Alzheimer’s Prevention Initiative investigates genetic risk of Alzheimer’s disease

Research data collected from participants around the world has grown our understanding of genetic risk for Alzheimer’s disease. Guest Jessica Langbaum, PhD, is the co-director of the Alzheimer’s Prevention Initiative at Banner Alzheimer’s Institute, which conducts clinical trials in people at high risk for developing Alzheimer’s disease. Langbaum discusses some recent findings in genetic predisposition for Alzheimer’s disease, the psychological consequences of learning one’s risk, and testing interventions to delay or prevent the onset of symptoms. Guest: Jessica Langbaum, PhD, Banner Alzheimer’s Institute

Episode Topics:

  • What is the Alzheimer’s Prevention Initiative? 3:44
  • What is the difference between the APOE gene and the presenilin gene? 6:07
  • How are you approaching disclosure of genetic risk to participants? 12:15
  • What kind of responses have you received from participants who were told about their genetic risk? 15:32
  • What would you recommend to an individual interested in learning their genetic risk? 22:19
  • What are your recommendations for preventing dementia? 24:25
  • What is the GeneMatch program? 26:35 
  • How can individuals find a study to volunteer for? 29:48
  • What is the most feasible form of therapy for dementia? 31:06

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Show Notes

Jessica Langbaum PhD
Jessica Langbaum, PhD

Learn more about the Alzheimer's Prevention Initiative, or sign up for the Alzheimer's Prevention Registry.

You can learn more about Dr. Langbaum's work in Colombia in this "60 Minutes" program she referenced in the podcast.

Transcript

Nathaniel Chin: Our guest today on Dementia Matters is Dr. Jessica Langbaum, an Alzheimer's disease researcher from the Banner Alzheimer's Institute in Phoenix, Arizona. Dr. Langbaum is director of Banner's Alzheimer's Prevention Initiative, the goal of which is to identify presymptomatic treatments or interventions that will postpone slow or prevent Alzheimer's disease progression. Much of Dr. Langbaum's work is on the science of recruitment, such as designing research studies and the art or science of choosing participants for research studies. Welcome to Wisconsin, and thank you for taking time for an episode on Dementia Matters.

Jessica Langbaum: Thank you for having me.

Nathaniel Chin: I'll start out with a question I ask a lot of researchers who joined us on the podcast. How did you get involved in Alzheimer's disease research?

Jessica Langbaum: Well, like many people I've been personally impacted by the disease. I lost my grandfather to Alzheimer's disease, but even before he had Alzheimer's disease, I was very interested in the brain and how it works. And my graduate studies focused on cognitive training interventions that might delay or slow down the onset of memory and thinking problems common in dementia. So while I was in graduate school, that's when my grandfather developed mild cognitive impairment and it really propelled me into a career in this area.

Nathaniel Chin: And you've taken that career to the Banner Institute. So tell us a little bit about the Banner Alzheimer's Institute and its research goals.

Jessica Langbaum: Banner Alzheimer's Institute is part of Banner Health, which is based in Phoenix, Arizona. Banner Health is a very large not-for-profit healthcare system and Banner Health made a strategic investment close to 15 years ago to develop centers of excellence and Banner Alzheimer's Institute was its first center of excellence. And it was really built off of the research that had been going on at Banner Health for a number of years, led by Dr. Eric Reiman, who is now our executive director at the Banner Alzheimer's Institute. Banner Alzheimer's Institute has really three missions. One is setting a new standard of care for our patients and families. Care is front and center in everything we do. The second is forging a new model of collaboration. So we within Arizona, probably very similar to here in Wisconsin, we have a few metropolitan areas and then a large swath of the state that is perhaps more rural. And we always believe that we are better together than apart. So we work very closely with several of the other research institutions across the state building and collaborating together. So one area might be better in autopsy studies and another group is better in brain imaging or animal model studies. So we bring our research experiences together through collaboration. And the last mission is really ending Alzheimer's disease before we lose another generation. And that's what I focus on through the Alzheimer's Prevention Initiative.

