Strong Partnership Between Hussman Institute and African Geneticists Benefits Alzheimer’s Research
Summary
- John P. Hussman Institute for Human Genomics researchers recently visited Uganda for the African Society of Human Genetics meeting.
- Dr. Margaret Pericak-Vance gave a plenary presentation on the global genetics of Alzheimer’s disease as a pathway to prevention and treatment.
- Dr. Pericak-Vance and team’s work in Africa and Peru has allowed them to identify new areas of known genes and new genetic changes that can cause Alzheimer’s disease.
Fresh off a trip to Uganda for a conference on human genetics, Margaret Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics and the Dr. John T. Macdonald Foundation Professor of Human Genetics at the University of Miami Miller School of Medicine, sat down to discuss the Hussman Institute’s work across the continent and how it is spurring progress back home.
Dr. Pericak-Vance and Hussman Institute researchers Jeffery Vance, M.D., Ph.D., Anthony Griswold, Ph.D., Farid Rajabli, Ph.D., Katrina Celis, M.D., and Brian Kunkle, Ph.D., M.P.H., spent six days connecting with their African collaborators at the African Society of Human Genetics meeting. They presented groundbreaking research to geneticists not only from across Africa but also from other continents.
Dr. Pericak-Vance’s plenary presentation at the conference was on the global genetics of Alzheimer’s as a pathway to prevention and treatment. The Hussman Institute research team also presented on topics ranging from the use of artificial intelligence and machine learning to uncover the underlying mechanisms of Alzheimer’s to how differences in the ancestral genetic architecture of Alzheimer’s contributes to underlying functional outcomes.
You’ve been working with geneticists in Africa since 2022 for the Hussman-led DAWN Alzheimer’s Research study funded through the National Institute on Aging of the National Institutes of Health. You’re recruiting 5,000 research participants across Africa through the Africa Dementia Consortium led by Dr. Rufus Akinyemi from the University of Ibadan. How does your collaboration with Africa, in particular, help advance your research into Alzheimer’s disease?
Our research highlights a remarkable ancestral variation across Africa. For example, besides the rich variation in indigenous African ancestry in West Africa, we observed genetic influences from European and Middle Eastern populations, while East Africans displayed admixture with South Asian and Middle Eastern ancestries.
Therefore, leveraging genetic variation from African individuals will benefit not only those from Africa but Alzheimer’s patients worldwide. It’s all about using these differences as a tool, not only because there are things unique to each population and Alzheimer’s is a global problem, but because you learn things from each group that you are then able to target and get a new treatment for another group.
For example, the Christchurch variant, which is a protective variant now being considered for Alzheimer’s therapy, was discovered in the country of Colombia. We have discovered a common protective locus for APOE4 that is only in African ancestry. Both, when the mechanisms are understood, can be applied globally to all individuals.
How does the Hussman team’s seminal discovery that the APOE4 gene is less toxic if inherited from African ancestors as opposed to European ancestors move Alzheimer’s research forward?
We used the difference in risk between ancestries as a tool to further investigate APOE4. Dr. Rajabli and I led a study that demonstrated that differences in risk from APOE4 between ancestries was due to the DNA closely surrounding the APOE4 gene and not elsewhere in the genome. This finding led Drs. Griswold, Celis and Jeffery Vance and colleagues to show that Africans express a significantly lower amount of APOE4 in their brain, which suggested that APOE4 is toxic and having less of it around lowers your risk for Alzheimer’s disease.
Next, an international group of senior scientists followed this finding and, along with data from animal studies, concluded that, indeed, APOE4 is toxic and therapy needs to be focused on lowering its expression. This was published in early 2024 and has focused and excited researchers on working to create methods to accomplish this for therapy of APOE4.
It’s like working on a huge puzzle, looking at different ancestries and genes, and trying to see how the pieces interact and work together.
Dr. Margaret Pericak-Vance
Following up on their APOE4 findings, Drs. Rajabli and Jeffery Vance discovered a protective variation on the African background that lowered the APOE4 risk effect by up to 75 percent. The idea is that these protective effects are found in Africans, but if you can understand the mechanism, you could then take that and figure out how to reduce the toxic effect of APOE in people with other backgrounds. It’s like working on a huge puzzle, looking at different ancestries and genes, and trying to see how the pieces interact and work together.
This collaboration with Africa has probably been one of my most fruitful collaborations. We share data and we share knowledge. Beyond genetics, we look at environmental factors of everyday life that could also increase risk for Alzheimer’s disease.
For many U.S. citizens, including African Americans and Caribbean Hispanics, on average up to 80 percent of their genome could come from African ancestry. However, the diet and lifestyles between their own groups and those individuals living in Africa can be extremely different. Given the shared ancestry between the groups, how these different lifestyle influences interplay with similar genetics could give us additional clues to how to reduce Alzheimer’s disease risk.
You were able to purchase a DNA extraction machine for your collaborators in Africa. How has this been beneficial?
They were doing all their extractions of DNA by hand. When they received the machine, this was key for them to be able to move things at a faster pace since, for the DAWN study, we are collecting DNA from 5,000 individuals from Africa.
What we are doing that is unique is the DNA will be stored there, so we are helping them set up a DNA bank for researchers. In the past, the DNA would often come and be stored in the U.S. or Europe, and they wouldn’t be left with anything. Now, they just send us an aliquot for sequencing, and they can use the DNA for future research. It was critical to change the paradigm because they are fantastic collaborators and understand they are working for themselves as well as the global research world.
For your fifth trip to Africa, what did you do when you weren’t at the conference?
We were excited to visit our local site in Kampala, Uganda, led by Dr. Kamada Lwere, and meet all our collaborators there. We were able to go into the villages where they are enrolling patients. The effort to contact these patients is considerable, and we were impressed by the dedication and passion of their research teams.
Led by Dr. Celis, we also visited a local orphanage, New Hope Children’s Centre in Entebbe, Uganda, and donated food and clothes to the children. It was an amazing experience. It has been wonderful going to Africa and learning so much about different groups and cultures.
What is on the horizon?
We are constantly analyzing new data to show variation. Now that we are in Africa and in Peru, we have identified new areas of known genes and new genetic changes that can cause Alzheimer’s disease. We then study how these changes effect function to understand the mechanism behind the process. This gives us a better idea of how we can develop therapies, even for rare forms of genetic Alzheimer’s, some of which haven’t been reported before.
It’s exciting and helps fill gaps in the global understanding of the disease. It also helped us to understand that Alzheimer’s disease is heterogenous, it has many starting causes which all lead to a similar outcome. We realized early on that taking a global approach to Alzheimer’s disease and understanding the complete genetics landscape contributing to risk in Alzheimer’s disease was the way to find new treatments and preventions for all.
Tags: Alzheimer's disease, APOE4 gene, DAWN Alzheimer's Research Study, Dr. Anthony Griswold, Dr. Brian Kunkle, Dr. Farid Rajabli, Dr. Jeffery Vance, Dr. Katrina Celis, Dr. Margaret Pericak-Vance, Jeffery Vance