2022 Alzheimer's Association Research Grant (AARG)

Single-Cell Analysis of DNA Damage and Mutation in Alzheimer's Disease

How might the pattern of mutations in single nerve cells change as Alzheimer’s progresses?

Michael Lodato, Ph.D.
University of Massachusetts Chan Medical School
Boston, MA - United States

Background

One focus off Alzheimer’s research involves the search for genetic factors that may be linked to increased risk of developing the disease. Some genetic variations are inherited, while others, called “somatic mutations,” can accumulate over an individual’s lifespan due to lifestyle factors or general aging. Since somatic mutations exist in only some cells, they are too rare to be studied using standard genomic (DNA) analyses.

Dr. Michael Lodato and colleagues believe that certain somatic mutations in nerve cells may promote brain changes associated with Alzheimer’s. The research team has used a sophisticated technique called single-cell whole-genome sequencing (a complete readout of the genetic material) to study somatic mutations in the human brain. In previous studies, they have shown that somatic mutations accumulate in human nerve cells during aging, sometimes impacting nerve cell function. However, whether these somatic mutations e impact disease progression in Alzheimer’s is not yet known.

Research Plan

Dr. Lodato and colleagues will build on their work using single-cell whole-genome sequencing to study somatic mutations in single nerve cells during the course of Alzheimer’s. The researchers will study brain tissue from individuals who had either early or late Alzheimer’s, as well as cognitively unimpaired individuals. They will focus on two brain regions associated with early and late Alzheimer’s, respectively: the hippocampus (a structure involved in learning and memory) and the prefrontal cortex (a structure implicated in higher brain functions, such as language, reasoning, planning, and problem solving). Dr. Lodato and colleagues will compare somatic mutation patterns between the three groups to identify changes associated with different stages of Alzheimer’s.

Impact

The results of these studies could shed new light on how certain genetic factors may influence individual variation in the onset or progression of Alzheimer’s. A better understanding of these mechanisms could inform the development of novel strategies for the detection or treatment of Alzheimer’s disease.