Study Shows APOE e4 Not Associated with Alzheimer’s Disease in American Indian Populations

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.

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. 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.

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.

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. 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. 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. 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. 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. 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. 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.

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. 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. 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.

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.

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. 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:

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