19-Protein Blood Panel Estimates When People with ALS-Linked Genes May Become Symptomatic

An NIH-backed study published Monday in Nature Medicine found that a 19-protein blood biomarker panel could estimate when people carrying ALS-linked genetic variants were likely to develop symptoms, with an average error of about 18 months.

The finding could help researchers decide when to start preventive treatment and when to enroll symptom-free participants in clinical trials aimed at delaying or preventing disease. But the test is not ready for routine clinical use, and the authors said it still needs more replication and validation before any clinical deployment.

The research draws on serial blood samples from Pre-fALS, a long-running NIH-funded study of people at genetic risk for familial ALS that has operated for about 18 years. ALS, or amyotrophic lateral sclerosis, is a progressive and fatal neurodegenerative disease that damages motor neurons, the nerve cells that control movement.

In the discovery cohort, investigators analyzed 516 plasma samples from 137 participants. That group included 33 people who later developed clinically manifest disease, 35 people with manifest ALS, 10 pre-symptomatic carriers of pathogenic variants who had not developed symptoms, and 59 controls.

After quality control, the researchers measured about 5,300 blood proteins and identified 92 that changed before symptom onset. From that set, they built a core predictive panel of 19 proteins, including neurofilament light chain, or NfL, a leading blood biomarker candidate in ALS research.

Using the 19-protein panel, the model predicted phenoconversion — the transition from carrying a disease-linked variant without symptoms to clinically manifest ALS — across roughly six-month to five-year time horizons, with cross-validated performance measures ranging from about 0.80 to 0.89. It estimated time to symptom onset with a mean absolute error of about 1.6 years, which NIH described as about 18 months.

That matters because the key challenge is no longer simply showing that biomarkers change before symptoms begin. Earlier work had already suggested that NfL can rise in the pre-symptomatic phase. What is new here is the broader multi-protein signature, which the paper said outperformed NfL alone in estimating when symptoms may begin.

The study was led by senior author Dr. Michael Benatar, a University of Miami professor of neurology and public health sciences. First and corresponding authors include Ximing Ran and Joanne Wuu. NIH highlighted the work in a news release Monday, the same day the paper, “Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS,” was published.

The researchers also sought outside support for the findings using UK Biobank proteomic data. That replication was partial: It supported several candidate proteins and the value of a multi-protein panel, but it was limited because UK Biobank did not include precise, real-world symptom-onset timing and instead relied on hospital coding as a proxy. The authors also noted the lack of a comparable independent cohort with detailed onset timing, and said the approach will need validation using simpler immunoassays before it could move closer to practice.

The timing question has become more urgent as gene-targeted ALS treatments and prevention trials advance. Tofersen, sold as QALSODY, was approved by the Food and Drug Administration in 2023 for ALS associated with SOD1 mutations. Prevention studies, including the Phase 3 ATLAS trial in clinically pre-symptomatic adults with confirmed SOD1 mutations, have created a practical need for tools that can identify which symptom-free carriers may be closest to onset.

“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,” Benatar said in the NIH release. “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.”

The work was supported in part by the NIH’s National Institute of Neurological Disorders and Stroke. The paper also disclosed industry relationships among several authors, and said the University of Miami has licensed intellectual property to Biogen related to ATLAS design.