Finding Genes Contributing to Risk in Alzheimer Disease

Margaret A Pericak-Vance, PhD
University of Miami (Miami, FL, United States)

Co-Principal Investigators

Stephan A Zuchner, MD, PhD
University of Miami
Year Awarded:
Grant Duration:
July 1, 2011 to June 30, 2015
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southeastern

This grant is made possible due to a generous bequest from the Estate of Frederick J. Pelda.

Margaret A Pericak-Vance, PhD

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 Zhuchner, 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.

Research 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.

About the Researcher

Margaret A. Pericak-Vance, Ph.D., is a founding fellow of the American College of Medical Genetics and a board-certified Ph.D. medical geneticist. She is a global leader in the genetics of common diseases. She has a particular interest in neurogenetic diseases such as Alzheimer’s disease. Her research group’s seminal 1993 paper describing the genetic role of APOE in Alzheimer disease remains one of the most-cited papers in biomedical research. Currently, she chairs the analysis committee of the Alzheimer Disease Genetics Consortium whose recent efforts have had a major impact on our understanding of the genetic architecture of late-onset Alzheimer disease (Naj et. al., Nat. Gen. 2011). In addition to her AHAF award, Dr. Pericak-Vance was named to the “Century Club: 100 People to Watch as We Move to the Next Millennium” by Newsweek magazine. She also received the international “Louis D” Scientific Prize from the Institut de France’s Académie des Sciences for her AD APOE discovery. Her other research honors include: the Hauptman-Woodward Pioneer of Science in 2004, the McKnight Memory and Brain Disorders Award and Alzheimer’s Association Zenith Award in 2001 and the Alzheimer’s Association T.L.L. Temple Foundation Discovery Awards for Alzheimer's Disease Research in 1998. She was elected to the Institute of Medicine in 2004. In 2011, she was honored with the Provost’s Award for Scholarly Activity at the University of Miami and the Alzheimer’s Association Bengt Winblad Lifetime Achievement Award. In 2012, she was named a fellow of the American Association for the Advancement of Science, for her distinguished contributions to the field of genetics.


Stephan Zuchner, Martin A. Kohli, Adam C. Naj, Kara L. Hamilton, Ruchita Rajbhandary, Timothy Plitnik, Krista John-Williams, Patrice L. Whitehead, John R. Gilbert, Eden R. Martin, Gary W. Beecham, Jonathan L. Haines, Margaret A. Pericak- Vance Exome sequencing of extended late-onset Alzheimer disease families identifies a variant in the TTC3 gene, ICAD, 2012

Martin A. Kohli, Adam C. Naj, Eden R. Martin, Gary W. Beecham, Kara L. Hamilton, Patrice L. Whitehead, John R. Gilbert, Jonathan L. Haines, Stephan Zuchner, Margaret A. Pericak-Vance Exome sequencing of extended late-onset Alzheimer’s disease (LOAD) families identifies rare variants associated with AD risk., ASHG, 2011

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