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. Scott Roberts, the interim chair and professor of health behavior and health education at the University of Michigan’s School of Public Health where he also was the prior director of the public health genetics program and continues to teach a course on public health ethics. Since 2001, he has served as co-principal investigator on the NIH-funded REVEAL study — REVEAL standing for Risk Evaluation and Education for Alzheimer’s Disease — a series of clinical trials examining the impact of genetic susceptibility testing for people at risk for Alzheimer’s disease. Dr. Roberts has also published numerous articles on genetic testing and disclosures. Today, we will discuss genetic testing and disclosure specifically for APOE, a gene that increases one’s chance of developing Alzheimer’s disease. Dr. Roberts, welcome to Dementia Matters.

Dr. Scott Roberts: Yeah, thanks so much. Great to be here.

Chin: Well, I will say I’m very excited to have you. When we think about disclosure work in the field of Alzheimer’s, certainly your name comes up quite frequently. I’d like to start by asking, what got you interested in this work covering genetic testing, disclosure and ethical considerations?

Roberts: Yeah, it’s a good question. I certainly would not have predicted this for myself when I was doing my PhD in clinical psychology here at Michigan, but it just so happened I ended up doing a summer internship at the Duke Alzheimer’s Disease Research Center in the mid 90s. This was right about the time that Allen Roses of their team identified this link between APOE, particularly the E4 allele, and risk of Alzheimer’s disease. I was casting about for a dissertation topic, and I thought “Wow it would be really interesting because there’s a lot of debate on ‘should we even offer this testing?” This is a very serious incurable condition. The test is informative, but not certainly as predictive as other genetic tests like Huntington’s. Should we even be doing this in the first place? When I was a graduate student I was thinking “Wow it’d be really interesting to get the perspective of those with the family history of Alzheimer’s to see what they think about this rather than just letting us experts decide what’s appropriate or not.” I ended up doing my dissertation work surveying first degree relatives of people with Alzheimer’s, trying to give them some education about what APOE testing was about, and then appraising their sense of the pros and cons of this. Would they be interested? What do they see as the risks and benefits? That kind of got me launched into the field. I ended up doing a postdoc in Boston. At the time my mentor-to-be Robert Green was there at Boston University, and he was launching this program that you mentioned in the intro — the REVEAL study had just gotten his first NIH grant, so I was looking in my dissertation more just like hypothetically at “Were people interested?” and then he was actually offering APOE testing as part of a clinical trial to this same group. I got linked up with him and the rest was kind of history because together we embarked on a series of these trials where we looked at different issues involved in disclosing APOE genotype to people at risk for Alzheimer’s, looking at the psychological and behavioral impact of that kind of testing.

Chin: It sounds like the timing was just right for your work, first with the dissertation and then with the beginning of the clinical trial. You really went into it and have expanded so much of our understanding of not only APOE, but the actual process of disclosure — which we’re going to talk about in a few minutes. Your work on the REVEAL study, though, has really been pivotal to the field. Before we get to that, I’m hoping you can explain to our listeners what exactly APOE means and why it matters so much in Alzheimer’s disease research and even now clinical care.

Roberts: APOE stands for Apolipoprotein E. It’s a gene found on chromosome 19. We all have an APOE genotype. We just have different forms of it. We inherit one allele from each parent and — as you know — there’s a certain type that if you inherit it, it elevates your chances of getting Alzheimer’s — that’s the E4 allele. People can have either one or two copies of that depending on what they inherit from each parent. It’s — as I mentioned — this kind of initial link to Alzheimer’s was discovered at Duke in the 1990s. Hundreds if not thousands of studies have kind of confirmed this important linkage. I think it’s also important to know that just having an E4 allele — I like to say it’s neither necessary nor sufficient to cause Alzheimer’s. You could have an E4 allele and never get the disease. You could have the disease and not have the E4 allele present. It’s a very important risk factor. It’s not — as I mentioned earlier, there’s some other genetic tests, as you know, in clinical practice that are much more predictive like Huntington’s being a classic example, where if you have a certain genetic mutation, you’re almost inevitably going to develop the disease. That’s not the case with APOE. On the other hand, it is a very important risk factor and there’s a lot of people — as we found out — who are very interested in learning their APOE genotype, especially those who’ve had a family history of the condition.

