickness indicates the strength of associations, and numerical values for the largest and smallest effect sizes are provided for reference. The number of participants with complete data for these inflammation markers were n = 342,268 (leukocyte), n = 342,771 (lymphocyte, neutrophil%, monocyte), n = 342,775 (lymphocyte%, monocyte%, neutrophil%), n = 343,371 (platelet), and n = 352,277 (CRP). Two-sided unadjusted P values and HRs were derived from Cox proportional hazard model (Z-tests). CRP, C-reactive protein. HR hazard ratio. Icons were made from https://www.svgrepo.com/. Source data are provided as a Source Data file.

Fig. 4. Associations between physical frailty, inflammatory markers, and depression incidence in matched data.

A The propensity score matching procedure generated two groups of 11,241 frail and non-frail participants who were matched on all 10 covariates. The risk of depression for frail people was 3.08-fold higher than the matched non-frail people. The size of the bar represents mean HRs. The error bar represents the corresponding 95% CI. B Significant differences between frail and non-frail individuals were observed for all inflammatory markers other than lymphocytes (two-sided T test). Boxplot elements were defined as follows: the center line is the median value; box limits are the upper and lower quartiles; whiskers are 1.5× the interquartile range. C Of all inflammatory markers, only CRP, neutrophils, and leukocytes significantly mediated the prospective association between frailty and depression incidence (frail vs non-frail: n = 11,241 vs n = 11,241). The significance of mediating effects was determined based on 5000 bootstrap iterations. Path thickness indicates the strength of associations, and numerical values for the largest and smallest effect sizes are provided for reference. Dots: mean HRs; Horizontal lines: 95% CI. CRP C-reactive protein. HR hazard ratio. Icons were made from https://www.svgrepo.com/. Source data are provided as a Source Data file.

Fig. 5. Brain structure associated with physical frailty and symptoms of depression.

The neuroimaging analyses revealed 46 and 7 regional brain regions significantly associated with physical frailty and depression symptoms respectively, while adjusting for potential covariates and multiple comparisons. Five brain regions were consistently identified by both physical frailty and PHQ-9 scores. The association map of frailty was significantly similar to that of depression symptoms, indicating a shared neurobiological basis (r = 0.569, two-sided, unadjusted P = 9.25 × 10⁻¹¹, t test). PHQ: patient health questionnaire. Source data are provided as a Source Data file.