Circulating extracellular vesicle lipidomics identifies distinct signatures of amyotrophic lateral sclerosis and spinal muscular atrophy

Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder lacking established biomarkers of underlying disease biology. Here, we identify lipidomic signatures of circulating extracellular vesicles (EVs) that distinguish ALS from neurologically healthy controls and related neuromuscular diseases. Using mass spectrometry-based profiling and multivariate modelling, we separate ALS (n=77) from healthy controls (n=89) with an area under the receiver operating characteristic curve (AUROC) of 0.90 (95% CI 0.85-0.94), rising to 0.92 (0.89-0.96) when low-confidence predictions are withheld, and retaining performance in an independent cohort (n=119; AUROC 0.78, 0.70-0.86). In Tofersen-treated SOD1-ALS patients, biomarker trajectories change in parallel with clinical measures while individuals with spinal muscular atrophy (n=50) exhibit a lipid fingerprint distinct from that observed in ALS, supporting disease specificity within a shared systemic framework of abnormal systemic lipogenesis. These findings establish EV-associated lipid signatures as a systemic, blood-based biomarker platform for ALS diagnosis, stratification, and treatment monitoring, with structurally distinct lipid species indicating widespread membrane remodelling.