Rare Brain Mutations May Spark Neurodegeneration in ALS and FTD

Localized genetic changes could 'seed' the spread of devastating diseases, study suggests

Apr. 16, 2026 at 5:39pm

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A highly abstract, geometric painting in muted earth tones, featuring sweeping arcs, concentric circles, and precise botanical spirals, conceptually representing the complex genetic and cellular processes underlying neurodegenerative diseases.Groundbreaking research suggests that rare, localized genetic mutations in the brain may be the spark that ignites devastating neurodegenerative diseases like ALS and FTD.Boston Today

Researchers have discovered that rare, localized genetic mutations in the brain may be the spark that ignites the onset of devastating neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), even when those mutations are present in only a tiny fraction of cells. The findings could lead to new methods for identifying these hard-to-detect brain alterations and treating the diseases at their earliest stages.

Why it matters

The study provides a new model for understanding the origins of ALS and FTD, which often arise sporadically without a clear genetic cause. Identifying these localized 'mosaic' mutations could be key to developing more effective treatments that target the disease process before it spreads throughout the brain.

The details

Researchers examined over 1,700 postmortem brain and spinal cord samples from patients with ALS, FTD, and healthy controls. They found that about 2.1% of sporadic cases carried damaging somatic mutations in neurodegeneration-related genes, but these mutations were extremely rare, present in less than 2% of cells. Crucially, the mutations were concentrated in disease-affected regions like the motor cortex and spinal cord, suggesting neurodegeneration may begin with a small cluster of genetically altered cells before spreading. The study also identified mutations in unexpected genes and provided evidence that disease-causing expansions in the C9orf72 gene can occur spontaneously within brain tissue.

  • The study was published in the journal Nature Genetics on April 16, 2026.

The players

Boston Children's Hospital

The research institution where the study was conducted.

Harvard Medical School

The university where the study's senior author is a professor.

Christopher A. Walsh, MD, PhD

The Howard Hughes Medical Institute investigator and professor at Boston Children's Hospital and Harvard Medical School who led the study.

NIH NeuroBioBank

The repository that provided the postmortem brain and spinal cord samples used in the research.

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What they’re saying

“Above all, it suggests that the genes, or at least some of the genes, that drive the disease don't necessarily have their toxic effects only in the neurons carrying the mutation. Or that some neurons are impacted and that leads to a domino effect that somehow impacts neurons that don't carry the mutation.”

— Christopher A. Walsh, Howard Hughes Medical Institute investigator and professor

What’s next

The researchers believe these findings could lead to new methods for identifying hard-to-detect genetic alterations in the brain and for developing treatments that target the earliest stages of neurodegenerative diseases before the damage spreads.

The takeaway

This study challenges the traditional view of ALS and FTD as diseases driven by widespread genetic risk factors, suggesting they may instead originate from rare, localized mutations that 'seed' the broader neurodegeneration process. This new model could open the door to earlier diagnosis and more targeted therapies.