2024 Alzheimer's Association Research Grant (AARG)

Mapping the X Chromosome Multi-Ome in Alzheimer's and Parkinson's Disease

Can novel gene mapping techniques determine how sex-related gene variations promote risk for Alzheimer’s and Parkinson’s?

Michaël Belloy, Ph.D.
Washington University in St. Louis
St. Louis, MO - United States

Background

Genes play complex roles in Alzheimer’s disease, Parkinson’s disease and other dementias. One gene variation called APOE-e4, which provides instructions for making ApoE protein, is thought to increase risk of Alzheimer’s in some populations. However, there are numerous other gene variations that likely affect dementia risk. 

Scientists have been using various analytical methods, including genome-wide association studies (or GWAS, analyses of genetic information from large groups of individuals), to identify dementia-related genes on chromosomes. Chromosomes are the organized structures of genetic material (DNA) in a cell. One human chromosome that may contain important dementia-related genes is the sex-related X chromosome. Women typically have two X chromosomes, while men typically have one X chromosome and one Y chromosome. Though the X chromosome has received relatively little attention from dementia researchers, Dr. Michael E. Belloy and colleagues have recently conducted an extensive X chromosome genetic analysis in people with Alzheimer’s disease and Parkinson’s disease. Their work has identified novel genes that may increase a person's risk for Alzheimer’s. However, the researchers have not yet learned exactly how such genes impact dementia risk or affect dementia-related processes in the brain.

Research Plan

In this project, Dr. Belloy and team will work to clarify the relationship between X chromosome gene variations and the risk of Alzheimer’s and Parkinson’s. Using genetic and other data from people with Alzheimer’s or Parkinson’s, the team will conduct a series of advanced computational techniques called qualitative trait loci (QTL) analyses. QTLs enable researchers to “map” disease-related genes – as well as the proteins made from those genes – in the brain and cerebrospinal fluid (or CSF, the biological fluid surrounding the brain and spinal cord). Disease-related changes can be measured in the CSF and often correspond to similar changes in the brain. 

Dr. Belloy’s group will create a database of protein and gene variations on the X chromosome that are related to Alzheimer’s and Parkinson’s. They will then use other analytical methods to assess how X chromosome genes impact various disease processes in each disease. Their work will focus on three disease processes in Alzheimer’s (the clumping of beta-amyloid and tau proteins, and the loss of volume in a brain region called the hippocampus) and one disease process in Parkinson’s (the build-up of proteins called Lewy bodies). For all of these experiments, Dr. Belloy and team will examine differences in how X chromosome variations relate to dementia risk in women and men.    

Impact

Results from this study could shed new light on the genetic underpinnings of Alzheimer’s and Parkinson’s diseases. It could also lead to novel methods of diagnosis that could be targeted to women or men.