Nathaniel Chin: Well, three very important fundamental pillars, I would say. And I, as a geriatrician in a memory clinic, I'm very appreciative that you started with care because that's obviously very important for the people currently affected or going through their own challenges. Now you're the director of the Alzheimer's Prevention Initiative. What is this program's focus?

Jessica Langbaum: The Alzheimer's Prevention Initiative, where I work alongside with Dr. Eric Reiman and Dr. Pierre N. Tariot, the goal of which is to conduct clinical trials in people who do not have symptoms of the disease, or are asymptomatic, but are at elevated or high imminent risk of developing symptoms of Alzheimer's disease based on their age, their genetic risk for developing the disease. So we are conducting clinical trials in people who are at high risk for developing the disease and trying to see if our interventions delay or prevent the onset of symptoms in these high-risk populations. We started off with our first trial in Columbia, South America with Dr. Francisco Lopera and his team at the University of Antioquia in Medellín, Columbia. And that happens to be in a very rare form of Alzheimer's disease, an autosomal dominant Alzheimer's disease or an early familial Alzheimer's disease. It happens to be in this area of Columbia that is home to the world's largest known extended family of people, about half of whom carry this genetic mutation that causes them with certainty to develop symptoms of Alzheimer's disease. The average age of onset of mild kind of impairment in these individuals is 45, full blown dementia fears, you know, in their early fifties. And it's caused by this Presenilin-1 E280A mutation. So we, in collaboration with the National Institute on Aging through a grant and with what was Genentech and now Roche have been doing a study of an experimental immunotherapy Crenezumab in these individuals, and it will be a few more years and we'll have results. We have another trial that is winding down right now called the Generation Program, which enrolled people who were at elevated risk based on their APOE genotype. And then we have other trials in various stages of planning

Nathaniel Chin: And for our audience members who haven't listened to earlier episodes, could you clarify for them the difference between APOE and presenilin only so that they understand the difference?

Jessica Langbaum: APOE, the gene, all of us have APOE, right? And it comes in what we call three different alleles or sometimes flavors, if you will. And those are APOE two, three, and four, and everybody gets a copy of the APOE gene from mom and one from dad, and that determines your APOE genotype or or risk. APOE is just a risk factor, a susceptibility factor. Just if you happen to have the high risk form of APOE that increases your chances of developing Alzheimer's disease, but it does not mean that you will, with a hundred percent certainty, develop the disease. An autosomal dominant mutation on the Presenilin-1 gene or Presenilin-2 or APPG. If you carry one of these mutations, it is hereditary passed down from generation to generation. If a parent has that gene, you have a 50/50 chance of receiving that gene from your parent. And it means that assuming you live to that age, you will, with a hundred percent certainty, almost always develop Alzheimer's disease.

Nathaniel Chin: And that's a very rare form.

Jessica Langbaum: It's a very rare form; it accounts for less than 1% of all cases of Alzheimer's disease. And again, it is a hereditary gene. Many people think, well, I have a family history of Alzheimer's disease, my parents had it, or my grandparent had it, so therefore it's hereditary. And this is generation after generation after generation, you can look at a family tree and it's a very clear pattern of a gene going down from generation to generation and multiple siblings, aunts, uncles, cousins. It's a very, very different hereditary pattern than the more common sporadic form of Alzheimer's disease for which APOE is just a susceptibility factor. There is a very interesting case that we found in Columbia recently with a Presenilin-1 mutation carrier, a woman who also happened to carry a very rare protective form of the APOE gene. And so this woman despite care at having the Presenilin-1 mutation had a very rare variant of APOE and has not yet developed symptoms due to Alzheimer's disease. So genetics is really playing a very interesting role. So while I said, with a hundred percent certainty of developing the disease, there are very rare cases, very, very rare cases where that isn't the case.

Nathaniel Chin: And while infrequent, it's really important to study these cases as a way of understanding Alzheimer's disease and coming up with treatment.

