Researchers from the Perelman School of Medicine at the University of Pennsylvania and the University of Miami Miller School of Medicine launched a major effort on September 22, 2026 to identify the earliest biological and clinical changes signaling whether carriers of a specific genetic variant will develop amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD), funded by a $26 million grant from the NIH. The five-year study, spanning 13 research sites across the U.S., focuses on a variant in the C9orf72 gene known as a “C9 expansion” — the most common inherited cause of both ALS and FTD.
Michael Benatar, MD, PhD, Walter Bradley Chair in ALS Research and Professor of Neurology and Public Health Sciences at Miami’s Miller School, and a multi-principal investigator on the study, said: “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. 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.”
Breaking Down Research Silos Between Two Related Diseases
Researchers currently can’t reliably predict whether a C9 expansion carrier will develop ALS, FTD, both, or remain symptom-free. Although the two conditions are increasingly recognized as related, research and clinical care have traditionally focused on one or the other — ALS specialists emphasizing motor and muscular symptoms, FTD specialists emphasizing cognitive and behavioral change. To close that gap, the study combines neurologists and psychiatrists with both motor and cognitive specializations, plus neuropsychologists, to evaluate participants across the full ALS-FTD spectrum.
Corey McMillan, PhD, Associate Professor of Neurology and Co-Director of the Penn Frontotemporal Degeneration Center, and the study’s other multi-principal investigator, said: “This disease does not fit neatly into one specialty. 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.”
Building on an Earlier Success in ALS
The effort draws on lessons from a related inherited form of ALS caused by mutations in the SOD1 gene, found in about 2% of ALS cases. There, researchers found that levels of a blood biomarker called neurofilament light chain rise roughly a year before symptoms begin — a finding that helped support the ATLAS prevention trial, testing whether the FDA-approved ALS drug tofersen (Qalsody) can prevent symptoms in at-risk individuals before motor dysfunction starts. No equivalent single biomarker currently exists for C9 expansion carriers; while neurofilament light chain remains relevant, researchers say it won’t be sufficient alone.
“Identifying other markers is the critical missing piece,” Benatar said. “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.”
Laying the Groundwork for Future Prevention Trials
The study’s authors caution that effective prevention trials will also require promising therapeutic candidates worthy of testing — work the field still needs to prepare for. “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,” Benatar said.
McMillan added: “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. 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.” The research is fully funded by the NIH under grant number 1R01AG103000-01. More information is available by emailing [email protected].
