Gene Changes in Individual Cells Assessed Across the Progression of Alzheimer's Disease

Alzheimer’s disease (AD) and other neurodegenerative diseases involve a loss of brain function and brain cells over time and eventually cause death, affecting one third of people over the age of 85. Recent research has found that brain cells build up new mutations in the DNA (known as somatic mutations) as we get older, which appears to harm the brain cells. This proposal will test the hypothesis that somatic mutations contribute in important ways to the pathologic progression of Alzheimer’s disease, and are related to other kinds of disease damage in brain cells, including oxidative stress.

The goal of this project is to study the amount and mechanisms for how new DNA changes, called somatic mutations, happen as Alzheimer’s disease progresses from early to later stages. In Aim 1, I will use a cutting-edge technology called single-cell whole genome sequencing (scWGS) to count the number of somatic mutations in brain cells. I will compare the number of mutations between individuals with different stages of Alzheimer’s disease. In Aim 2, I will study the types of somatic mutations that happen in Alzheimer’s disease stages, to learn whether some types of mutations happen earlier than others. I will also look into a particular suspected cause of some mutations, which is oxidative damage, caused by oxygen molecules with the wrong number of electron particles in them. This project applies state-of-the-art technology to study all the genes of individual cells in the brain from Alzheimer’s disease. In this way, the project can learn about events that affect many genes at the same time and use this information to learn what is causing somatic mutation DNA changes in brain cells during disease. Findings from this study will be of value for Alzheimer’s disease by casting light on how genome changes are involved in harming cells. In addition, knowledge of these events can teach us about particular pathways that are involved in Alzheimer’s disease and how they may be changed using medicines to improve health of people with Alzheimer’s disease.