Chin: Knowing that — especially with what you just said at the end, people with the family history or others perhaps without one — there can be this strong interest in wanting to know this result and know what it means. It really hasn’t been a part of clinical practice, and certainly when I started in medicine and geriatrics it was very much “We do not order this test and there is no purpose because they — ” well I’ll let you go to this. Why hasn’t APOE been used in clinic until this sort of movement of monoclonal therapy?

Roberts: I think there have been some understandable concerns from the clinical community about offering this. I mean I think there’s kind of two main buckets of concern. One is just as I was alluding to earlier — the idea is that the test in and of itself isn’t kind of a super predictive. It just gives you a kind of probability estimate of developing the disease, but it’s not highly predictive in and of itself. Alzheimer’s is a multifactorial condition where many other factors besides genetics play into whether one develops that type of dementia. I think that lack of predictive value is one factor. On the other side, what do you do if you learn you’re at high risk? We don’t have of proven prevention options. When you think about genetic testing in other medical contexts that are recommended, they’re often in contexts like cancer where, “Hey, if you’re at elevated risk you can do chemoprevention,” or there’s other very proven ways where we know that if you engage in certain behaviors or we have very proven screening tools to monitor the potential of developing cancer for example. We don’t have those same kinds of options with Alzheimer’s, at least not yet. I think the field is moving towards that, but right now we don’t have those kinds of evidence-based approaches to the kind of screening and prevention that we have in other medical contexts. Finally I think there’s this concern about how there might be harms from learning this information. I think there was a lot of concern — particularly back when it first came out — “Are people going to become clinically depressed or anxious if they learn they’re at high risk?” “Might they even contemplate suicide?” was talked about. There’s also at a broader level concerns about stigma and discrimination. You might be looked at differently by friends and family, or even insurance companies or employers — if they knew their genetic status — discriminate against them. I think this combination of those limitations that I’ve mentioned made experts really say, “Let’s err on the side of caution here, and let’s not really offer this because of these concerns about the risk-benefit ratio not being favorable.”

Chin: In looking at the risk side of this, is disclosing APOE results — or is it safe to do this, and this is certainly one part of your research, and what is it that you have found?

Roberts: Yeah,  I guess the short answer is we found that generally, yes, it is safe to disclose this information but that comes with some caveats I think. In our studies, we’ve tended to involve genetic counselors in delivering the information, who are experts in both genetics and in interpersonal risk communication. They tend to be kind of experts in their field and are very skilled in delivering this information. The people we’ve recruited for our studies are certainly not fully representative of the broad U.S. population. They’ve tended to be more highly educated overall. They are people who are coming forward for this information as volunteers, they’re interested in it. So I think you have to take some of our findings with a grain of salt given that as well. We’ve done this across many different trials, different ways of looking at this. One constant finding has been that although sometimes people do react with some initial distress, that in general does not really translate into some of those more severe concerns people were talking about in terms of this information causing people to have psychiatric symptoms that are debilitating and prolonged over time. Sometimes people do maybe have some initial distressing reactions, but they tend on average to revert back to their baseline after a few weeks. We’ve also found I think there’s a lot of concern about, “Oh people are going to misunderstand this information.” There’s this concept of genetic determinism or genetic exceptionalism where just because something’s labeled genetic they tend to think maybe it’s more predictive than it actually is. We’ve been able to educate folks so that they know that an E4 result, for example, doesn’t mean that they’re destined to develop the disease. I think the good news has been from a safety perspective — at least in terms of psychological safety — and from an understanding perspective we’ve found that most of our participants have tended to fare well, even if they get bad news from the genetic test result.

