Breakthrough Prize Awarded for Discovery That C9orf72 Mutation Links ALS and Frontotemporal Dementia

A repeat expansion in a single gene — C9orf72 — is now understood to be the most common known genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia, two devastating neurodegenerative diseases that were long considered unrelated, and the scientists who made that discovery have now been awarded the 2026 Breakthrough Prize in Life Sciences for work that fundamentally reshaped the field's understanding of neurodegeneration.

Bryan Traynor of the National Institutes of Health, Rosa Rademakers of the University of Antwerp, and Jonathan Cooper-Knock of the University of Sheffield shared the $3 million prize, recognized at the April 18 ceremony in Santa Monica. Their research, published in 2011 in Neuron and Nature Neuroscience in back-to-back landmark papers, identified an abnormal hexanucleotide repeat expansion — a stuttering repetition of six DNA letters, GGGGCC — in a region of the C9orf72 gene that causes it to malfunction in ways that kill motor neurons and, in many patients, simultaneously destroy the frontal lobe neurons responsible for personality, behavior, and executive function.

Before the C9orf72 discovery, ALS and frontotemporal dementia were studied and treated as entirely separate diseases by different clinical specialties. Neurologists who treated ALS focused on motor neuron loss; psychiatrists and behavioral neurologists who managed FTD focused on the social and cognitive deterioration that was the hallmark of that disease. The observation that some families appeared to have members with ALS while others had what looked like early-onset dementia — sometimes in the same family — had puzzled researchers for decades without explanation.

The C9orf72 mutation, which is inherited in an autosomal dominant pattern but can also arise spontaneously, explains those family patterns. The repeat expansion causes disease through at least two distinct mechanisms: the abnormal RNA produced by the expanded gene folds into toxic aggregates that sequester proteins away from their normal functions, and the repeated translation of the stuttering sequence produces aberrant proteins — called dipeptide repeat proteins — that accumulate in neurons and interfere with a wide range of cellular processes. The relative contribution of each mechanism remains an active research question.

The identification of C9orf72 has had immediate practical consequences for patients and families. Genetic testing for the expansion is now standard in ALS diagnosis, and identification of carriers within families has enabled presymptomatic counseling. More significantly, the discovery created a clear molecular target for therapeutic development: multiple clinical trials are now underway testing antisense oligonucleotides and other gene-silencing approaches designed to reduce the expression of the expanded C9orf72 gene.

"Finding the mutation was the moment when ALS went from being a disease we could only describe to being a disease we could begin to think about attacking at the root," Traynor said at the Santa Monica ceremony. "Every trial running today for C9orf72-related disease traces directly back to knowing what the mutation is."

Approximately 40 percent of familial ALS cases and 5 to 10 percent of apparently sporadic ALS cases carry the C9orf72 expansion, making it the single largest genetic contributor to the disease. The same expansion accounts for roughly 25 percent of familial frontotemporal dementia. Rademakers noted in her acceptance remarks that the unification of ALS and FTD under a common genetic umbrella had transformed clinical trial design, allowing researchers to study both conditions in the same trial population.