Clotilde Lagier-Tourenne, MD, PhD

Although amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD) all have distinct causes and clinical features, researchers have found that neurons in all three conditions accumulate a distinctive pattern of DNA damage—suggesting they may share a common mechanism of neurodegeneration.

In a recent study led by a team of researchers at Mass General Brigham, Boston Children’s Hospital, Harvard Medical School and other collaborating institutions, scientists compared somatic (non-inherited) mutations in individual neurons in brains affected by ALS, FTD and AD. Specifically, they measured single-letter changes and small insertions or deletions, then used computational analyses to determine which DNA damage processes were most likely responsible for these mutations.

Compared to healthy nerve cells, neurons from all three diseases carried higher levels of DNA damage and mutations, including an excessive buildup of small DNA deletions that would normally take hundreds of years to accumulate. The researchers linked this pattern of DNA damage to dysregulated activity of the DNA repair enzyme, TOP1. Notably, this pattern was absent in the cerebellum, a region these conditions typically spare.

Together, these findings reveal a shared pattern of DNA damage across ALS, FTD and AD and suggest that therapies aimed at restoring normal TOP1-mediated DNA repair could be a future therapeutic for multiple neurodegenerative diseases.

Published in Cell on July 1, 2026 | Read the paper: “Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders”

Summary reviewed by: Clotilde Lagier-Tourenne, MD, PhD, co-senior author