Jessica Langbaum: That's exactly right. So this a rare variant on the APOE gene it's called the Christchurch mutation, and this woman happened to have two copies of this rare variant that somehow is protecting, she has a head full of amyloid, happens to also carry the Presenilin-1 E280A, has very little tau and no cognitive symptoms despite being well past the age of onset. So that is giving us a glimpse into potential routes for future drug discovery. How can we mimic biologically this rare genetic mutation?

Nathaniel Chin: So genes aren't just necessarily bad for us.

Jessica Langbaum: They can be protective. Also there is the Icelandic APP mutation that provides base inhibition at a very low level. And the rates of Alzheimer's dementia in this population are very low. So right. Genes can be protective as well as risk factors.

Nathaniel Chin: When you're finding made international news, this Christchurch allele in this particular individual, and we never would have known about it, if you hadn't engaged with this community, had their trust and conducted these studies.

Jessica Langbaum: The families and Columbia have been remarkable research participants and partners in our research days, I should say. And it's really due to Dr. Lopera and his team building that trusting relationship with them over decades. First even building the trust for the first family who was willing to donate their loved one's brain to research so that they could see, Oh, here's what's going on in the brain. It is, we see Alzheimer's disease. And then allowing for genetic testing down there. So it's been a community involvement, and it's been remarkable. And then for this woman, this research participant, in who we discovered this rare variant who is willing to say yes, you can publish my case study. This woman doesn't know what she did, I mean, she probably knows now, but what she has done for research is extraordinary. And like you said, yes, it made the cover of the New York Times. But also I think what it's going to do for us as a field, for new drug discovery pipelines, is remarkable.

Nathaniel Chin: And for those that are interested in learning more, am I right in saying that you guys have been featured in "60 Minutes" a few times.

Jessica Langbaum: We have actually, yes. And "60 Minutes" has traveled down to Columbia with us and interviewed many of the family members. So you can find coverage on "60 Minutes." BBC has also covered our work and has featured it in some longer news coverages. And so there's a lot of coverage out there for the Colombian kinder, the pace of mutation as they call it in Medellin.

Nathaniel Chin: Well, so I want to ask a few questions about the study and the program itself, when it to prevention. It requires researchers to identify people at risk when they have no symptoms and enrolle these individuals in the studies. So for many studies, this could mean telling people they have this genetic risk, like the APOE that you just mentioned, or even that abnormal protein, such as the amyloid protein that we can identify on PET scans or in spinal fluid. How are you approaching the disclosure of this genetic and or protein risk?

Jessica Langbaum: That's a great question. I think we always lead with respect for persons and everything in our programs that we create and understanding what the participants want to know. And is it ethically justified? And does it, is it important for the research question? So I'll just step back and say for our study in Columbia, these individuals for our clinical trial in Colombia, these individuals do not know whether they carry the genetic mutation or not, and that was purposeful and intentional because at the time of designing the trial, they did not want to know whether they carried the genetic mutation or not. So we were respecting the community standards, so that trial enrolls mutation carriers and randomizes them to drug or placebo as well as you take mutation noncarriers from that same family who are assigned to just placebo. So it's a nested cohort study inside of a clinical trial. Now, switching gears to trials in sporadic, late, and people who are at risk for sporadic late onset Alzheimer's disease based on genetics, such as APOE or presence of a biomarker, such as having elevated brain amyloid. The will of the people, if you will, not everybody, of course, but there's reasons to think about disclosing this information. So we have worked with ethicist psychologists, genetic counselors to develop education and training materials on how to effectively disclose APOE, and in some cases, amyloid results to individuals, and monitor the psychological and emotional impact of learning this information. Frankly, Alzheimer's disease is behind compared to other fields like oncology. That is that which is disclosing very complex genetic results to individuals. And we think that with proper genetic counseling and education, that learning this information can be safe and we'll tolerate it. But again, I am a firm believer that it needs to be accompanied by counseling and education and not just receiving this information on a computer screen with no proper preparation.

Nathaniel Chin: Yes. And for those interested, we have talked about this on other podcasts, and I would echo and completely agree with you in that counseling is needed both before one chooses to have this. And then afterwards.

Jessica Langbaum: I agree entirely.

