Work

Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS

Year: 2026

Type: article

Abstract: The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6 years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.

Source: Nature Medicine

DOI: 10.1038/s41591-026-04528-x