Somatic mutations in neurodegeneration: from detection to disease mechanisms

Abstract Somatic mutations are postzygotic DNA alterations that accumulate throughout development and aging, underlying somatic mosaicism across cell populations. Neurons are particularly vulnerable due to oxidative stress, high metabolic demand, and age-related decline in DNA damage response pathways, promoting cell-type-specific dysfunction. Somatic repeat instability is an established driver in Huntington’s disease, yet the extent and functional impact of somatic mutagenesis in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis remains unresolved. This article highlights how advances in single-cell and single-molecule sequencing, integrated with computational and machine learning approaches, support detecting ultra-rare variants and establishing causal links between somatic mutagenesis and neurodegeneration.