Chin: I think one of the most important things for our listeners to know is that a lot of thoughtful planning and time went into the education of the participants and the process when sharing this information. You did mention genetic counselors, but like many fields in healthcare there’s a shortage so there’s not a lot of genetic counselors. Is this something that you have studied and looked at in non-genetic counselors, and how those individuals in healthcare do?

Roberts: Yeah. In one of our trials we had both genetic counselor and physician-based disclosure and we did not see huge differences in our outcomes there. These were kind of typically neurologists who are experts in dementia care and APOE, so it’s not just any kind of physician we were involved in disclosure. To this point that you’re making about kind of the workforce shortage of genetic counselors, we’ve also, in our studies, tried to look at the process of delivery in terms of not necessarily using the traditional genetic counseling model — which is kind of a lengthy pre-test education session, a lengthy post-test disclosure session where the face to face time might end up being like multiple hours and always in person. We’ve kind of mixed it up over the years where sometimes — even though we might still have a genetic counselor involved — but maybe it’s just on the post-test disclosure end. We did one trial where we replaced that lengthy pre-test education session with a brochure education and some other related studies of, “Can you do kind of a web-based interactive tool,” or something like that to kind of prime people for the information they’re going to get without actually having that specialist having to meet with them for an hour ahead of time. We also did a trial where we looked at phone-based versus in-person disclosure. We’ve tried to think about, can we have similar outcomes in these more streamlined approaches or just moving away from in-person based disclosure? Fortunately those trials have shown pretty comparable results both in terms of participants comprehension of the main points and their psychological reactions. We’ve found equivalence across these arms of the study when we’ve tried these different approaches.

Chin: Of course, as a clinician, I appreciate you really addressing these perceived barriers from the research world, where everything is very controlled and there’s a lot of time, to the clinical world, where we don’t have that type of system. With this work, it certainly has allowed for some clinicians to feel comfortable when they’re informed. I think that’s a key part of this is when the person doing the disclosure — whether it’s a geneticist or a neurologist or a specialist — when they are informed and skilled and sharing this information, people are leaving with a good understanding and not having long-term psychological distress. I say that because my next question for you is, without using any specific names of direct-to-consumer tests, what do you think of people in the community learning their APOE genotype from these private direct-to-consumer tests?

Roberts: Yeah, I’m kind of — I have mixed reactions. In some ways there are some understandable concerns that particularly — because some of these services people might be blindsided by an APOE result — because sometimes they’re offered as like a package of, “Oh, learn about your ancestry, learn about some traits you might have”, oh and then by the way learn about your cancer and Alzheimer’s risk as well. I think — to my mind — the risk of psychological harm might be greater if someone is more just stumbling into that without really having thought through this decision of APOE test information. That being said, I do think some of these companies do a pretty good job of providing some background education information online. I think one of the companies was able to get FDA approval for offering APOE testing, and before FDA would grant that approval they wanted to know “Did the company have what we call analytic validity of its genetic testing? Are they accurately calling APOE genotype from the samples they’re getting?” So the company had to demonstrate that when they report out an APOE result, that’s the true genotype of the person. They also had to provide FDA with comprehension data on “Did the user — even if it wasn’t meeting with a genetic counselor or another clinician — were they able to kind of demonstrate that they understood the take home points?” I think it’s not the total wild west that sometimes people portray — at least certain companies have tried to have some quality control measures in delivering this information — but that said, in an ideal world I think people would not be just going online and getting it because a lot of times maybe the result brings up questions. It’s nice to have the ability to have that encounter with a clinician who might help talk about, “Well what next now that you know your results?” What might be some sensible next steps or what are some limitations of the information they’re getting?”

Chin: Certainly the individual can do research and lots of information, good information, is available online prior to learning one’s own result if they decide to go the direct-to-consumer route, but it is good to know that some of these tests had to go through the appropriate channels of FDA approval to be able to do this.

