Aims

Alzheimer’s disease (AD) is characterized pathologically by neuronal loss and the deposition of misfolded proteins. Research on β-amyloid and tau have led to important advances in AD, but resulting therapeutic strategies have not shown clinical success. It is therefore important to examine pathogenesis from a broader lens.

Neurons each harbor somatic single nucleotide variants (sSNV) in their genomes, which increase with age, at a rate of ~20 sSNV per year, a phenomenon known as genosenium. In AD, DNA damage is increased, leading to the question of whether pathogenesis increases the somatic mutation burden.

Methods

We performed single cell whole genome sequencing on neurons from AD and age-matched controls, and analyzed the burden of somatic mutations and associated nucleotide change signatures for mutational patterns.

Results

We found significantly increased sSNV in AD, with >800 additional somatic mutations per neuron, and a distinct mutation pattern. Unlike normal aging, where clock-related Signature A accumulates, AD neurons show an increase in Signature C, which contains distinct nucleotide changes including C>A variants. Mutations show influences of transcription in sSNV generation. Somatic mutations are predicted to produce deleterious effects on the neuron, including gene inactivation and neoantigen-stimulated immune attack.

Conclusions

AD neurons show increased somatic mutations, with mutagenic causes that illuminate upstream components of disease pathogenesis including DNA oxidation and transcription-coupled DNA repair. Furthermore, somatic mutations position neurons for dysfunction and death. Somatic mutation accumulation is a novel process in neurodegeneration, through which we can dissect the cascade of events in disease pathogenesis.