Study Shows APOE e4 Not Associated with Alzheimer’s Disease in American Indian 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. I'm with Dr. Astrid Suchy-Dicey, an epidemiologist and researcher at the Washington State University Institute for Research and Education to Advance Community Health, also known as I-REACH. She is also an assistant professor at Washington State University's Elson S. Floyd College of Medicine. In March 2022, Dr. Suchy-Dicey published a study in Alzheimer's and Dementia which found that ApoE4, the gene associated with increased genetic risk for Alzheimer's disease, does not link to our degeneration or cognitive impairments in American Indian populations, contrasting with past research findings. This study has led to a new hypothesis that American Indians should contrast with past research findings. This study has led to a new hypothesis that american indians' unique, genetic cultural and environmental influences act as protective factors against alzheimer's disease. Dr. Suchy-Dicey, welcome to Dementia Matters.

Dr. Astrid Suchy-Dicey: Yes, thank you so much for having me.

Chin: I'd like to start by asking how you got involved in Alzheimer's disease research and what your focus has been within the field?

Suchy-Dicey: Thank you for that question. I came to epidemiology in a bit of a circuitous route, so I won't start you know with the dark and stormy night of my birth but I'll go back a little bit to my Baccalaureate education at Smith College. I studied history and biology and was really interested in disparities and anthropology, kind of sociological questions and differences in populations. I thought that I would go to medical school after that, but in between I decided to do a Post-Bacc stint at Brigham and Women's Hospital in Boston working in molecular biology. During that time I kind of worked a little bit in cardiovascular disease research. At some point I ran across Tracy Kidder's Mountains Beyond Mountains, a book about Paul Farmer – the renowned public health scientist at Harvard School of Public Health and Medical School. I was really inspired by the field of epidemiology and public health. So that led me to University of Washington where I went on to do a PhD instead in epidemiology, where I actually continued to work in cardiovascular disease but eventually connected with my current mentor, Dr. Dedra Buchwald, working in minority health disparities. That kind of closed the loop of my initial interest in population differences and social justice. I, after graduating, took over this cohort, this ancillary study within the Strong Heart Study, a longstanding 30-year cohort. This ancillary cohort is kind of focused on vascular dementia, and from there we've expanded into Alzheimer's disease and dementia. That's kind of how I've gotten into Alzheimer's research, is through this field of cardiovascular disease and health equity and social justice. Then from there you know this work in American Indian communities, who are of course not at all well represented by Alzheimer's cohorts and studies that already exist, so we're trying to overcome that disparity a little bit through improving their representation in dementia research.

Chin: And so it makes sense to me how you go from cardiovascular disease and health to eventually brain health and cognition. How did you transition or expand into genetics within this field?

Suchy-Dicey: Yeah, that's a great question. During my molecular pathology work at Harvard and Brigham, I did some genetic work and so I had some background. During my work at University of Washington during my PhD, I did a genetic certification and actually my master's thesis was in public health genetics. I kind of had a little bit of a background on genetics and was interested in the genetic basis for atherosclerosis and cardiovascular disease and then so I've kind of got a little bit of that background. But, of course, ApoE is such a huge gene risk for Alzheimer's disease. It just makes sense, even without that genetic background, to consider ApoE as a risk factor when looking at Alzheimer's research, so I think I would have come to it either way.

Chin: I find it such an interesting combination, though. When I think of public health, it's large groups of people, potentially anonymous data. Then when I think of genetics, it feels very personal and precision. You've been able to kind of marry the two of these concepts, which is fascinating and we’ll get into that in just a few minutes. Before we talk about your actual publication and your findings, can you explain for our audience some of the basics of ApoE and how it relates to lipid metabolism or cardiovascular disease and Alzheimer's disease?

Suchy-Dicey: Yeah. ApoE is a gene that encodes an apolipoprotein, which is a protein that – it combines with lipids to form molecules, large molecules, that are responsible for packaging and transporting cholesterol through the body and moving them through the bloodstream. This helps to maintain normal levels of cholesterol and other fats and that can have effects on different disease processes like atherosclerosis and also affect risk of diseases like stroke. It is known to also influence Alzheimer's disease as one of the largest risk factors for Alzheimer's disease. So there's 3 major known alleles for the ApoE risk variant in Alzheimer's. The one that we were really interested in was the main risk allele, the E4 allele or epsilon-4 allele, but there's also a protective version called E2, which is a kind of newer, on an evolutionary scale, and that's considered to be a more protective version. The one that's most common is this E3, this kind of intermediary or intermediate version of the allele.

