Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.

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.