Affiliation:
1. Department of Neurology First Affiliated Hospital of Wenzhou Medical University Wenzhou China
2. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation First Affiliated Hospital of Wenzhou Medical University Wenzhou China
3. Department of Neurology Peking University Third Hospital Beijing China
4. Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Disorders Beijing China
5. Key Laboratory for Neuroscience, National Health Commission/Ministry of Education Peking University Beijing China
6. Department of Neurology Shanghai East Hospital, Tongji University School of Medicine Shanghai China
7. Department of Pediatrics Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
8. College of Mathematics and Physics Wenzhou University Wenzhou China
Abstract
ObjectiveAlthough metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS.MethodsThis study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms.ResultsIn this study, a total of 539 cases of ALS were recorded after a median follow‐up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19–1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19–1.95; HR: 1.31, 95% CI: 1.06–1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ‐glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega‐6 fatty acids to omega‐3 fatty acids ratio.InterpretationMetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024
Funder
National Natural Science Foundation of China
Natural Science Foundation of Zhejiang Province