Blood Proteins May Predict When Genetically At-Risk People Develop ALS

By: Josh Baxt | July 27, 2026 | 8 min. read |

An international research team led by University of Miami Miller School of Medicine scientists identified blood-based protein signatures that predict when genetically at-risk individuals are likely to develop ALS symptoms, creating new opportunities for prevention trials and earlier intervention.

Dr. Michael Benatar, standing with his arms crossed in front of a window

Genetic inheritance can determine a person’s health destiny. But not always.

This is certainly true for people with genes that make them susceptible to amyotrophic lateral sclerosis (ALS). Some people progress from being high-risk to actually having the disease when they are relatively young. Some develop symptoms later in life. Still others never get the disease.

This has been an intractable problem for patients, clinicians and researchers. Without a way to predict if and when disease symptoms will emerge, it is difficult (if not impossible) to know who should be studied in a clinical trial or offered early therapeutic intervention.

Research Impact

Why This Study Matters

Researchers have long struggled to predict which people carrying ALS-related genetic mutations will develop symptoms and when disease onset will occur. The new findings could help scientists identify those most likely to benefit from prevention therapies and future clinical trials.

ALS age of onset varies tremendously, even within the same family and for people that carry the same genetic cause of disease.
Scientists currently have limited tools to predict who will develop ALS and when.
Researchers identified blood-based protein signatures that begin changing years before symptoms appear.
A new 19-protein panel could help identify individuals most likely to develop ALS in the near future.
These biomarkers may improve prevention trials by helping researchers enroll the right participants at the right time.
The findings could ultimately support earlier interventions design to delay or prevent emergence of symptoms of ALS.

An international research group, led by University of Miami Miller School of Medicine scientists, has identified protein markers in blood that can predict when an at-risk person will first develop ALS symptoms, an event called phenoconversion. Published in the journal Nature Medicine, these insights shed new light on the biology of pre-symptomatic ALS and could empower future prevention trials.

“By studying blood samples from people at elevated genetic risk for ALS, we identified protein signatures that predict whether someone is going to phenoconvert in the relatively near future,” said Michael Benatar, M.D., Ph.D., the Walter Bradly Chair in ALS Research, chief of the Neuromuscular Division and professor of neurology at the Miller School and executive director of the ALS Center. Dr. Benatar is senior author on the study. “This could be an incredibly valuable tool for us to select appropriate people for inclusion in future ALS prevention trials and ultimately to develop effective treatments.”

Two Decades of Research Illuminate the Earliest Stages of ALS

Though completed recently, the analyses in this publication were almost 20 years in the making. In 2007, Dr. Benatar, along with Joanne Wu, Sc.M., research associate professor of neurology, launched the Pre-Symptomatic Familial ALS (Pre-fALS) study. Pre-fALS tracks people with elevated genetic susceptibility to ALS, as well as ALS and frontotemporal dementia (FTD). Using a wide variety of assessment techniques (neurological exams, blood draws, cerebrospinal fluid collection and others), the study has shed light on the earliest biological changes in people destined to develop ALS and ALS-FTD.

This long view paid big dividends. Pre-fALS helped the team identify a biomarker called neurofilament light chain, a protein that enters the spinal fluid and blood when neurons are damaged.

We do this work in partnership with, and in service to, the carrier community. Every year, they take a few days off to see us because they are profoundly committed to the idea that, someday, we can more effectively treat and possibly even prevent this disease.
Dr. Michael Benatar

This knowledge was critical to design the ATLAS study, a pivotal phase 3 clinical trial that will help determine the optimal timing to deliver the ALS drug, Qalsody. ATLAS will also test whether Qualsody can delay or prevent ALS symptoms in unaffected people who carry a mutated SOD1 gene. Still, researchers and clinicians have needed additional biomarkers.

“Neurofilament levels are great, but they aren’t informative for everyone at risk for ALS and ALS-FTD,” said Dr. Benatar. “We needed to identify other biomarkers to understand what is happening before symptoms appear in the broader population at elevated risk for disease.”

The Power of Proteomics

To better understand the earliest biological changes before people develop ALS, the current research analyzed more than 5,000 proteins in blood samples from Pre-fALS participants. Samples had been collected over many years. These analyses showed how each patient’s proteomic profile shifted over time as they did (or did not) develop symptoms.

The team identified around 100 proteins that changed as people progressed towards ALS phenoconversion. In fact, many of these markers began changing years before neurofilaments showed evidence of neuronal damage, providing an earlier and more in-depth readout on disease biology. From there, the researchers constructed a 19-protein panel that can predict when at-risk people are likely to develop ALS.

By the Patients, for the Patients

This early panel is an important step towards developing better tests to predict the timing of ALS phenoconversion. Eventually, these tests could be invaluable tools to identify the best people for clinical studies, enriching trials with those who are most likely to develop symptoms in the relatively near future.

“Let’s say we had a gene therapy for people who carry a C9orf72 repeat expansion (short DNA sequences that are repeated many times in a row), the most common genetic cause of ALS,” said Dr. Benatar. “Without these markers, it would be difficult to run a trial because we’d have no idea who would actually develop ALS or FTD and when. Because we can now predict when phenoconversion is likely, we have a much better sense of who to enroll, and we have a measurable way to know if a therapy is working.”

Now that the group has established this proof of concept, they will continue to refine their efforts. They are currently interrogating cerebrospinal fluid from Pre-fALS participants to find other important protein markers.

While Dr. Benatar and the research team are excited about these results, they’re also mindful that none of this happens without their many Pre-fALS volunteers, who endured blood draws, lumbar punctures, neurological exams and other clinical procedures, year after year, to set the stage for these discoveries.

“We do this work in partnership with, and in service to, the carrier community,” said Dr. Benatar. “They’re regular people, with busy family and professional lives. Some come from far away. But every year, they take a few days off to see us because they are profoundly committed to the idea that, someday, we can more effectively treat and possibly even prevent this disease.”