Whole Exome Sequencing in Alzheimer Disease

The proposed research will look for rare variants in AD in a unique set of large multigenerational AD families that have been followed by our group for over 25 years. Together with ongoing efforts of ours and others to identify common AD risk variants the whole exome approach outlined in this proposal will afford us the best chance to understand the genetic causes of AD and to determine the functional role of the genes underlying this risk.

There are a number of genes that are associated with Alzheimer’s disease, but there are many more yet to be discovered. In this proposed project, Drs. Margaret Pericak‐Vance, Stephan Zuchner, and colleagues will study large families with Alzheimer’s, to increase the chances of discovering a strong genetic risk of developing this disease. These researchers will use new gene reading techniques to look at the “whole exome” (or the DNA spelling of the most‐used books in a person’s genetic library) to filter out a small set of candidates. These candidates will then be double‐checked by confirming their identities in the DNA from other groups of people with Alzheimer’s. Knowing the identity of Alzheimer’s genes could aid with initial diagnoses and lead to future preventions and treatments.

Progress Updates

Clinical relevancy of this project: The need for studies to understand the contribution of genetic rare variants (RVs) to complex diseases such as Alzheimer’s disease are timely and necessary. However, the problem of how to sift through the millions of changes to find those RVs of causative effect still remains, and is not trivial—like finding a needle in a haystack. Because they are rare, the RVs may be below the levels of detection of even large GWAS studies. However, in the individuals carrying the genetic variant, the increased risk of disease may be substantial. This means that relatives of affected individuals with these variants may be at substantially increased risk of Alzheimer’s and, logically, that these variants will be abundant in families with larger numbers of affected individuals. Thus, the best resource for finding RVs is large extended families with multiple affected individuals.

Dr. Pericak-Vance’s and Dr. Stephan Zuchner’s team has developed a unique resource of 60+ such families which they have followed for over 25 years. So far, the team is busy analyzing the DNA from these families with new methods that can efficiently sequence large portions of a person’s genome, allowing direct detection of RV genes in Alzheimer disease.