Researchers Explain Differences in Alzheimer’s Disease Risk

When it comes to the chances of developing Alzheimer’s disease, what is it that makes the same DNA change or allele (a specific version of a gene) very risky for some people, but less so for others? That’s the question scientists at the John P. Hussman Institute for Human Genomics in the University of Miami Miller School of Medicine were determined to answer.

From left, Farid Rajabli, Ph.D., Margaret A. Pericak-Vance, Ph.D., and Gary W. Beecham, Ph.D.

The study, published December 5, in the journal PLOS Genetics, explored the source of the differing population risk to ApoE e4 in Alzheimer’s disease, finding that the variation is due to an ancestral difference in inheritance of the ApoE gene region. Inheriting the ApoE e4 allele from an African ancestor is not as “bad” as inheriting it from a European or Asian ancestor. These data strongly suggest there is a potential protective change located near the ApoE gene. Identifying what this change is could lead to future interventions and therapies.

The research was led by Farid Rajabli, Ph.D., a post-doctoral associate in the Hussman Institute; Gary W. Beecham, Ph.D., director of the Division of Research Informatics in the Center for Genetic Epidemiology and Statistical Genetics at the Hussman Institute and an associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics; and Margaret A. Pericak-Vance, Ph.D., director of the Hussman Institute and the Dr. John T. Macdonald Foundation Chair of Human Genetics.

“The question of why the same version of a gene is riskier for some people than others is the focus of our latest study in PLOS Genetics,” said study author Dr. Rajabli. “Knowing the answer can help us better predict who will develop Alzheimer disease and set the stage for more effective treatments.”

Researchers have known for quite some time that inheriting the ApoE e4 allele increases the likelihood of Alzheimer’s disease. In fact, it was Dr. Pericak-Vance who identified this genetic correlation more than 25 years ago. The journal article describing her pivotal discovery (Corder et al, Science, 1993) is a seminal work — and still, to this day, the most frequently cited paper in biomedical research on Alzheimer’s disease.

A person can carry zero, one, or two copies of the ApoE e4 allele. Everything else being equal, the more copies you carry, the more likely it is you will develop Alzheimer’s disease.

Recently, though, geneticists have learned that the risk conferred by ApoE e4 differs across ethnic and racial groups.

Specifically, when one looks at only ApoE e4 carriers, people with African ancestry are less likely to develop Alzheimer disease due to ApoE e4 than people of European or Asian ancestry. The reason why ApoE e4 would increase the risk for people of European or Asian ancestry more than it does for people with African ancestry has been a mystery, as there is no difference in the ApoE protein between populations. Two main explanations have emerged: 1.) The difference could be due to environmental or cultural factors that are correlated with ancestry, such as diet and lifestyle activities, or 2.) The difference could be caused by ancestry-specific genetic factors.

To gather and interpret the data needed to clarify which explanation was more likely to be right, UM researchers collaborated with scientists in Puerto Rico and across the United States, including Briseida E. Feliciano, M.D., at Universidad Central del Caribe; Christiane Reitz, M.D., Ph.D., at Columbia University; Gerard D. Schellenberg, Ph.D., at the University of Pennsylvania; Jonathan L. Haines, Ph.D., at Case Western Reserve University; and Goldie S. Byrd, Ph.D., at Wake Forest University,

So what is causing the difference in risk?

“Ethnic, cultural, and environmental factors don’t completely explain the differences,” Dr. Beecham said. “Our study strongly suggests the existence of beneficial genetic information that lies somewhere on the chromosome near the ApoE gene, lowering the risk of Alzheimer’s disease due to the ApoE e4 allele among certain populations.”

Pinpointing exactly where this beneficial genetic information is located and how it protects against dementia is a promising avenue for future research. Discovering the ApoE4 protective effect in African carriers is important, as it is a natural “proven” change that reduces risk.

“It is our hope that further exploration will reveal previously unappreciated biological pathways and provide translational opportunities,” Dr. Pericak-Vance said. “Every new piece of information helps us get closer to ending Alzheimer’s disease.”

Additional UM collaborators include Katrina Celis, M.D.; Kara L. Hamilton-Nelson; Patrice L. Whitehead; Larry D. Adams; Parker L. Bussies; Clara P. Manrique; Vanessa Rodriguez; Jacob L. McCauley, Ph.D.; Brian W. Kunkle, Ph.D.; Jeffery M. Vance, M.D., Ph.D.; Michael L. Cuccaro, Ph.D.; and Eden R. Martin, Ph.D.