Nathaniel Chin: Now, what kinds of responses have you gotten from people who've learned their risk? Do they want to be more involved in research or do they feel like there are other negative consequences that they've experienced?

Jessica Langbaum: I will say we have a bias sample to start off with, because these are people who in order to join the research study agreed that yes, I would be willing to learn this information. So I suspect that what I'm going to say is not true for everybody, that there are people who don't want to know that information. And that is perfectly okay. However, in people who say yes, I want to know this information, and who go through the counseling process and say, the counselor always pauses at the time and says, here's all the pretests. Here's all the considerations. Here's what you may learn here. Considerations you might want to take into account emotionally or for your family, or for insurance. The counselor always pauses and says, now I have your results. Would you like to learn them? Almost everybody says, yes, I still want to learn them. And I'd say, what we're seeing in the data so far is that this information is safe and well tolerated. We will occasionally see a slight increase in emotional distress after learning this information. And that usually goes away within just a few weeks after receiving it for most people, the information is not entirely unexpected. It can also go the reverse. So there are cases certainly where people have believed that they're at high risk, they've spent their whole life saying, well, my parents, grandparents have had the disease. I must be an, I believe I'm at high risk and they get their results and they're not, they don't have the high risk version of the gene. And they're not sure how to process that, that doesn't mesh with their perceived risk. So there's this like disappointment for these individuals? Not that the low risk is disappointing, but they maybe can't participate in the research study. Like they had planned, they had gotten their hopes up that this would lead to something else and they can no longer participate. We're now looking at different ways to communicate this information with people because most individuals do not have access to a genetic counselor where they live. So how do we provide this information either through telephone based genetic counseling, video-based genetic counseling, or even self-directed genetic counseling. So while a person is at a research site, can we create video vignettes that are created by genetic counselors, have people learn this information at their own pace, be able to go back or click on information to say, tell me more about this, that they might not feel comfortable asking to a healthcare provider sitting face to face. And then of course always having the opportunity to speak with a healthcare provider afterwards to ask additional questions. So we're looking at taking this information, which I think is disclosure is going to become more increasingly common as people, as research studies require it, or perhaps people want to know for their own life planning. But making sure that people have access to counseling in some shape or form before they go down the path of saying, yes, I want to know this information.

Nathaniel Chin: Have you found in people who do learn the information that they change their behavior?

Jessica Langbaum: We're collecting that data right now. So I don't have the answer to that. Some studies from the reveal study program did suggest that there were some changes in health care and health behaviors or purchasing of you know, putting plans into place. So it might not that they, some people would adopt a healthy lifestyle. Other people said, well, right now, I'm going to now put my finances in order. I'm going to be proactive about making sure I have advanced care directives and expressing my wishes I want to have, but we're collecting more and more data on this so that we can better adapt.

Nathaniel Chin: And I know that there was a recent study that talks about emotional distress as well, and this perceived symptom being due to this perceived risk. And are you seeing that where people after learning that they might have a higher risk, not the disease, but a higher risk, feel like they're noticing more thinking symptoms?

Jessica Langbaum: We've looked at this. And so both their perceived symptoms as well as how are they objectively doing on tasks? So there's this concept called stereotype threat. I now know something about myself. So I'm a woman; I can't be good at math or sciences, or things like that. So that's also true for, I know my genetic profile; I must do poorly on memory and thinking tests. And what we're seeing is that there is while there is a very short-term increase in procedures that really goes away very quickly People start to again, for the most part, at least in our samples, are able to digest this information. They take it in and they're not constantly looking for, Oh, that word slipped and I don't remember anymore. And therefore I must have Alzheimer's disease. So again, these are very, I think the perceived risk, once you follow people over out for a little bit of time, that does seem to go away.

Nathaniel Chin: And I would suspect that's because you're doing complete and proper education and counseling beforehand.

