Study Shows APOE Gene Affects Hispanic Populations’ Risk of Cognitive Decline Differently to Non-Hispanic Populations

Transcript

Intro: I'm Dr. Nathaniel Chin, and you're listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Today, I'm joined by Dr. Cally Xiao, project specialist for the Global Alzheimer's Association Interactive Network, or GAAIN, which is part of the University of Southern California's Laboratory of Neural Imaging. She's the lead author of a new paper called “Comparison of Genetic and Health Risk Factors for Mild Cognitive Impairment and Alzheimer's Disease Between Hispanic and Non-Hispanic white Participants.” This is an open-access, available to anyone article, and it is found in “The Journal of the Alzheimer's Association” called “Alzheimer's and Dementia.” In this paper, Dr. Xiao and her team look at whether APOE4, the gene considered to be a major genetic risk factor for Alzheimer's disease and mild cognitive impairment, and other health risk factors like hypertension, stroke, or depression, impact the risk of Alzheimer's disease for Hispanic populations. Dr. Xiao, welcome to Dementia Matters.

Dr. Cally Xiao: Thank you for having me.

Chin: For background, can you start by describing the relationship between APOE or APOE4 and Alzheimer's disease?

Xiao: Yeah, so the gene APOE has three alleles, e2, e3 and e4. The most common one is e3 and has not been shown to affect Alzheimer's disease risk, and then e2 is the least common and has shown to actually decrease the risk for Alzheimer's disease. e4 is somewhere in the middle, and it has been shown to have increased risk. This increased risk between APOE e4 and Alzheimer's disease has been discovered, reported back in the early 90s. So it has been 30 years of studying this very important gene for Alzheimer's disease.

Chin: And you get one copy from your mother and one copy from your father, correct?

Xiao: Yes, so each person will have two alleles at this gene. So your genotype, there's six possible genotypes for APOE. So you can be 2-2, 2-3, 2-4, 3-3, 3-4, or 4-4.

Chin: There's a different level of risk, as you described, kind of protective, neutral, and then increased risk, so depending on which combination you have, there's probably varying degrees.

Xiao: Yes, exactly.

Chin: Well, one caveat to this relationship, though, between APOE and Alzheimer's is that the bulk of the evidence behind it comes from studying non-Hispanic white populations. So is there any evidence that this relationship may be different in other racial and ethnic backgrounds?

Xiao: Yeah, so one of the first meta-analysis studies in this field, which is a secondary analysis of existing studies, they already reported that there was some difference between APOE4 and AD risk between African-American and Hispanic participants. So this has been reported before, and some more recent studies have reported different outcomes. Some reported better outcomes for Hispanic population with APOE e4, some reported worse outcome, and some reported even within the Hispanic population, different outcomes with people from different Hispanic ancestries. So whether they're from Latin America or South America or Africa.

Chin: Okay, so we have this established relationship between the certain gene and Alzheimer's disease, but then it really becomes a little bit cloudier or less clear once we start breaking it down based on people's racial and ethnic backgrounds, which of course speaks to the importance of having a diverse sample when we're a population of people when we're conducting our research, so thank you for providing that context. I want to get into your great publication. What did your research study really aim to investigate in the field?

Xiao: Yeah, so our primary goal was to be able to include as many participants as we could find in in one analysis. So by using a secondary analysis approach, we can include participants that have already reported their genotypes and outcomes, so we can analyze all of them together.  By including more participants in the study, we can have greater statistical power and can make more generalized descriptions.

Chin: So not only are you trying to really look at representation, but I mean, by having more participants and more data, it makes those results more valid, hopefully, and then more applicable to the whole population.

Xiao: Right. Yeah. Hopefully.

Chin: And then you mentioned the secondary analysis, which means really this wasn't, you weren't the one conducting the study, but you're able to access the data from these, these other studies and look at it in a different way. Is that right?

Xiao: Yes.

Chin: Okay. So how do you go about doing something like this?

Xiao: Yeah, so I started this in GAAIN actually. So using GAAIN, I was able to discover existing data sets, and I can preview this data before even having full access to the data, so I can see that the trend was already there that the APOE gene had a weaker association with Alzheimer's disease outcome in Hispanic participants versus non-Hispanic white participants. So knowing this, I can apply for full access to these data sets. I know that there's something there, so it's going to be very interesting to look at these full data sets in more detail.

Chin: And what data sets did you look at?