Chin: And so in your study, you mentioned this before, but you focused on participants from Strong Heart Study and they're 65 and older. What exactly do you measure in these particular participants and what were you actually looking for?

Suchy-Dicey: Yeah, so we had data on the ApoE gene already from previous studies that have been done on lipid metabolism in the Strong Heart Study. Of course, you know, when you measure genetic variance that doesn't change over your life for the most part, so you know we had those data already. Then we had the data that we had been collecting more recently on cognition and brain imaging in the group that's 65 and older. That's the group that is considered to be most at risk in terms of developing cognitive decline, in terms of showing symptoms of Alzheimer's disease or vascular dementia, and so that's the group that we really focused on for this analysis both because that's the group we have data on and that's the group that's most at risk. So we used structural imaging – structural brain MRIs – to look at changes in the brain, in atrophy and vascular changes, and then also cognitive markers in multiple cognitive domains that might be related to cognitive impairment or dementia that could be markers of Alzheimer's.

Chin: So then, in the study you separated the participants into those carrying the ApoE4 genetic risk and those that are not, and you knew that ahead of time because you had that data. Were there other differences in the group that would be noteworthy? I'm thinking about things like gender, high blood pressure, diabetes, obesity.

Suchy-Dicey: Yeah, that's a really great question. We did look at the E4 carriers versus non-carriers. That's, of course, not the most ideal comparison, but that's what we ended up looking at because we had so few E2 carriers that we really couldn't even really look at that, and so the comparison just ended up being between people who have any versions of the E4 allele versus none. We did look at what's called precision factors in genetic studies – gender and other factors. But if you're looking at genetic risk, you don't necessarily need to stratify or control for confounders because they're not considered true confounders. You're not going to consider that – somebody's high blood pressure is not going to change their genes. So that's not really something that – it's more that that could potentially be something that's changed by their genes. It's not usually considered a confounder. It might be considered a precision factor or something that would change your ability to see an effect, so we did control for some of those factors. We consider those sensitivity analyses and we still didn't – it didn't have any effect on our analysis at all.

Chin: And so then, I guess, the big question is what exactly is it that you found that was different between the two groups?

Suchy-Dicey: Yeah. We really didn't find anything. We looked a number of different ways. The only thing that we were able to see that was different was blood cholesterol and that was a really encouraging, positive control finding. You would expect that blood cholesterol would be different because this gene is something that's specifically focused on transporting blood cholesterol. It will change the levels of your blood cholesterol. The fact that we could identify that difference meant that it wasn't, probably, that we had a lack of statistical power but rather that some of these other differences don't exist. So when we look at differences in cognition or differences in brain structures like hippocampal atrophy or overall brain atrophy or memory impairment, things like that. We didn't have any differences in any of the ways that we looked at it.

Chin: Do you share the findings of this publication back with the participants and I'm wondering how that looks? And then also, do participants ever ask you what is my ApoE status since you're doing all of this research on me and my community?

Suchy-Dicey: Yeah, definitely. We absolutely share results. That's a key part of our research and we have agreements with our tribal partners that involve dissemination of research findings to them and to their communities. I'll get to the direct dissemination of clinical actionable findings to people as individuals but we share information in the broader, research results as a whole, at community meetings, at our steering committee meetings which are annual. We have also community advisory board meetings that are open to the public sometimes. Some of our field centers also host ongoing research dissemination for – like a recent one in our Dakota centers, which is the kind of coffee hour on Saturday mornings held by Missouri Breaks Industries Research. I actually just gave a talk a couple weeks ago at that. The Strong Heart Study also disseminates newsletters and outreach, doing education events and stuff like that. These are all different ways that you can disseminate research directly to communities outside of the kind of scientific conference talks and peer-reviewed research journal publications and stuff like that. It's really important to work to communicate that research and those research findings. As far as direct dissemination of an individual's results, we limit that to clinically actionable findings that have meaning. It's not really, I think, appropriate to provide results of research materials that don't have information that somebody can really interpret, and so we really limit that to things that have informativeness that they can take to their doctor and their doctor would know what to do with that. That would be things like blood pressure or potentially – the ApoE genetic allele result I think would potentially fall into that. Those assays were done before I joined this research group. Those were in a previous phase of the study and so I actually am not sure if those were shared with participants but I would imagine they probably were. But yeah, we do give them a little card that gives them their blood pressure and their blood glucose and their cholesterol and stuff like that.

