Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS

This study examined 516 longitudinal plasma samples from pre-symptomatic ALS gene carriers, phenoconverters (those who progressed to clinical ALS), patients with manifest disease, and controls. Among 92 proteins showing concentration changes before phenoconversion, a core panel of 19 proteins collectively predicted phenoconversion across 0.5-to-5-year timeframes with cross-validated AUCs of 0.80–0.89, and estimated time-to-phenoconversion with a mean absolute error of 1.6 years. This multi-protein approach substantially outperformed neurofilament light chain alone, with partial replication in UK Biobank data supporting its utility for ALS prevention trial design.

Recommended citation: Ran X., Wuu J., Qin Z.S., McDermott M.P., Cooper-Knock J., Li Y., Granit V., Grignon A.L., Lin E., Fernandez M.C., Colato D., Carberry N., Lill C.M., Piazza P., Malaspina A., & Benatar M. (2026). "Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS." Nature Medicine.
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