Xiao: I included three data sets in the secondary analysis. The first one was the National Alzheimer's Coordinating Center, or NACC. They have multiple sites across the United States, so there are a lot of participants included in this study. The second one was the Alzheimer's Disease Neuroimaging Initiative, or ADNI. They also have multiple sites, but across the US and Canada. And the third one was Health and Aging Brain Study, Health Disparities, or HABS-HD. This was actually a community study from Texas. They really increased their efforts to recruit diverse participants. In this study, they have about 50-50 non-Hispanic, White, and Hispanic participants.

Chin: So Cally, it seems to me that one of the important aspects of your research and your research project was the ability to access data from other centers, from other projects. Can you speak to the value and importance of data sharing and how to keep that as standard or as usable as possible?

Xiao: Yeah, so I definitely appreciate the studies that have contributed to our analysis. In the spirit of data sharing and data reuse, researchers such as myself, we would like to be able to use data that's collected more than once so that we can really get value out of this data, and perhaps a new set of eyes that can look at the data can find a different trend that wasn't even the primary aim of the study at first. So definitely appreciate the studies that are open to data sharing and can establish a lot more collaborations with studies that are open to contributing to the research community. One of the challenges I faced during this analysis was definitely going through the studies and seeing how it was the same, but also different, so data harmonization was something that as a community, like as a research community, something that we definitely should need to work on.

Chin: No, I couldn't agree more. For our listeners, I did a podcast with Dr. Sarah Biber, who is the one of the leads of the NACC dataset, and she also speaks to the importance of harmonization in this effort to share data. We'll have that in the show notes for those who are interested in Dr. Biber’s episode, but I completely agree. For participants, when they do one visit, it is the gift that we'll keep on giving if we're allowed to have other researchers look at that data in a different way and hopefully come up with important findings like you have.

Xiao: Yeah. Of course, personal health information and privacy is all protected, even upon data sharing. It's only the general data that's out there. So it's not like there's any personal health information.

Chin: What I really love about your work in this project is your ability to, one, kind of get a sense of, is there a signal here? And you see it, and so then you're able to access all of this data. On this podcast, we talk about the importance of data and the reason that participants are so important in the research, because really, when participants come in, they do their study. I think they may not recognize that their data can then be used by researchers such as yourself, who maybe aren't there the day of doing the visit with them but able to look at that reliable standardized data and ask new questions and important questions that may may change our understanding of the field, and you were able to do that three separate studies and of course our program in Wisconsin's a part of NACC and ABNI too. So of course we like knowing that our participants are giving not only to ourselves, but to this broader research group, and you've been able to do that. I think that's wonderful, and I do wonder though, as you start looking at all of this data, and I imagine it was a lot of it. What did the participants look like? What was the breakdown as you were analyzing three separate cohorts of individuals?

Xiao: Yeah, so after combining all three data sets, and then also looking at who had genotype information, who had Alzheimer's disease, who had the diagnosis outcomes, which could be cognitive normal, mild cognitive impairment, or MCI, or Alzheimer's disease, and also looking at only the non-Hispanic white and Hispanic participants in these three studies. We ended up with 24,000 participants and 11% were Hispanic. This could be improved because, you know, to be closer to the population, it should be closer to 20% Hispanic, but this is something that, you know, would be a considered effort amongst researchers.

Chin: You're getting there, you're getting closer and closer to true representation. But that's a lot of people. I mean, you can never conduct one of these studies alone. So being able to pool the data is helpful. Did you see the full spectrum then of the APOE that you were talking about, the six different possibilities?

Xiao: Yeah, I did see all six different genotypes and it follows previous reported trends that 3-3 was the most common and 2-2, for example, was the least common.

Chin: Okay, well then knowing that, knowing you're now the backdrop of the participants that you're starting to analyze, what did your analysis of all the data show? What did you take away from it?

Xiao: The first thing we found was that APOE e4 having one or two APOE e4 alleles had a weak association with malcognitive impairment in Hispanic participants. We also did not find a protective effect of APOE e2 allele. In this case, we excluded 2,4 from the protective analysis. So we did not find a protective effect of APOE e2 from Alzheimer's disease in Hispanic participants.

Chin: So that's pretty compelling, so in a White population, if you have APOE 2-2 or 2-3, it is potentially protective, reducing your risk of Alzheimer's disease, but in a Hispanic population, the same genes just aren't protective.

Xiao: Yeah, that's what we saw in the results.

Chin: And then also, it seems when you say weaker. In a White population or European American population of people, if you have APOE4, you have a certain level of increased risk of developing Alzheimer's disease, but if you happen to be Hispanic, Hispanic American, you still have a risk, but it's not as much as if you were a White individual.

Xiao: Yes, exactly. That's what the analysis showed. The risk is still there, but not as high as compared to a non-Hispanic white population.

