What Role Do Genetics Play in Determining Alzheimer Disease Risk?

Jeffery M. Vance, MD, PhD, professor of neurology, and director, Center for Genomic Education & Outreach, John P. Hussman Institute for Human Genomics, University of Miami

Jeffery M. Vance, MD, PhD

Despite having the same genetic markers, there is much variation between risk levels for individuals of different ethnicities due to regulatory mechanistic differences. This component accounts for 98% of the chromosome, according to Jeffery M. Vance, MD, PhD, professor of neurology, and director, Center for Genomic Education & Outreach, John P. Hussman Institute for Human Genomics, University of Miami.

At the 2019 Alzheimer’s Association International Conference held in Los Angeles, California, July 14—18, he was involved in a number of presentations highlighting the work he and colleagues have done in attempting to discern the differences between ethnic backgrounds and risk in developing Alzheimer disease. While the field has known for some time about existence of risk differences, the overall understanding is still limited.

Vance sat with NeurologyLive^® to discuss the role of genetics, specifically the APOE4 allele, in distinguishing Alzheimer disease risk between groups. One of his notable takeaways is that this knowledge plays a role in clinical trial enrollment, as just the presence of the APOE4 allele does not mean there is no variance between patients. Vance underlined the need for this to be taken into account as clinical trials expand to be more diverse.

NeurologyLive^®: Can you discuss the overall role and motivation for exploring genomics in relation to Alzheimer's disease?

Jeffery M. Vance, MD, PhD: It's been known for a long time that APOE—the risk from APOE—is different among different racial and ethnic groups. Africans have very low risk secondary to APOE4 relative to Europeans, and Asians appear to have the highest risk from APOE4. The reason for that has not been known for a long time, and so what we have done recently is we've collected samples on African-Americans and Hispanics from the Americas—both of these groups are admixed, and they have different ethnic backgrounds. Hispanics from the Americas, originally of course in South America and the Caribbean, there were Ameri-Indians. Then the Spaniards and the Portuguese came in and intermarried. Then there was the slave trade, which came around the Caribbean and the Northern parts of South America, so Hispanics in the Americas have backgrounds of African, African-European, and Ameri-Indian. African-Americans also have a background of European and African mix.

We were collecting samples from both of these groups and using that, we were able to identify the different parts of the chromosome that come from different ancestors. You see this with 23andMe, and things like that, and what we showed was that if you inherited your APOE4 allele from your European ancestor, that you've got the European risk, and if you inherit it from your African ancestor, you got the lower, African risk. This was because there's something around the APOE4 allele that is protective for Africans from the APOE4 allele. It's not their global ancestry or their environment, it's something fairly close to the actual gene.

What does that mean for the clinical aspect of Alzheimer treatment?

Well, first of all, it means that people that have APOE4—not all have the same risk for APOE4, particularly. If you’re an individual with Hispanic background—say Hispanic of the Americas because obviously, Hispanics from Spain or Portugal don't have as much admixture, very little—so it really matters where that APOE4 came from. You could have an APOE4 that's really not much risk to you, relatively. This is a good example of how precision medicine is beginning to come into this effect. I think from a clinical aspect we're going to see this more and more. This idea of the risk being different between different groups for the same genetic marker.

What is the current understanding of why this risk is different?

That's probably because the regulatory areas, which make up about 98% of your chromosome, your genomes, that's the differences. So, some people may have like a part of their genome that's kind of like a turbocharger and ups the output of some gene. The gene may be the same, but the regulatory mechanism may be different. This is going to be something that clinicians are going to have to deal with more and more. It's going to be important in clinical trials. Obviously, if you're measuring people with APOE4 in a clinical trial, not all people are going to be the same, and as we expand into including other diversities—which we have to do other groups—this is going to become something people have to take into account.

Transcript edited for clarity. For more coverage of AAIC 2019, click here.