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

作者：Pei‐Yang Gao, Yan Fu, Xiao‐Yu He, Dandan Zhang, Hao‐Chen Chi, Yiming Huang, Zhibo Wang, Wei Zhang, Ya‐Nan Ou, Yi‐Jun Ge, Jia You, Lingzhi Ma, Yi‐Xuan Qiang, Bing Zhao, Haihong Yu, Jianfeng Feng, Lan Tan, Wei Cheng, Yaru Zhang, Jin‐Tai Yu · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.06.046 · 被引用次数：9 · 研究领域：Frailty in Older Adults、Dementia and Cognitive Impairment Research、Nutrition and Health in Aging

INTRODUCTION: 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. OBJECTIVES: To comprehensively investigate the association of physical frailty with brain function and neuropsychiatric disorders and explore the potential mechanism. METHODS: 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. RESULTS: 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 =...