Roberts: I was just gonna add that you’re talking about good information being out there on the web — some of my colleagues at Virginia Tech developed a very valuable online decision aid for APOE testing. If I find someone who’s kind of interested, I will often refer them to that website where it kind of walks them through “This is what APOE testing is about.” It helps to do some values clarification — like well “Why would you be interested?” and “Can APOE testing give you the answers you’re looking for or not?” I think there are these interactive web tools that, again, don’t require a clinical appointment but might still be a valuable adjunct to the actual testing, whether it’s clinical or direct-to-consumer.

Chin: That’s great information and we’ll try to put some of this information in our show notes so that our listeners can be able to find these great resources. I’m hoping you can walk us through, just briefly, what a disclosure visit or a process looks like in that research setting — having a participant come in, just a general outline — because then I’m going to want you to to share with me what you think it would look like in the clinical world.

Roberts: Yeah, so in our studies, again, it’s typically been a genetic counselor who has been the one who’s meeting with the person. They typically have had some pre-test education, so they’re kind of aware of “What’s the purpose of the test? What are the possible range of results?” Usually the session opens by seeing if the person has any kind of questions before the result is shared and maybe like a brief reminder of what you’re going to learn today. Then the actual result is shared, so this is your APOE genotype. Typically we try to also provide what that means in terms of your percentage likelihood of developing Alzheimer’s in the future based on — usually it’s not just the genotype, we try to factor in other factors like age, gender, family history. At least in our studies, we’ve had a very strong genetic epidemiology database to base our quantitative risk estimates on. We try to not just give, “Here’s what your APOE genotype is,” but, “Here’s our best guess of what that means in terms of your percentage likelihood of developing the disease in the future.” We try to underscore this point of, “Even if you’re at elevated risk, it doesn’t mean you absolutely will get the disease”. We try to use visual aids — because I think for some people pictures are worth a thousand words — and not just verbally sharing the information. We like to use a certain visual aid called the pictogram where it shows the risk in ways where they can see it — I’m getting a little wonky here — both in terms of absolute risk and relative risk, not just using percentages but they can see the frequency information within the the pictogram itself. These are some tools that help drive the point home. We talk about, “Well what can you do to lower your risk?” We usually talk about — there’s more of a science now behind risk reduction in terms of behavior change so we try to highlight certain behavior changes that might be helpful. Again, none of these are absolutely a guarantee that — you could do all the right things and still get Alzheimer’s but, as you probably know, there’s more of a literature now on things like physical activity and diet and mental and social engagement that seem like they can be helpful in reducing one’s risk of Alzheimer’s. Being researchers at a Alzheimer’s center, we try to put in a plug for, “Maybe this might make you interested in taking part in other Alzheimer’s research.” As you, I’m sure, know, there are now even some clinical drug trials where genetic testing is being used to identify people who might be eligible for a prevention trial. We try to give them credible resources through organizations like the Alzheimer’s Association where they can learn more just about the disease in general. Those are some of the elements of what happens in our research visits — hopefully that gives you a feel.

Chin: Yeah, it’s a very comprehensive process and that’s why I’m glad you walked us through that step by step. I agree with you that a picture is worth a thousand words — a picture is also easier to understand when you’re trying to communicate very complicated subjects like risk or likelihood. It makes perfect sense to me as someone who works with amyloid disclosure — we use a very similar model that we’ve learned from REVEAL. Now I’m wondering — knowing this process that you’ve created with REVEAL — what does this actually look like in the clinical setting? When you think of APOE and disclosing APOE to patients now, what is it that you can translate from research to the clinic that you think is feasible, or at least the most important components?

Roberts: Well I do think some of our materials are hopefully translatable — maybe it wouldn’t be the whole nine yards of all what we do. Again, some of these visual aids I think could be useful. In the early days of REVEAL, everything we did was kind of print-based but it’s easy enough these days to send people to a website — interactive or not — to get some of just the basic background, again to maybe help them come into a session primed. It could be tailored to their need for information — you don’t want to go through the whole genetics 101 spiel with someone who either is not really interested or doesn’t need to know that information. I do think hopefully some of the materials we’ve developed could be adapted for clinical use. Also hopefully some of the measurement tools could possibly be adapted in certain ways, like ways to just check understanding. If a clinician could either do it in the moment or could still be feasible to do a brief assessment just to make sure somebody got the take home points — like you probably know about this teachback method that’s often used in clinical practice — just to confirm understanding of the points. I think some of the resources we’ve developed for, again,  “Where can you go from here?” — we’ve kind of vetted some organizations that I think have developed some quality tools, so that it’s not like, “All right? Well good luck with that information,” but then they have some follow up steps to take. I think hopefully some of what we do could translate to a clinical setting relatively painlessly.

