Analysis of somatic mutations in Alzheimer's disease

Our objective is to study somatic mutations in the genome of human neurons in Alzheimer's disease (AD).
Our study design is as follows. We will identify somatic mutations present in the single-cell whole-genome sequencing datasets in this dataset using established algorithms. We will then characterize those mutations in various ways, including 1) location of mutations (exons, introns, intergenic regions), 2) mutation types (substitutions, indels, aneuploidy), and 3) mutation signatures (exact nature of base changes, for example C>T vs. C>A mutations, small vs. large deletions).
Our analysis plan is to compare patterns of mutation in advanced AD neurons to neurotypical controls. AD stage was determined by the authors using the Braak staging system. The Braak staging system uses the intensity and brain region distribution of staining of Tau neurofibrillary tangles in the brain to assign the severity of AD pathology. Donors with significant staining in the prefrontal cortex are considered late-stage. We will not analyze germline genetic markers in this study.

Alzheimer’s disease (AD) and other neurodegenerative diseases are characterized by age-related loss of neurons in the brain, and afflict about half of individuals over the age 85. Scientists currently have a poor understanding of the causes of these disorders. This study will examine how DNA damage and somatic mutation changes during healthy aging relates to AD, with the goal of better understanding the causes of these diseases so that treatments and cures can be developed.