DNA Is Not Your Destiny: Genetics and Alzheimer’s Disease Risk

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Transcript

Nathaniel Chin: My guest today on Dementia Matters is Dr. Corinne Engelman, director of the graduate programs in population health and epidemiology, also a genetic epidemiologist and vice chair at the University of Wisconsin School of Medicine and Public Health in the Department of Population Health Science. She studies complex diseases in the context of aging and genetics. In her research, she examines disease risk from both genetic and environmental perspectives. What people often refer to as “nature versus nurture.” Dr. Engelman, welcome to Dementia Matters.

Corinne Engelman: Thank you.

Nathaniel Chin: Today we are going to talk about genetic risk and protective factors for Alzheimer's disease. Now, before I get into my questions, I want to remind our listeners that while there are slight semantic differences between genes, genetics, and DNA, people generally use the terms interchangeably, which is what you'll probably hear us do today. So basically, when we talk about genes or DNA, we are talking about our genetic blueprint, the molecular recipe that defines or influences our eye color, height, nose shape, and even our susceptibility to certain diseases.

Corinne Engelman: Right, and actually, while eye color might be a hard and fast rule, something like height, for example, is actually very complex and can be influenced by multiple genetic factors. Then also by environmental factors, as well.

Nathaniel Chin: That's why you see some children who end up being taller than their parents. 

Corinne Engelman: That’s right.

Nathaniel Chin: It's much more complicated than just your genes ending up dictating what you're going to look like.

Corinne Engelman: That’s right.

Nathaniel Chin: Dr. Engelman, can you tell us about the genetic influences on a person's risk for Alzheimer's disease?

Corinne Engelman: Yeah, there are a handful of genetic mutations that are very rare but have a strong effect on a person's risk for Alzheimer's disease. These mutations generally result in a younger age of onset in Alzheimer's disease. But most of the cases of Alzheimer's disease are caused by a mix of genetic factors with smaller effect and also environmental factors. One genetic variant, the APOE gene, has a variant called E4 and this can increase a person's risk for Alzheimer's disease, but it does not guarantee that the person will go on to develop Alzheimer's.

Nathaniel Chin: Often times, we think about genetic risk and we separate those who have “early onset,” or diagnosed before the age of 65, and then late onset, which I would see in my clinic. APOE tends to be more often in late onset, but there are other genes that are affecting people in early onset. Is that right? 

Corinne Engelman: That’s correct. The age, as you know, is kind of artificial. There are a handful of genes. There are three that are very well established, and then a couple of others that tend to have an earlier age of onset, could be as early as 40s, 50s, or 60s, but even it could be as late as the 70s. It depends on the variants that you have in one of those genes. Some will result in an earlier age of onset, some a little bit later.

Nathaniel Chin: I think that's good for our audience to hear too, because we are so fixated on the age of diagnosis and of course in clinic that's what we deal with. But it is good to know that frankly that's just not made up, per se, but that's not relevant to the genes themselves.

Corinne Engelman: Right. Yeah, that's right. It is kind of an artificial distinction that we make. There's a little bit of a gray area basically.

Nathaniel Chin: Now, are there also genes that protect against Alzheimer's disease or at least reduce the risk for Alzheimer's disease?

Corinne Engelman: Yeah, there are. I mean, one genetic variant is actually in that APOE gene and it’s the E2 allele and that one provides protection against Alzheimer's. But there are also other genes that have been found to protect against Alzheimer's risk.

Nathaniel Chin: How do you determine if a gene or a set of genes has an impact on a disease like Alzheimer's disease?

Corinne Engelman: We've studied people who have or do not have Alzheimer's, and we look for genetic variants that are more common in the individuals who have Alzheimer's than they are in those who do not end up developing Alzheimer's.

Nathaniel Chin: Once you get a signal, does that help us figure out potential mechanisms as to why some people will develop the disease?

Corinne Engelman: It does, and actually, in the last 5-10 years we've learned a ton about the potential additional pathways to Alzheimer's disease, for example, cholesterol, metabolism, inflammation. So really, these genetic findings are helping us learn about the biology of Alzheimer's.

Nathaniel Chin: How do we know if it is one gene, such as APOE, or a variety of genes that come together to increase or decrease someone's risk?

Corinne Engelman: So again, I think that for the early onset forms of Alzheimer's, it's more likely that it is just one gene. That would be pretty common for it to be one gene. Whereas for the later onset forms, I think it probably is more likely a mix of different genes coming together to influence our risk.

Nathaniel Chin: And genes can sort of counter each other. You could have, for instance, an APOE-4 that increases risk, but then somewhere else, a gene that helps reduce inflammation and, therefore, they're not working together. One's helping, one's hurting,

Corinne Engelman: Right, and there is some work in the field to develop genetic scores for a person's risk. This is something that is really being done in some other fields, like breast cancer and cardiovascular disease, and something that's starting to be done for Alzheimer's also. It's possible that in the future, we'll be able to kind of add together all the effects of different genes across the whole genome and know someone’s genetic risk.

Nathaniel Chin: I think not only would that be helpful in research and clinical care, but I think from the perspective of the person worried, it would be nice to know that while you have this one risk, you also have some other things going in your favor. So maybe it's not as bad as you thought it was. Is it reasonable to think then that there are other important genes that influence one's risk of Alzheimer's disease that we simply haven't found yet?

Corinne Engelman: I think it is. I think that those will probably end up being less common in the population, but they are still important for the biology of the disease in general.

Nathaniel Chin: Can the genes themselves help us determine possible causes, like you said, cholesterol, inflammation, but other things that haven't been discussed even 10 years ago.