Chin: So then I guess – I should also clarify, did any of these participants have a clinical diagnosis of mild cognitive impairment or dementia?

Suchy-Dicey: Yeah, so that's a really great question. We don't have an ability really to assess cognitive impairment or dementia, per se. We can apply cognitive thresholds that are used in other populations to this population, but these cognitive tests have not been validated. Most cognitive tests have not been validated for this population and we have looked at these cognitive tests in this population and we know that the distributions are different than they are and should be compared to other populations. We know that the impairment thresholds are probably not appropriate, so we generally don't use the thresholds that are developed for white populations or other populations to determine dementia. This is an active area of research for our group and we're trying to understand how to define dementia, how to define cognitive impairment, and it's really challenging to do. First, we need to validate these tests psychometrically and then look at what would be an appropriate way to define impairment. We did use a kind of algorithm to try to define memory impairment with one of these tests, a verbal memory test. That comes with, you know, a number of assumptions and so it's kind of a first pass. I think future research could definitely benefit from more rigorous impairment definitions and so we hope to, when we have that information, to be able to do those analyses in the future.

Chin: But I think one of the truly key findings here is that between those that had ApoE4 genetic risk and those that did not, you did not find a difference in brain shrinkage, in vascular findings in the brain, or in actual scores on these non-validated cognitive tests

Suchy-Dicey: It's true. I mean when we looked at the scores continuously, we found no difference across the distribution which is really important, because you would expect if there is a difference at least it would be up or down comparing the different carriers. We didn't see that. I can't say that we were terribly surprised because there's some previous data in other populations to suggest that that might be the case, that you know this gene doesn't necessarily have the same effect in all populations or have the same association in all populations. We were struck by how null the findings were. That's for sure.

Chin: So prior studies from Strong Heart showed that ApoE is present though at the same rates or levels in the American Indian participants as they are in European Americans. So your findings then, that ApoE4 does not have this negative effect on American Indian population regarding cognition. It's not because there just isn't ApoE4. How do you – if you were in front of an audience of your participants, what does this mean when we think of ApoE4 for American Indians, especially since they remain at an increased risk for developing Alzheimer's disease despite the fact that this genetic risk is not one of their risk factors?
 
Suchy-Dicey: I think that that's a really important point. The gene frequency – the allele frequency – is similar, and it's similar to previous examinations suggesting that we don't have a loss of people in our study that were at high risk. That's called selective survival or selection bias, and so we did think about whether that could potentially explain our findings but we thought that that was probably an unlikely explanation or at least an unlikely sole explanation because of that sustained frequency and the comparable frequency to other populations. We looked at two other possible explanations. The first is, of course, that those that don't have the risk allele are at high risk, so the risk is kind of maximized. As you say, American Indians are at higher risk for Alzheimer's disease and so maybe the risk is already maximized. Everyone has such high risk that we can't see a difference because it's already just maxed out. Or it's possible that there's a kind of protective factor here going on that people with the risk allele are being protected against that risk in ways that we don't fully understand, maybe by factors that we haven't even measured. Maybe there's a kind of lowering effect of that risk bringing them down to the kind of baseline level. I suspect that both of these are probably true to some degree and that that's why we can't see a difference between these two groups because there is that higher risk but there's also maybe some really novel protective factors going on too. 

Chin: When I first read your results and conclusion, I thought to myself – well, this speaks to the social determinants of health and all these other really important non-biological factors that are at play in a person's life experience that lead to changes in the brain. Then when I read your commentary about this idea of a foraging, agricultural lifestyle and how this could lead to different pressures on our lipid metabolism and things like ApoE4, I thought it was very fascinating. So can you explain this hypothesis of ApoE4 carriers in an Indigenous population actually being a sort of a protective factor?

