September 23, 2026 – MIAMI–Funded by a $26 million grant from the National Institutes of Health, the University of Miami Miller School of Medicine is part of a major effort underway to identify the earliest biological and clinical changes that signal whether people carrying a specific genetic variant will develop amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).
The five-year study, led by investigators at the Miller School and the University of Pennsylvania Perelman School of Medicine, will span 13 research sites across America. The work focuses on a variant in the C9orf72 gene known as a C9 expansion, the most common inherited cause of both ALS and FTD. By identifying markers that predict when symptoms are likely to begin, researchers aim to establish the foundation for prevention trials that would entail intervention before irreversible damage to brain and nerve cells occurs.
“One of the biggest barriers to developing effective treatments for ALS and FTD is that we may be intervening too late, after the diseases have progressed too far,” said multi-principal investigator Michael Benatar, M.D., Ph.D., the Walter Bradly Chair in ALS Research, chief of the Neuromuscular Division, professor of neurology and public health sciences and executive director of the ALS Center at the Miller School. “If we can identify biological changes that occur before symptoms start, we can begin developing therapies that prevent disease rather than treating it after it starts.
Uniting ALS and FTD Research
While C9 expansion is the most common inherited cause of ALS and FTD, researchers cannot reliably predict whether a person carrying the C9 expansion will develop ALS, FTD, both conditions or remain symptom-free.
Although ALS and FTD are increasingly recognized as related neurodegenerative diseases, research and clinical care have traditionally focused on one condition or the other. ALS specialists focus more on motor and muscular symptoms, while cognitive and behavioral changes may receive less attention. Conversely, FTD specialists typically monitor for changes in thinking and behavior, with less emphasis on motor function.
To address this gap, the researchers brought together expertise from both fields. The study combines neurologists or psychiatrists with motor and cognitive specializations and neuropsychologists to evaluate participants across the full ALS-FTD spectrum.
“This disease does not fit neatly into one specialty,” said multi-principal investigator Corey McMillan, Ph.D., an associate professor of neurology and co-director of the Penn Frontotemporal Degeneration Center. “Understanding C9-related disease requires us to study cognition, behavior and motor function together. By breaking down those silos, we hope to unlock key understandings of how these conditions develop and how we might be able to prevent it.”
What Can Researchers Learn from Advances in SOD1-Related ALS?
The effort builds on lessons from recent advances in another inherited form of ALS caused by mutations in the SOD1 gene.
Research on the SOD1 gene, found in approximately 2% of people with ALS, showed that levels of a blood biomarker called neurofilament light chain rise approximately one year before symptoms begin. Those findings helped support the development of a prevention clinical trial called ATLAS to investigate whether the recently approved ALS treatment tofersen (Qalsody) can be used to prevent ALS symptoms before at-risk individuals begin to experience symptoms of motor dysfunction.
Researchers hope to achieve a similar breakthrough in carriers of the C9 expansion, but there is currently no equivalent single biomarker that identifies when a person carrying the variant is approaching symptom onset. While neurofilament light chain remains a key biomarker, it is also clear that it will be insufficient on its own.
“Identifying other markers is the critical missing piece,” said Dr. Benatar. “It is clear that we’ll need a panel of markers in order to identify the subset of C9 expansion carriers who are most likely to develop ALS or FTD in the near term, and this is the overarching goal of C9 ALS/FTD Prevent.”
Building the Foundation for New Clinical Trials
Future disease prevention trials will obviously require development of promising therapeutics that would be worthy of study in a prevention trial paradigm. But there is much preparatory work to be done so that the field is ready to initiate such trials when these experimental therapeutic candidates emerge.
By identifying a panel of biomarkers that reliably predicts which C9 expansion carriers are at the greatest short-term risk of developing ALS or FTD, the C9 ALS/FTD Prevent study will lay the critical foundation to define the study population to be enrolled in future prevention trials.
“We have an unprecedented opportunity to understand how these diseases develop in their earliest stages by focusing on the full ALS-FTD spectrum of C9-related disease,” Dr. McMillan said. “The more we learn about what happens before symptoms appear, the closer we get to preventing disease rather than simply treating it after the fact.”
This research is supported in full by the National Institutes of Health (1R01AG103000-01).
