Researchers have identified a panel of 19 blood proteins that can predict when a person carrying an ALS-linked genetic variant will begin showing symptoms, often years before 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,” said Michael Benatar, professor of neurology and public health sciences at the University of Miami and the study's senior author. “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.”
For the study, published in Nature Medicine, researchers analyzed data from the NIH-funded Pre-symptomatic Familial ALS (Pre-fALS) study, which has tracked people at high genetic risk for ALS for nearly 20 years. This approach lets scientists study the disease before it starts—a rare opportunity that recent research suggests also applies to the broader ALS population, not just this genetically predisposed group.
Investigators used a high-throughput proteomic method called Olink to analyze plasma samples from 137 participants, including 33 who had already developed ALS or frontotemporal dementia symptoms. Screening more than 5,000 proteins, researchers found 92 whose levels shifted before symptoms appeared. A 2017 study had already flagged one marker—neurofilament light chain, a structural protein in neurons—as a signal that spikes in the months before ALS symptoms emerge.
Using machine learning, the researchers narrowed the field to a panel of 19 proteins, including neurofilament light chain—which was flagged as a possible biomarker in a 2017 study—that best predicted phenoconversion across time windows from 6 months to 5 years.
The models estimated a patient's symptom onset within about 18 months of the true timing—accurate enough, researchers say, to guide treatment decisions. Similar results emerged from an analysis of the UK Biobank, a more broadly representative population than the Pre-fALS cohort.
Tofersen, a drug approved for symptomatic ALS, is currently being evaluated as a preventative therapeutic in pre-symptmoatic ALS through ATLAS, a clinical trial designed by Benatar in partnership with Biogen. ATLAS will test whether starting treatment shortly before symptoms appear could avert or delay the onset of ALS.
With these more reliable timing estimates in hand, doctors could identify exactly who should enroll in such trials and when.
Data from NIH