Identifying a DNA Change that Reduces ApoE Risk in Alzheimer’s Disease

Jeffery Vance, MD, PhD
University of Miami (Miami, FL)

Co-Principal Investigators

Margaret Pericak-Vance, PhD
University of Miami (Miami, FL)
Gary Beecham, PhD
University of Miami (Miami, FL)
Anthony Griswold, PhD
University of Miami (Miami, FL)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2018425S
Award Type:
Standard
Award Region:
US Southeastern
Jeffery Vance, MD, PhD

Identifying a Protective Variant(s) for the ApoE e4 Allele

Summary

ApoE is a gene that is the strongest risk factor for Alzheimer disease (AD), but African carriers of the risk form of ApoE get AD less frequently than European carriers of the same form of the gene. We have localized the area on the chromosome that contains the DNA change that is lowering the risk for AD in Africans.  By using DNA sequence data from different populations, comparing the sequence differences, and then seeing how the differences affect DNA function, we will create a small list of potential "protective" changes, changes that can be tested in biological models.  The purpose is to identify how the protective DNA change works in Africans, and use that information to develop a drug to reduce the risk to get AD. 

Details

The goal of the project is to identify a protective genetic change that greatly reduces the risk of the ApoE4 allele to cause AD.

It has been previously known that the risk for developing AD due to the ApoE4 allele is very different between populations.  The risk of developing AD based on carrying the ApoE4 allele is the lowest in Africans, greater in Europeans and the highest in Asians.  We have shown that this difference in risk comes from a small area of the chromosome that surrounds the ApoE4 allele (which we will call the “ApoE4 local ancestry”).  The National Institute of Aging currently is sequencing a large number of African-Americans and Hispanics with AD, which we will use to identify which DNA sequences are different in ApoE4 local ancestry between the carriers of the African ApoE4 allele and the carriers of the European ApoE4 allele.  We next will identify which of these DNA changes also make a difference in the function of the genes in the local ancestry region.    We will do this using new laboratory techniques that allow us to test the effect of many sequence differences at once in the laboratory.  The sequence differences that change function are candidates to cause the protective effect of the African local ancestry on the ApoE4 allele. 

Most genetic studies in AD have focused on genetic changes that increase an individual’s risk for AD.  This proposal in innovative in several ways; it focuses on protective changes rather than risk and utilizes the difference in ancestry between individuals as a tool in the study of AD.  We have shown that all ApoE4 alleles are not alike; ApoE4 ancestry is important when determining the risk to develop AD.

This study will provide us with potential candidates for the protective variant of ApoE4.  We will use this information in future studies of neurons and other brain cells to identify the actual protective change.  Once identified, it will provide a new target to treat AD, one that attacks the strongest genetic risk factor, ApoE.

About the Researcher

Jeffery M. Vance, MD, PhD, is a professor and founding chairman (2008-2012) in the Dr. John T. Macdonald Foundation Department of Human Genetics, and professor of neurology, at the University of Miami, Miller School of Medicine.  He is boarded by both the American Board of Psychiatry and Neurology, and the American College of Medical Genetics.  Dr. Vance is the director of the Center for Genomic Education and Outreach in the John P. Hussman Institute for Human Genomics at the University of Miami.  Dr. Vance obtained his PhD degree in the Department of Medical Genetics at Indiana University and his MD degree at Duke University. He completed his neurology residency at Duke University and rose to the rank of professor of neurology before moving to the University of Miami in 2007, to help found the Hussman Institute.  Dr. Vance’s primary area of expertise and national recognition is neurogenetics, specifically in neurodegenerative disorders and peripheral neuropathies.  His research has focused on the application of clinical, molecular, and mathematical genetic techniques to identify genes leading to human disease. He has identified multiple gene defects for Charcot-Marie-Tooth disease and other neurologic and inherited disorders. Dr. Vance has also been a leader in applying genetics to common medical diseases. He led the NIH-funded Morris K. Udall Parkinson Disease (PD) Research Center of Excellence at Duke and Miami for 17 years. He is currently conducting research on AD as a member of the Puerto Rican Alzheimer Disease Initiative (PRADI), the Research in African-American Alzheimer’s Disease Initiative (REAAADI) and the Alzheimer Disease Sequencing Project (ADSP), all funded by the National Institute of Aging.    He has over 290 publications and his work has been cited more than 19,000 times. 

Personal Story

Human genetics is a field where you can be creative and make a difference in the world.  I fell in love with genetics while an undergraduate at the University of Puget Sound, working on a project saving red wolves, which is still ongoing at the Point Defiance zoo. I also have always been fascinated by the complexity and power of the human brain, for, unlike the other organs in the body, the brain is “us.” This is why neurodegenerative disorders like Alzheimer disease (AD), Parkinson disease, and rare disorders like Huntington’s disease, are so devastating:  we lose the person we know, yet they are still physically there to remind us.  

 Over the past several decades, I have watched the world develop amazing technology and tools to explore the contributions of genetic mechanisms to human disease, especially in neurology. But having the tools is only one part, we need funding to use them. Thus, organizations like the BrightFocus Foundation are so important, and as researchers we appreciate the support and confidence they have in supporting our research. Over the past several years, my colleagues and I have worked to bring all populations, such as African-Americans and Hispanic/Latinos, into the genomic era of research. It is rewarding to see that this work, which focuses on a protective factor for AD, is an outcome of this inclusion, and underlines the importance of this effort, both scientifically and to minimize medical disparity. 

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