Blood protein panel predicts ALS onset in gene carriers

Clinical takeaway: A blood test that predicts when ALS symptoms will begin is not yet available, but this work moves the field toward one, with the first practical use likely in selecting participants for prevention trials rather than in routine care.

Testing a drug to prevent amyotrophic lateral sclerosis (ALS) requires enrolling into a clinical trial people who will convert soon enough to show whether the drug worked. But there has been a catch: there's not a good way to predict which presymptomatic gene carriers are close to being symptomatic.

The standard approach, neurofilament light (NfL), flags patients only in the last few months before symptoms and can miss slower-progressing carriers. A new longitudinal study developed and tested a 19-protein blood panel that estimated time to onset within about 1.6 years, extending the useful prediction period out to five years.

ALS gene carriers, mostly those with SOD1 or C9orf72 variants, can be told their lifetime risk is high but little about when symptoms will start. That timing gap has become more consequential as prevention moves within reach. Trials are now testing whether treating carriers before symptoms begin can delay or prevent disease. Enrolling carriers who are close enough to conversion for a drug to show an effect has been an obstacle.

The panel predicted whether a carrier would develop symptoms within windows ranging from six months to five years. It identified carriers headed for conversion with good accuracy, clearly beating NfL at every window. The call was sharpest close to onset and fuzzier years out. Among carriers who converted, the panel estimated time to onset within about 1.6 years on average, roughly a year tighter than NfL.

Researchers drew on Pre-fALS, which followed carriers of ALS-linked variants with serial blood draws through the transition to symptoms, and measured thousands of plasma proteins. The panel was built and cross-validated on the roughly three dozen carriers who converted. A UK Biobank check supported the findings only directionally, since those data were cross-sectional and onset timing was approximated.

The proteins were measured on a research platform, so the panel would first have to be rebuilt as standard immunoassays for use in clinical labs. Results would then need to hold up in larger, more genetically varied groups. If the panel were to clear both hurdles, the near-term use would still be narrow: helping prevention trials pick carriers who are near their symptom window.

"With preventative gene-targeting treatments now becoming available, there is a particularly urgent need for reliable biofluid-based signatures that indicate near-term onset in individuals that carry ALS risk genes," said Amy Bany Adams, PhD, acting director of the National Institute of Neurological Disorders and Stroke.

Michael Benatar, MD, PhD, of the University of Miami, who led the study, added, "If someone carrying an ALS-associated genetic variant had asked me in the past when they would become symptomatic, I would have struggled to provide a reasonable estimate. These biomarkers give us a far better idea of the timing, allowing us to estimate the time to symptom onset with an average error of about 18 months. That's something we can work with." Routine testing of individual carriers to anticipate their onset is a separate question that this study does not address.

Source: Ran X, et al. Nat Med. 2026 Jul 27. Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS