Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.
9 affiliations
- 1Department of Neurology, Peking University Third Hospital, Beijing, China.
- 2Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
- 3University of Chinese Academy of Sciences, Beijing, China.
- 4Department of Radiation Oncology, Peking University Third Hospital, Beijing, China.
- 5Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
- 6Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, China.
- 7State Key Laboratory of General Artificial Intelligence, Peking University, Beijing, China.
- 8Beijing Key Lab of Innovative Diagnostics, Therapeutics and Translational Research for Neurological Rare Disorders, Beijing, China.
- 9Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China.
Abstract
Objective
Although both pre-symptomatic adiposity and dysregulated lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS), the mechanistic pathways linking adiposity to disease remain unclear. This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.Methods
We conducted mass spectrometry-based quantitative lipidomics on plasma from 104 ALS patients and 78 age- and sex-matched controls. Life-course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole-body fat-free mass were constructed. Associations and PRS-by-disease interaction effects on the lipidome were evaluated.Results
Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy-eight lipid species were significantly altered (FDR < 0.05, |Cohen's d| > 1.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three-acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out-of-fold AUC of 0.958. Exploratory PRS-by-disease-status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.Conclusion
These findings identify robust ALS-associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.
Related
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BibTeX
@article{zhang2026plasma,
title = {{Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.}},
author = {Linjing Zhang and Leyuan Zhang and Yongping Zheng and Zhenhuang Zhuang and Lu Tang and Wei Zheng and Kailin Xia and Shan Ye and Tielun Yin and Tao Huang and Dongsheng Fan},
journal = {Journal of cachexia, sarcopenia and muscle},
year = {2026},
month = oct,
doi = {10.1002/jcsm.70410},
url = {https://europepmc.org/article/MED/42904859},
note = {CC BY},
}
RIS
TY - JOUR
TI - Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.
AU - Linjing Zhang
AU - Leyuan Zhang
AU - Yongping Zheng
AU - Zhenhuang Zhuang
AU - Lu Tang
AU - Wei Zheng
AU - Kailin Xia
AU - Shan Ye
AU - Tielun Yin
AU - Tao Huang
AU - Dongsheng Fan
PY - 2026
DA - 2026/10/01
JO - Journal of cachexia, sarcopenia and muscle
DO - 10.1002/jcsm.70410
UR - https://europepmc.org/article/MED/42904859
AB - Objective Although both pre-symptomatic adiposity and dysregulated lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS), the mechanistic pathways linking adiposity to disease remain unclear. This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.Methods We conducted mass spectrometry-based quantitative lipidomics on plasma from 104 ALS patients and 78 age- and sex-matched controls. Life-course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole-body fat-free mass were constructed. Associations and PRS-by-disease interaction effects on the lipidome were evaluated.Results Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy-eight lipid species were significantly altered (FDR < 0.05, |Cohen's d| > 1.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three-acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out-of-fold AUC of 0.958. Exploratory PRS-by-disease-status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.Conclusion These findings identify robust ALS-associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.
SN - 2190-5991
SN - 2190-6009
ER -