Looking for New Insight into the Genetics of Alzheimer’s Disease in Diverse Populations
Article Summary
- The John P. Hussman Institute for Human Genomics has received a $28.6 million NIH grant to study the genetics behind Alzheimer’s disease in people of African descent.
- Alzheimer’s disease is expected to affect as many as 150 million people in the next 25 years.
- The grant builds upon the ongoing, Hussman-led DAWN study.
The John P. Hussman Institute for Human Genomics (HIHG) at the University of Miami Miller School of Medicine has received a $28.6 million grant from the National Institute on Aging to launch a comprehensive study over the next five years that will offer new insights into the genetics behind Alzheimer’s disease in people of African descent.
The ultimate goal: to use these insights to develop targeted therapeutics against a disease expected to affect more than 150 million people over the next 25 years.
“Alzheimer’s disease is a worldwide epidemic, but individuals of diverse ancestries have been underrepresented in genetic studies,” said Anthony Griswold, Ph.D., author and contact principal investigator of the grant as well as associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and associate director of the Center for Genome Technology in the John P. Hussman Institute for Human Genomics. “Our grant will analyze genetic factors that contribute to Alzheimer’s disease in more than 9,000 individuals of African ancestry to expand our global efforts to identify therapeutic targets.”
Joining him as co-principal investigators from the University of Miami are:
• Margaret Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Professor of Human Genetics
• Jeffery Vance, M.D., Ph.D., professor and founding chair in the Dr. John T. Macdonald Foundation Department of Human Genetics and professor of neurology in the Miller School
• Brian Kunkle, Ph.D., M.P.H., assistant professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and head of the Genetic Epidemiology Division in the Center for Genetic Epidemiology and Statistical Genetics at the Miller School
This is a far-reaching collaborative study also including co-principal investigators from around the U.S.:
• Jonathan Haines, Ph.D., chair of the Department of Population and Quantitative Health Sciences at Case Western Reserve School of Medicine
• Goldie Byrd, Ph.D., director of the Maya Angelou Center for Health Equity at Wake Forest University
• Christiane Reitz, M.D., Ph.D., associate professor of neurology and epidemiology at Columbia University
Critically, this proposal will continue to build collaborative links with the African Dementia Consortium (AfDC) led by Rufus Akinyemi, Ph.D., professor of geriatric neurology and translational neurosciences at the Institute for Advanced Medical Research and Training at the College of Medicine, University of Ibadan, Nigeria.
Studying Alzheimer’s in Diverse Populations
The new grant marks the next step for Hussman Institute researchers in their quest to shed light on the genetics of Alzheimer’s in diverse populations. The study builds upon the ongoing, Hussman-led DAWN study. Led by Dr. Pericak-Vance in collaboration with researchers at Case Western Reserve University, Wake Forest University, Columbia University and the AfDC, the DAWN study is recruiting thousands of research participants across Africa and the U.S.
“In addition to identifying population-specific genetic risk factors, the sequence data will enable us to explore genetic differences in risk across populations with the potential to identify novel protective genetic loci, further enhancing our understanding of AD,” said Dr. Pericak-Vance. “The HIHG continues to expand its global footprint, championing inclusion in research participation. The insights gained from the diverse genetic makeup across these populations will help develop more effective, precision therapies and preventions that are globally relevant.”
The newly funded study will expand upon the DAWN infrastructure of databased clinical data and stored biological specimens (DNA and plasma) to generate whole genome sequencing, plasma biomarker data and cardiovascular disease biomarker data on 5,000 Africans and 4,000 African Americans. The study will also conduct initial clinical follow-ups on cognitively unimpaired or mildly cognitively impaired DAWN participants.
Alzheimer’s Disease Sequencing Project
The whole genome sequencing from this project will become part of the Alzheimer’s Disease Sequencing Project (ADSP), established in 2012 by the National Institute on Aging to investigate genes that increase dementia risk and translate those findings into therapies. The addition of nearly 9,000 sequences of individuals of African ancestry is a game-changer, nearly doubling the amount of such data in the ADSP to provide sample sizes large enough for analyses to identify meaningful results toward new factors involved in dementia risk and protection.
Researchers also will analyze blood samples for Alzheimer’s plasma biomarkers and cardiovascular disease risk biomarkers. Using the genetic and biomarker data, they will build comprehensive models to look at disease risk and prevention as they consider environmental factors that might be having an impact.
By doing genetic studies across diverse populations, we aim to identify broadly applicable therapeutic targets to reduce the global burden of Alzheimer’s disease.”
—Dr. Anthony Griswold
“Depending on what country they are from, what level of education they have, what diseases they have, combined with their genetics, we will build comprehensive models for disease risk and come up with a polygenic risk score that includes genetic and environmental data,” Dr. Griswold said.
The grant also includes plans to do the initial clinical follow-up with DAWN study participants who were found to be cognitively unimpaired or mildly cognitively impaired, timed to four years after their initial evaluation. The team also will acquire MRI data from 200 Nigerian participants.
“Oftentimes, when someone sees us in a study, we do cognitive assessment and collect biospecimens, and may never see them again,” Dr. Griswold said. “The clinical teams of the AfDC and institutions in the U.S. will revisit unimpaired or mildly impaired individuals from the DAWN study as an initial clinical follow-up.”
Diversity Key to New Insights
Previously, most of the genetic research into Alzheimer’s has been focused on European populations. However, recent work led in part by the Hussman Institute has identified several factors that vary in their impact on dementia, depending on ancestry. This is evident by the ancestry-modified risk of the APOE4 allele, where individuals of European ancestry have higher risk than those of African ancestry with the same genetic variant.
“So they need to be included in this research, to identify the interplay between genetics, environment and ancestry on dementia” Dr. Griswold said.
Studies like this one mean hope for future treatments is brighter than ever.
“Across every disease, targets for therapy are much more likely to be efficacious when there is genetic evidence supporting that target,” Dr. Griswold said. “By doing well-powered genetic studies across diverse populations, we aim to identify broadly applicable therapeutic targets to reduce the global burden of Alzheimer’s disease.”
Tags: Alzheimer's disease, DAWN Alzheimer's Research Study, Dr. Anthony Griswold, Dr. Brian Kunkle, Dr. Jeffery Vance, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Margaret Pericak-Vance, genetics, John P. Hussman Institute for Human Genomics, NIH grant, USNWR Geriatrics