Chin: Yeah, clinics are not starting from scratch. There’s a lot of great work from research that they can start incorporating, but it is slightly different in the REVEAL study and the work you’ve done. These are individuals who you’re talking to about at-risk for Alzheimer’s disease and then talking about lifestyle strategies, enrollment in clinical trials. With monoclonal therapies being used in some clinics across the country, APOE has come up — because those with APOE 44 [two APOE 4 alleles] genotype are at very high risk, or the highest risk, of developing ARIA (Amyloid-Related Imaging Abnormalities) — and our listeners who have listened to prior episodes know that — if they haven’t they can tune into one of the one of those episodes. I’m wondering how you feel like APOE then fits in this process from, “I’ve been diagnosed with either mild cognitive impairment or mild stage dementia. My provider thinks I could have Alzheimer’s disease and has mentioned I could be eligible for a therapy that involves one of these monoclonals.” Where do you see APOE being a part of that? How is that different than what the REVEAL study was looking at?

Roberts: Yeah I certainly think it  should be a part of it, because my understanding is the appropriate use recommendations for these new therapies you’re talking about do recommend routine APOE testing prior to decisions being made because of the point you made earlier, that people with certain APOE genotypes might be at elevated risk for some notable side effects.  Therefore that information might help influence the decision, “Do I even want to do this in the first place and, if I do, how frequently should I be monitored for these potential side effects?” I think it is different though for a variety of reasons. We did one trial with people with mild cognitive impairment but most of the time we were enrolling people kind of middle aged to older age who were cognitively intact. This idea of maybe trying to think about disclosure more often being a dyadic process — not just the person with Alzheimer’s but hopefully a caregiver, as well, being involved. Sometimes that did happen in REVEAL but it wasn’t routine, so trying to think through how might the patients’ cognitive impairment needed to be addressed in the context of disclosure. We’re already talking about pretty complicated jargon, complicated statistics and so it’s even more complicated when someone has dementia. Maybe having — again in this idea of tailoring the disclosure, I think those issues would have to be thought through carefully. The end result is really — in our studies, the kind of take-home message was, “What is your likelihood of one day developing Alzheimer’s?” Here you’re talking about someone who already has the disease and it’s more, what does this genetic testing mean in terms of your decision whether or not to go on this new therapy, so I think there’s a different take home message. Some of the principles might be the same — you’re still talking about trying to explain what are the different APOE genotypes and what are their implications. Another thing that we didn’t talk about earlier that I think is also relevant in both cases though, is what do these results mean for family members? You mentioned that the possibility of the 44 genotype. In that case that patients — any adult child they have is also E4 carrier just by definition of how inheritance works for this gene. So that might be information — maybe the adult child is there in the room, maybe they’re the primary caregiver who’s joining the patient for the encounter and the result might then have immediate amplifications and so they should hopefully be aware of that and maybe have thought through how would they feel if they learned that they were an E4 carrier by virtue of their parents getting this result. I think some of the implications for that adult child might be one thing — and we didn’t really talk about yet — is this idea of one finding from REVEAL was that people who learned they were at elevated risk were more likely to purchase long-term care insurance in response. I think making people aware of these genetic discrimination issues — there is this federal law called GINA, stands for the Genetic Information Non-Discrimination Act, that protects against health insurers and employers using genetic information against people, but long-term care insurance is not a domain that GINA covers. That’s not to say that long-term care insurers are actively discriminating against people who have an E4, but I think people should be aware of what their legal protections are in this space. Sometimes state laws go beyond what that federal law does. I think disclosure ideally might involve a little bit of education, just introducing people to the idea of this concept of genetic discrimination and making them aware of what are their legal rights and protections. I’m just kind of curious if I can ask you a question. What’s your sense of how, with these new therapies where APOE testing is being recommended, what has been the approach of dementia care specialists? Is your sense that a lot of them are taking on APOE disclosure themselves? Are they trying to refer out? Where do things stand in your experience either at Wisconsin or beyond?

