Association of Frailty With Dementia and the Mediating Role of Brain Structure and Immunometabolic Signatures

Physical frailty is associated with a higher risk of developing dementia, but it remains unclear whether this relationship is causal and whether the biological biomarkers and neurologic underlying mechanisms are involved. We aimed to elucidate the link between physical frailty and dementia, establish their causal relationship, and investigate the underlying biological mechanisms. This prospective cohort study was based on UK Biobank participants without dementia at enrollment (between 2006 and 2010). Physical frailty was defined by 5 criteria (weight loss, exhaustion, physical inactivity, slow walking speed, and low grip strength). Incident dementia was tracked through linked hospital admission records and death registries, using the International Classification of Diseases, Tenth Revision (ICD-10) codes. Cox proportional hazard regression models and bidirectional Mendelian randomization (MR) analyses were used to evaluate the causal association of physical frailty with incident dementia. In addition, the potential roles of genetic background, brain structures, and biological biomarkers in the association were evaluated using structural equation modeling. Among 489,573 participants (mean age 57.03 years, 54.4% female), 8,900 dementia cases were documented over a median follow-up of 13.58 years. Compared with nonfrail individuals, the risk of dementia was 50% higher in those with prefrailty (hazard ratio [HR]:1.50, 95% CI 1.44-1.57) and 182% higher in those with frailty (HR: 2.82, 95% CI 2.61-3.04). Participants with frailty and high genetic risk had the highest risk of dementia compared with those with low genetic risk and nonfrailty (HR: 3.87, 95% CI 3.30-4.55 for high polygenic risk score; HR: 8.45, 95% CI 7.51-9.51 for APOE-ε4 carriers). The forward MR analysis indicated a potential causal relationship between physical frailty and dementia (odds ratio [OR]:1.79, 95% CI 1.03-3.12) while the reverse MR suggested a null causal association (OR: 1.00, 95% CI 0.98-1.01). Structural equation modeling points to genetic background and neurologic and immunometabolic function as potential underlying mechanisms linking physical frailty to dementia. Our findings support the causal association between physical frailty and dementia, which is possibly mediated through genetic background and neurologic and immunometabolic function. However, this association deserves close consideration because frailty may also be a correlative marker of dementia vulnerability.