Chin: So that's a pretty important finding. Of course, because in general, we say, well, APOE e4 is a risk factor, but it may not be as much of a risk factor depending on your racial or ethnic background. So do you, after analyzing this, do you have any of your own theories or ideas as to why we might see this difference?

Xiao: Yeah. This difference has been reported before. Others have speculated that it could be biological or genetic. Maybe APOE e4 interacts differently with their neighboring genes in different populations. Also, APOE e4 on the mechanism level can affect amyloid beta load. Amyloid beta is one of the hallmarks of Alzheimer's disease. Perhaps in Hispanic population, APOE4 has less effect on amyloid, but it could also be socioeconomical or cultural factors, maybe including access to healthcare. So for example, perhaps Hispanic participants who have APOE e2, maybe they have other post-coexisting health conditions or some socioeconomical factors that prevent them from seeking health care or leading to maybe different diagnosis outcome.

Chin: So here you have this important finding that just the genes, the genetic risk may not be the same and what isn't the same. When you look at it at a mechanistic level, some of the things I’m hearing from you are what we talk about in social determinants of health, all these other factors that may interplay with our health, our life our experiences, which in essence may then interact with our gene expression, or our the interaction of our genes. So you looked at part of that in this study because you were also looking at other chronic health conditions. From reading your study, you looked at high blood pressure, strokes and depression, so what did you find when you started looking at those health conditions too?

Xiao: Yeah, so we did wonder if a coexisting health condition could describe these differences. The three you had mentioned, they were examined in all three data sets. That's why we looked at those three in particular, hypertension, stroke and depression, and we did not find that any one of these or all three could explain the difference in APOE genetic risk. But it does not mean we can exclude other coexisting conditions or a combination of two or more. There are other health conditions. There are other health risk factors for Alzheimer's disease that we did not look at because they were not examined by all three studies.

Chin: Right. So you were limited by the data that was actually collected at the visits. For our participants listening, this is why we ask you so many questions and why we want to collect all of this data so that eventually people like you, Dr. Xiao, can look at it too. But you did find something important when it came to depression in Hispanic individuals. Is that right?

Xiao: Yeah. We saw that Hispanic participants who reported a history of depression had a higher risk for Alzheimer's disease than non-Hispanic White participants. The risk was high for both as well, and it was even higher for Hispanic participants. Even though we reported this, we only looked at self-reported depression or history of depression. That it was not a uniform scale that was used by all three studies, and also we did not consider if depression came before or after an Alzheimer's disease diagnosis, for example.

Chin: Okay, so those are some limitations to it, but you still see the signal, and I guess I'm wondering, do you also have any ideas mechanistically? Like, why is this? Why is depression accentuate more thinking change in someone from a Hispanic background?

Xiao: Yeah, that was a good question, but we don't have enough information to answer that.

Chin: So that really speaks to my next question, which is that you've really touched on an important subject, and I suspect that there's more questions that come up from your analyses. So really to end today, what are the next studies that you think about? Where do you want to go from here now that you have this important publication out?

Xiao: Yeah. There's so many. This paper raises so many questions. We could look at, for example, exactly genetically why there's a difference between APOE risk and Alzheimer's disease? We could look at neighboring genes, other genotypes, for example. We could also dive deeper into the different Hispanic ancestries and see what differences there are, because there also has been reported some differences. Also, for example, bilingualism has been shown to protect against Alzheimer's disease. If a Hispanic participant can speak both Spanish and English, perhaps they would be at less risk for Alzheimer's disease. But personally, I'm looking at what else we know about Alzheimer's that could be different in other races and ethnicities. So right now, biomarkers is a widely discussed topic right now, so I'm also wondering the biomarkers that we know for Alzheimer's disease. Could they also be different in different ethnicities and populations?

Chin: All great questions, and I hope you pursue all of them, Dr. Xiao, because frankly, in order to understand the disease, we need to know what it's like in all types of individuals, and as we are starting to pool data together in a standardized way, great researchers like yourself can really start looking at it. For our listeners, I just want to highlight that this is an article in the Journal of the Alzheimer's Association called “Alzheimer's and Dementia”, and it's titled “Comparison of Genetic and Health Risk Factors for Mild Cognitive Impairment and Alzheimer's Disease Between Hispanic and Non-Hispanic white Participants.” And our guest today, Dr. Cally Xiao, is the lead author of this publication, so I encourage people to take a look at it. Thank you, Dr. Xiao, for being on today and sharing your work.

Xiao: Yeah, thank you for having me. I definitely enjoyed talking about the research and what else we could look at.

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin--Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink and edited by Taylor Eberhardt. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.