Corinne Engelman: Yeah, I think that we're getting there. There's still a lot that's unknown in this area, but I think that we're moving in that direction.

Nathaniel Chin: How much can our environment or our lifestyle habits affect these genetic risks?

Corinne Engelman: So again, it's unknown exactly how much, but there's some preliminary findings that indicate — and one of them is a study that was done here at the ADRC in collaboration with Dr. Ozioma Okonkwo — that we can probably negate some of the risk due to APOE and other genes in the cholesterol metabolism pathway by being physically active. There's some interesting results that are coming out on this.

Nathaniel Chin: I anticipate more and more people are looking at genetic risk and these lifestyle interventions.

Corinne Engelman: Definitely. In fact, there are some bigger groups that are forming risk scores with respect to behavioral factors that are modifiable, and then also looking at how that might modify these genetic risk scores that I talked about. My group is working on that and there are other groups that are working on that. I think that there will be some exciting findings coming out in the next couple of years on that.

Nathaniel Chin: Are you doing your genetic testing all through blood samples or how are you analyzing these things?

Corinne Engelman: Most of it is through blood, if we have that, and we usually do. Sometimes we use saliva. It's an easier way if we have a participant who has Alzheimer's disease and we can get saliva through their caregiver. We can also use the banked brains through the ADRC if an individual is deceased, maybe if we’re studying some of their family members. So, we've done that as well.

Nathaniel Chin: What kind of machines are you using in order to make these kinds of observations?

Corinne Engelman: Yeah, so my lab doesn't actually do that work. We are either using, there's a biotechnology center on campus that we have worked with and sometimes we're working with international or national groups, collaborations with the national institutes of health, and sending it to some of their labs.

Nathaniel Chin: So it really is a team.

Corinne Engelman: Yes.

Nathaniel Chin: Wow. It used to be that people only learned about genetic factors for Alzheimer's disease if they underwent genetic testing in their doctor's office or in a research study. But a few years ago, companies that specialize in at-home ancestry genetic testing started offering these health-related trait reports and even these health predisposition reports. Now what can these reports tell people about the risk for Alzheimer's disease?

Corinne Engelman: Right. One of the most popular companies is 23andme and they have gotten approval to do some health testing. One of them is with Alzheimer's disease, which was surprising to me because it's not recommended actually that you do genetic testing. But they're doing it. And the only gene that they test on is APOE, and they only test on the E4 Allele. So they only give you results for your increased risk due to E4, but not the protective effect of E2, not the early onset mutations, and not any other genetic variants that would provide protection or risk. It's very limited.

Nathaniel Chin: It's sort of an incomplete picture. 

Corinne Engelman: Yes.

Nathaniel Chin: I appreciate they have approval, so they're not breaking any rules here, but it's such a complex process that we might be missing out on things when we talk to people about their genetic risk.

Corinne Engelman: That's right. It's a very incomplete story, but it's what that company is doing. I believe there are others that are probably also using that incomplete picture as well.

Nathaniel Chin: I must tell you in clinic there is a demand for people to want to know their genetic risk, but I don't think it's fully clear that we don't have all of the answers yet. I can see a demand for this information, but do you think if we are to learn our genetic risk, even whatever information we have, that there really should be some sort of genetic counseling afterwards?

Corinne Engelman: Absolutely. I definitely think that most people in the field feel that that is preferred. In fact, the recommendation is that if you are going to get genetic testing for Alzheimer's that you do so with a genetic counselor being involved through the whole process.

Nathaniel Chin: What about inflammation? Cause again, people will often think, well yeah, I've got inflammation in my joints. Is that going to translate to my brain?

Corinne Engelman: Right. The types of tissue and the cells that help with inflammation in the brain are a little bit different than the ones that we have in the rest of our body. One of the genes that has been discovered recently is called TREM 2. That is thought to help with the immune response in the brain. But again, we're still really learning more about the role of TREM 2 and how it helps kind of fight or work with the immune system in the brain.

Nathaniel Chin: Then another thought that comes to mind: Aging is a big risk factor for Alzheimer's disease. Have we found any genetic risks that are either too active or not active enough when it comes to a person's aging genes in the brain?

Corinne Engelman: Yeah, and again, this is, you know I really focus on Alzheimer's disease, but there are studies that are being done in people who age very healthy, you know, living to be a hundred or more. Those studies are really giving us some interesting results of just general healthy aging.

Nathaniel Chin: Because it seems very clear that, you know, to address something as complicated as Alzheimer's disease, we really need a team. We need multiple people looking at different aspects of our genes, the environment, and aging and disease. That it isn't going to be just one thing. It's going to be multiple things with multiple pathways.

Corinne Engelman: Right. That's right. As you know, there's information or more research coming out that there’s a vascular component, and so that's another area. But yes, it's very complicated.

Nathaniel Chin: In closing, I want to ask over the course of your research career, what advice can you offer to our listeners about taking their destiny into their own hands in regard to Alzheimer's disease? How much is environmental? I know you can't give me a specific answer, but what kinds of things do we have control over that may help us prevent Alzheimer's disease or delay its onset?

Corinne Engelman: For late onset Alzheimer's disease, maybe about half of the factors are environmental, so there are things that we can do to either prevent Alzheimer's or to at least delay the onset. Even for the early onset forms, there are probably things that you can do to at least delay the onset. The nice thing is that these are things that are also helpful for other health outcomes, you know, things like a more healthy diet, being more physically active. These are things that are good for us for other outcomes, as well. 

Nathaniel Chin: Well, I'd like to thank you for being on the show today and we do hope to have you back once you've learned more information. 

Corinne Engelman: Thank you very much.