Jessica Langbaum: I think so. I mean, the stories that you see on the news, or you read about in the papers about people who did direct-to-consumer genetic testing and were caught off guard by these results, they weren't expecting to learn what they learned or they weren't prepared for it. And then they started going on the internet and seeing these very high risk estimates for developing Alzheimer's disease. There's estimates out there that if you carry APOE, if you have two copies of the APOE four gene, you know, your risk is 90%, that's not necessarily true. And there are healthy lifestyle modifications and things that people can do that play into a person's actual risk. So I think that counseling piece is so important. It doesn't mean that counseling piece can't be provided through online mechanisms like we're looking at. But again, it has to be provided in an interactive way to educate people before they learn this information.

Nathaniel Chin: So knowing that and knowing that direct-to-consumer testing is available and people are accessing it, what would you recommend to someone who says, well, I'm going to do this, or I'm thinking about getting this test, but what would you say to them?

Jessica Langbaum: I would encourage somebody to speak with a counselor before, afterwards; there are telegenetic programs popping up so that people can get access to counselors before they decide to go down the direct-to-consumer route. I don't want to be paternalistic and say, you can't receive this information. It's not that, but I really want people to understand what they are about to learn, because there's not only considerations for themselves, but also their family members. How are you going to share this information with your biological children or your sibling? How might they feel about this information now? Because remember, it's not just about you as a person. If you learn that you have two copies of the high-risk gene, that means that your biological children, all at least have one copy or that your siblings might also, it tells something about your family. Have you thought about longterm care insurance? Have you thought about things, again, these are all things that somebody can deal with, but just putting it front and center and say, okay, even with these, I've taken these considerations, I want to learn, but I put plans into place where I've thought about how I might share this information. This is actually very interesting for identical twins -- one who wants to know, and one who doesn't. It's this era of genetics that I think is all doable, but we just want to educate people.

Nathaniel Chin: And you're speaking to really the complexity and the ripple effects of learning this information. And I know one of the reasons people want to know is because they're very interested in prevention. So outside of research, what do you and the Banner Alzheimer's Institute tell people that they can and should do to reduce their risk of Alzheimer's disease, or frankly, any form of dementia?

Jessica Langbaum: At Banner Alzheimer's Institute we're big believers in what's heart healthy is brain healthy. And I personally do not know my APOE genotype; I've been offered and I have chosen not to learn it because at this stage of my life, I don't know what I would do differently. I don't have a research study that I'm able to join based on knowing my APOE genotype. So I exercise, I try to do cardio exercise that increases my heart rate on a regular basis because that is one of the, I shouldn't say that's one of the proven ways, but there's really nice research on how exercise can positively impact the heart and brain and its role in amyloid production and things like that. Also staying calm, doing cognitive, stimulating activities, not online brain games, but staying engaged in things that give you enjoyment and pleasure as well, and that are challenging to the brain. Being socially engaged and active. Those pillars, and eating a balanced nutritional diet. Those are all pillars of good brain health that I think everybody can adapt that are not dependent on your genetic susceptibility or risk for developing the disease and could impact your health in a positive way that will likely play a big role in decreasing a person, your risk for developing the disease.

Nathaniel Chin: And the side effects of everything you just mentioned are pretty much feeling better and doing better functionally.

Jessica Langbaum: That's right. And, you know, I think they have positive effects on your blood pressure, cholesterol, mood. So it doesn't just help your risk of developing Alzheimer's disease. It helps so many things.

Nathaniel Chin: So part of the Alzheimer's Prevention Initiative is the Gene Match Program. Could you tell us about that?

