Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain

Aging in humans is associated with a host of brain diseases, including tumors of glial progenitor cells and degeneration of neuronal cells. However, the mechanisms by which age and disease risk interact are poorly understood. Recent studies from our group have shown that somatic single nucleotide variants (sSNV) accumulate even in nondividing neurons in the human cortex, resulting in thousands of sSNV per neuronal genome by old age. Further, the patterns of sSNV that are found can be classified, and normal brains appear to have somatic variants that were present at birth, variants that accumulate over time, and variants caused by oxidative damage. Our studies also find a significantly higher rate of sSNV accumulation in neurons from Alzheimer’s disease (AD) brain, likely related to increased oxidative damage. These studies relied on new techniques that allow deep whole genome sequencing of DNA isolated from a single neuron taken from frozen postmortem brain. This new study aims to further characterize the rates and patters of somatic variants that accumulate in single neurons and glia as an individual ages, and determine how this accumulation of mutations is related to AD as well as the formation of glial tumors. The first aim will examine neurons form different regions of normal brain at different ages. This will give us a better understanding of how these mutations accumulate with age, and the specific mutational forces at work in different brain areas. The second aim will perform a similar analysis, this time focused on glial cells instead of neurons. In the final aim, we will look at neurons in the brains of individuals who had AD, and analyze how the rate and patter of mutations differ compared to aged- matched normal brain. This will provide valuable insight into the causes of somatic mutations in AD. There is compelling evidence to suggest that somatic mutations in individual neurons are an important factor in at least some neurodegenerative disorders, and our data implicate them in normal cognitive aging. For the first time, the tools exist to examine these questions, and this study is designed to determine how somatic SNV impact normal aging, brain tumor formation, and AD. This is a crucial step in understanding the molecular cause of AD, and a prerequisite to the development of treatments and cures.