Suchy-Dicey: Yeah, thank you. I have a similar reaction to you in both ways. I do think that the social determinants possibly are important here. The nutrition hypothesis is an interesting one too. I think it came up because this is a lipid metabolism gene. It has an effect on lipids in the blood and we did see that effect on LDL. So the question of ApoE’s evolutionary pressures is something that medical anthropologists and geneticists have been working on for some time. The question of why does such a big risk gene still even exist in our population, considering that you would think that something that carries such a destructive power – how could it have existed for so long? The thought is that maybe this E4 allele, which is thought to be the original form of the gene actually, it's being kind of selected out of the population by this kind of more less risky E3 allele. Originally in foraging societies where food was scarce, it was advantageous to be able to deposit higher levels of fats and cholesterols, which are necessary for brain health, they're necessary for the function of a lot of different organs, that those were an advantage, that in a circumstance where food is scarce that that's an evolutionary advantage. When you have a context where food becomes more abundant, such as in our post-industrialized society, that actually becomes a risk and so we kind of have this switch that we've been seeing where this advantageous allele ends up being a risk allele just because we've changed the abundance of food or the types of foods that we're eating. Some people have argued that this kind of hypothesis might support caloric restriction diets or so-called paleolithic or historical dietary nutrition patterns in order to potentially reduce some of that risk. There's that whole kind of precision medicine approach of identifying what genes you have so that you can see what your best diet is. I think that's probably a little bit early for that kind of recommendation, but that's the kind of idea, is that there's maybe this switch between an advantage to a risk.

Chin: Well as someone who loves food and loves the science of food and how there's so many different things at play I was going to ask you, what does this mean for dietary recommendations. To me as a clinician, it makes me feel like there's no one size fits all dietary recommendation and it goes back to what we're hearing in other communities about the importance of being culturally competent and sensitive to the people in front of us, that there is no one way of eating and that we need to be cognizant of that. It seems to me that this is a conversation that's happening in your field too. 

Suchy-Dicey: Yeah, I think so. I definitely think it's too early to make recommendations. Certainly for myself because I'm not a nutrition expert. I know there are people working on this and I agree with cultural competency and sensitivity. I think that there's arguments for and against precision medicine approach and I think that those are important, but I do think that more research on diet and nutrition patterns and what is relevant for the peoples in study is certainly supported by this research. I think that that's the message that I would like to get across is that we just need more information that's relevant to the people that we want to understand.

Chin: So what needs to be done next then to better understand ApoE4 in the American Indian population?

Suchy-Dicey: Well personally, I would like to study younger groups and more direct measures of Alzheimer's disease, maybe more objective markers. I'd like to understand these cognitive impairment thresholds a little bit better in order to get more at that excess risk hypothesis, that explanation that we might already have maximized risk in this older-than-65 group. But, also, I'm working on some of these social determinants and resilience factors like social support and community context to understand whether there are protective factors that could be at play, to help reduce some of that risk, so both of those I think are really important directions. I do have colleagues as I mentioned that are working on some of those nutrition and diet studies that I also think are really important to hopefully unravel some of those other questions.

Chin: So the importance of these findings for the American Indian cohorts and populations, I mean, do you believe we should be conducting similar studies in other non-European populations to see if there exists other differences in how some of these genes may either be protective or detrimental when we think about cognition?

Suchy-Dicey: Yes, definitely. I think that using research that's focused on one population or historically uses only data from one population in order to understand all people I think is really problematic. I think if we want to understand genetic risk or even just the function of disease in humans, that's not specifically focused on genetics but the molecular underpinnings of disease, I think we need to understand the variance of that experience throughout all human populations and we can't do that just by studying one group. I think it is important to study a variety of peoples.

Chin: To end, I would like to know what you think is the most important lifestyle habit or habits that promote wellness and brain health, particularly in an indigenous population.

Suchy-Dicey: Yeah, so this is where we get into trouble because I don't want to make recommendations to people, especially to Indigenous peoples when I'm not a member of their community. I can't tell them how to live their lives and I can't speak for people of other cultures or communities. I can only say, for myself, I think that just trying to maintain connectedness and understand my place in the world is what really helps me to maintain a sense of balance. For me, that's like maybe spending time with my family and friends or my work, which is really focused on equity and justice. That helps me feel connected to the world and to myself interestingly, and so that helps me feel healthy and rooted in my place in the universe. That's my way of doing things but certainly other people might have their own way.

Chin: Well, I appreciate that and I appreciate you not speaking on behalf of others and giving your own personal testimony. With that, I'd like to thank you for being on Dementia Matters and we sure hope to have you back on in the future.

Suchy-Dicey: Yeah, thank you so much for having me. This was really fun.

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 edited by Caoilfhinn Rauwerdink. 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.