Sep 2026· Journal of Clinical Neuromuscular Disease· Vol 28 1, pp.
33-46
· 0 citations· 11 references
Medicine
TL;DR
ALS exhibits a measurable molecular prodrome detectable in blood years before diagnosis, and integrated proteomic and genetic profiling may support early identification and trial enrichment strategies.
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.
Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic...
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BACKGROUND
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