Evidence map›Paper›PMID 40543840›Full record

ArticleJournal of advanced research2026

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

Pei-Yang Gao, Yan Fu, Xiao-Yu He, Dan-Dan Zhang, Hao-Chen Chi, Yi-Ming Huang, Zhi-Bo Wang, Wei Zhang, Ya-Nan Ou, Yi-Jun Ge and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Pei-Yang GaoDepartment 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.
Yan FuDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Xiao-Yu HeDepartment 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.
Dan-Dan ZhangDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Hao-Chen ChiDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Yi-Ming HuangDepartment of Neurology and Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Zhi-Bo WangInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing 100053, China.
Wei ZhangInstitute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China.
Ya-Nan OuDepartment of Neurology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266000, China.
Yi-Jun GeDepartment 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.
Jia YouDepartment 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.
Ling-Zhi MaDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Yi-Xuan QiangDepartment 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.
Bing ZhaoDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Hai-Hong YuDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Jianfeng FengInstitute 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.
Lan TanDepartment of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. Electronic address: dr.tanlan@163.com.
Wei ChengDepartment 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.
Ya-Ru ZhangDepartment 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.
Jin-Tai YuDepartment 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.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

introductionPhysical 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.

objectivesTo comprehensively investigate the association of physical frailty with brain function and neuropsychiatric disorders and explore the potential mechanism.

methodsIn 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.

resultsAmong 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.

conclusionThis 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.

Indexed as

BrainFrailtyMental DisordersAgedBiomarkersCognitive DysfunctionCross-Sectional StudiesFemaleHumansLongitudinal StudiesMaleMendelian Randomization AnalysisMiddle AgedNeuroimagingRisk FactorsUnited KingdomBiomarkersBrain structureCognitionMental healthNeuropsychiatric disorderPhysical frailtyUK Biobank

Identifiers

PMID40543840
PMCPMC13000945

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.