Proteomic and Functional Signatures of Phenoconversion in Presymptomatic Amyotrophic Lateral Sclerosis
Journal of Clinical Neuromuscular Disease, 2026
Lehrer S., Rheinstein P.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology | Pathophysiology Patient Stratification | Plasma |  Olink Explore 3072/384 |
Abstract
Background:
Amyotrophic lateral sclerosis (ALS) likely has a prolonged presymptomatic phase. Identifying blood biomarkers that predict phenoconversion is critical for early intervention.
Methods:
We analyzed baseline serum proteomics in 270 UK Biobank participants who later developed ALS. A prespecified 19-protein panel was evaluated in relation to time-to-diagnosis. C9orf72 risk was proxied using rs10757668 genotype.
Results:
Neurofilament light rose sharply in the 2–3 years preceding diagnosis ( r = −0.37, P < 0.001). Muscle-stress markers, including EDA2R and MYL3, increased earlier, up to 4–6 years before onset. Higher EDA2R levels were associated with reduced grip strength at baseline. A combined 19-protein panel plus genotype predicted phenoconversion within 3 years with an area under the receiver operating characteristic curve of 0.77, outperforming neurofilament light alone.
Conclusions:
ALS exhibits a measurable molecular prodrome detectable in blood years before diagnosis. Integrated proteomic and genetic profiling may support early identification and trial enrichment strategies.