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

Pei-Yang Gao¹, Yan Fu², Xiao-Yu He¹, Dan-Dan Zhang², Hao-Chen Chi², Yi-Ming Huang³, Zhi-Bo Wang⁴, Wei Zhang⁵, Ya-Nan Ou⁶, Yi-Jun Ge¹, Jia You⁷, Ling-Zhi Ma², Yi-Xuan Qiang¹, Bing Zhao², Hai-Hong Yu², Jianfeng Feng⁸, Lan Tan⁹, Wei Cheng¹⁰, Ya-Ru Zhang¹¹, Jin-Tai Yu¹²

Affiliations

¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China.
² Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
³ Department of Neurology and Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
⁴ Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing 100053, China.
⁵ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China.
⁶ Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266000, China.
⁷ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China.
⁸ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai 200040, China.
⁹ Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. Electronic address: dr.tanlan@163.com.
¹⁰ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai 200040, China. Electronic address: wcheng@fudan.edu.cn.
¹¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: yaruzhang@fudan.edu.cn.
¹² Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: jintai_yu@fudan.edu.cn.

PMID: 40543840
DOI: 10.1016/j.jare.2025.06.046

Free article

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

Pei-Yang Gao et al. J Adv Res. 2025.

Free article

. 2025 Jun 19:S2090-1232(25)00455-2.

doi: 10.1016/j.jare.2025.06.046. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China.
² Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
³ Department of Neurology and Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
⁴ Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing 100053, China.
⁵ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China.
⁶ Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266000, China.
⁷ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China.
⁸ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai 200040, China.
⁹ Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. Electronic address: dr.tanlan@163.com.
¹⁰ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai 200040, China. Electronic address: wcheng@fudan.edu.cn.
¹¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: yaruzhang@fudan.edu.cn.
¹² Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: jintai_yu@fudan.edu.cn.

PMID: 40543840
DOI: 10.1016/j.jare.2025.06.046

Abstract

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 = 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.

Conclusion: 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.

Keywords: Brain structure; Cognition; Mental health; Neuropsychiatric disorder; Physical frailty; UK Biobank.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Research Materials