Chin: I think it’s certainly regional — depending on what resources a person has. Like you said, I think the confidence of the provider is paramount. If you are not experienced or comfortable talking about risk and genotypes, then I think that they’re going to try to reach out to a genetic counselor if they can. Unfortunately, I think it’s hard to find a genetic counselor for what I imagine is going to be this huge wave of people who want to learn this because they are interested in potentially being on new therapies. Then it’s a matter of educating and training health care providers of all levels to be able to have these really intimate and personal conversations with patients and families — because you’re right, multiple people are usually in the room. Then it speaks to, how do you build that into a clinic and how do you have the time for that? All of this though under the premise right now of therapy — most people are not coming to a clinic to simply just learn their APOE. They’re being told that, “I have MCI. I have mild stage dementia,” and then this is a part of the evaluation process for one of those drugs. It changes the way we talk about APOE because it’s no longer about the risk of Alzheimer’s, it’s about the risk of ARIA and we already have suspected Alzheimer’s. It just takes so much time. I certainly do not think many providers feel comfortable yet, which is why I’m hoping this episode can be helpful in letting people know the process and certainly resources, because they certainly could get to that point. It’s just not happening a lot, I think regardless, because I don’t think a lot of people are on the therapy.

Roberts: Yeah, makes sense. 

Chin: Well, Dr. Roberts, I want to end by asking more of a broad question. How do you feel disclosure of APOE in research has or will influence what we do in clinic, and certainly what the next steps in research are on just disclosure in general? Where do you see REVEAL impacting the field still, in Alzheimer’s disease and then in clinic?

Roberts: Yeah, I think hopefully what our studies have shown is that, while it’s understandable that sometimes the medical community is very wary of disclosing certain types of information because of the risks that might be involved, that doesn’t mean we should automatically shy away from it and just have like a blanket ban on it or make it highly restricted information. I think there are ways in which we can do this that wrestle with some of the complexities but still provide processes and tools that can make it accessible to a range of patient populations and give providers that kind of confidence in being able to deliver this information even if they aren’t total experts in the field. Hopefully some of our work provides the start towards a foundation to adapt, build on what we’ve done, and take it to the next level. Certainly there’s ways in which now — you know, you hear about all of these kind of uses now of AI and chat bots and there’s ways in which technology might be harnessed, particularly on the pre-test education side of things — I’m a little wary, I still like the idea of that high-touch encounter for the actual disclosure piece. In terms of broader pre-test education, I think there’s a lot of ways in which we can reduce the burden of genetic counselors and other clinicians through thinking about these more innovative ways of educating both patients and providers.

Chin: Well, that’s a pretty exciting answer too. I appreciate you bringing in AI technology since that is everywhere. For our listeners, we are both real — this is not created by AI — our own voices.

Roberts: (laughs) Yeah.

Chin: I really want to thank you, Dr. Roberts, for coming on the show and for explaining APOE in the work that has led to this point where we are now, for some clinics, sharing APOE genotypes to our patients. I certainly hope we can have a future discussion on disclosure on a different episode.

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’re doing. If you enjoy our show and want to support our work, consider making a gift to the Dementia Matters Fund through the UW Initiative to End Alzheimer’s. All donations go toward outreach and production. Donate at the link in the description. 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 on Aging for Alzheimer’s Disease Research. This episode of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink, and edited by Eli Gadbury. Our musical jingle is “Cases to Rest” by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer’s Disease Research Center, check out our website at adrc.wisc.edu. That’s 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.