The brain structure and immunometabolic mechanisms underlying the association between frailty and dementia.

BACKGROUND: Physical frailty, characterized by heightened sensitivity to stressors and decreased physiological reserves, is an established risk factor for incident dementia among older adults. However, the biological mechanisms underlying this association remain incompletely elucidated. This study aimed to dissect the potential roles of systemic inflammation, metabolic dysregulation, and accelerated brain aging in the association between physical frailty and dementia. METHODS: This study included 452,516 participants from the UK Biobank who were free of dementia at baseline and had data available for all five components of frailty, with the majority also providing inflammatory, metabolic, neuroimaging and genetic information. Cox proportional hazard models were utilized to examine the longitudinal association between frailty and dementia. Causal mediation analyses were performed to quantify the potential mediating effects of composite scores for inflammation and metabolism, as well as accelerated brain aging (quantified as the brain age gap) on the observed frailty-dementia association. RESULTS: Over an average follow-up period of 13.7 years, 7,777 individuals were diagnosed with dementia. Compared to non-frail individuals, frailty status was significantly associated with an increased dementia risk (adjusted hazard ratio 2.21; 95% confidence interval 2.02-2.42), with an interaction effect between frailty and polygenetic risk score (P-value = 0.033). Inflammation and metabolic composite scores were separately constructed using weighted combinations of relevant biomarkers. Mediation analyses revealed that the inflammatory score and metabolic score significantly mediated 4% and 13% of the frailty-dementia association, respectively. Moreover, accelerated brain aging, estimated using machine learning applied to neuroimaging data, mediated a substantial proportion (20%) of the association between frailty and dementia. CONCLUSION: The positive association between frailty and dementia is mediated through multiple biological mechanisms pathways, including inflammation, metabolic dysregulation, and accelerated brain aging. These findings underscore the importance of frailty-oriented preventive strategies against dementia.