Genetic mechanisms, brain structures, and peripheral biomarkers mediate the relationship between physical frailty and neuropsychiatric disorders

• Physical frailty was cross-sectional and longitudinal associated with mental unhealth and worse cognition. • Physical frailty increases risk of multiple neurodegenerative and psychiatric disorders. • Potential causal relationships exist between physical frailty and depression and anxiety. • Physical frailty correlates with changes in frontal cortex and subcortical brain regions. • Genetics, brain structure, and peripheral biomarkers mediates frailty’s impact on brain function and neuropsychiatric disorders. • Running title: Physical frailty and neuropsychiatric disorders. Physical frailty, which is characterized by multisystem functional decline, has emerged as a significant risk factor for adverse health outcomes. However, the relationship among physical frailty, brain function, and neuropsychiatric disorders, along with the underlying mechanisms, remains unclear. To comprehensively investigate the association of physical frailty with brain function and neuropsychiatric disorders and explore the potential mechanism. In the UK Biobank cohort study, physical frailty was assessed using the following five criteria: exhaustion, grip strength, physical activity, weight loss, and walking speed. We examined cross-sectional and longitudinal associations between mental health and cognition using regression and cross-lagged panel models. Cox proportional hazards models were used to assess longitudinal associations with neuropsychiatric disorders. We used Mendelian randomization (MR) to investigated potential causal relationships, whereas neuroimaging analyses identified frailty-related brain regions. Mediation analyses and structural equation modelling were used to explored the underlying mechanisms. Among 316,905 participants (median follow-up: 14.47 years), physical frailty showed significant cross-sectional and longitudinal associations with mental health deterioration and cognitive decline. Physical frailty increased the risks of all-cause dementia (HR = 2.14), Parkinson’s disease (HR = 1.47), stroke (HR = 1.69), sleep disorder (HR = 2.63), anxiety disorder (HR = 2.37), major depressive disorder (MDD; HR = 2.88), and schizophrenia (HR = 3.76). The MR analysis suggested potential causal relationships between physical frailty and MDD (OR = 1.25) and anxiety disorder (OR = 1.30). Moreover, neuroimaging analyses highlighted a correlation between physical frailty and changes in the frontal cortex, as well as subcortical regions such as the thalamus, lateral ventricle, and hippocampus. Genetics, brain regions, and peripheral biomarkers (total cholesterol, GDF15, WFDC2) substantially mediate the relationship between frailty and neuropsychiatric disorders. This study provides comprehensive evidence linking physical frailty to brain dysfunction, suggesting that early frailty intervention is a potential strategy for preventing brain dysfunction and neuropsychiatric disorder.