Jessica Langbaum: The Gene Match Program was started as a way to connect people to research studies that were looking for a very specific APOE genotype. And when we started this program, we weren't quite sure whether this would be something that people would be willing to do. Would they be willing to sign up for an online program? I review some information online that was filmed by a genetic counselor or talking about the APOE gene and what this means be mailed a cheek swab kit to their home, return the kit to our lab and not receive their APOE results. And the results have been remarkable. We had over 90,000 people across the United States between the ages of 55 and 75 join the research program in just a few years. These people have been so altruistic in saying, yes, here's my sample, match me to a research study. And the Gene Match Program was a very successful tool to help us meet enrollment goals for the API Generation Program, which was looking for people with two or one copies of the APOE allele. So we've shown that this is successful. The program has been paused temporarily and we'll reopen in the coming months, and we look forward to having it serve as a recruitment resource for a range of studies over the coming months. We're actively helping a few studies with their recruitment goals right now using existing Gene Match participants. And we really look forward to opening it up again and allowing new people to join and be matched to a research study based in part on their APOE results. You might say, well, if Gene Match invites me to a study, doesn't that mean that I have the specific APOE result that the study's looking for? And the answer is no. We worked with a great team to say that when Gene Match invites somebody to a research study, if that research study is only open to a specific genetic profile, we still have to invite people from Gene Match with a range of APOE profiles, so that the act of receiving that invitation in it of itself does not disclose results. So it's been carefully considered and things have been thought about. And of course the choice is always yours. Whether you want to accept that study in rotation or not, participants are under no obligation to, if they're matched to study, to actually participate in. It's merely opening the door for conversation.

Nathaniel Chin: And for those that will eventually want to sign up, should they go to your website in the future to see when it's back up:

Jessica Langbaum: If people want to join Gene Match, the best thing I can tell them is to join our main registry at endalznow.org. And then they will be notified when Gene Match is up and running.

Nathaniel Chin: How can people who are interested in Alzheimer's prevention find a study that is near them, or find information that they can learn from?

Jessica Langbaum: I think there's a study out there for everybody, and it's really about connecting them to what research studies are taking place in their community. We developed the Alzheimer's Prevention Registry back in 2012 as a way to give the general public access to credible information about what's going on in Alzheimer's prevention research, as well as letting them know when there are study opportunities available, taking place in their community. So this is a national registry, even though we're based in Phoenix, we have studies right now that we're recruiting for all across the United States, including here in Wisconsin. And so people can go to our website, which is www.endalznow.org. And you simply sign up with your email address, your zip code, your year of birth, and a few basic questions. You can receive our newsletters and you can search for study opportunities that we're actively recruiting for right now, as well as be notified by email when new study opportunities become available. It's a really good resource and a great source of information about research studies.

Nathaniel Chin: When it comes to Alzheimer's disease therapy, we often talk about prevention, postponing, slowing, and curing. So based on your experience, which do you think is the most feasible and the first to happen?

Jessica Langbaum: That's a tricky question. Thanks for that. I think a cure is while a noble and a lofty goal, I don't think that's going to be the first one we're going to do or truly prevent it forever from ever occurring in the first place. We're not there yet. But I think slowing the disease first and foremost, that's going to happen, and postponing or delaying the onset is going to be key. And even by postponing or delaying the onset by a few years, that has a major public health impact and an impact on people's quality of life, on care partners, on the healthcare system that is tremendous. And if we can delay the onset of the disease and eventually delay, maybe we start with delaying the onset by just a few years. And then that time period gets a little bit longer and a little bit longer. Will we ever get to true cure or primary prevention? That would be remarkable. But if we delayed the onset by 10 years, that in itself, I would say is a massive success.

Nathaniel Chin: And I think for those people who have been around those affected by Alzheimer's disease and the full spectrum of mild cognitive impairment and dementia, they see that you can have a very active, meaningful life throughout the course of the disease, but in particular, the earlier on, dementia isn't what people perceive it to be in general. And so by delaying that you're not only keeping a person healthy, but you're also an essence putting that still very good quality of life on the table for later on.

Jessica Langbaum: That's exactly right. And I love what you said there that life doesn't end with a dementia diagnosis, and you have to find joy and simple life pleasures while you had the disease and life can be very fulfilling. You can engage in social activities. You can still travel during very many stages of the disease with preparation and planning and in place so that life doesn't end. And I think that's really important. So we can give more quality of life during the, during the early stages or these presymptomatic stages. So wouldn't it be wonderful if even though the pathology is still accumulating in the brain, we've postponed the onset of symptoms for a few years. That would be remarkable.

Nathaniel Chin: So when you think of prevention, or delaying, I should say, are you thinking of more of this what we talk about cognitive resilience and plasticity, or sort of a brain buffer?

Jessica Langbaum: When I talk about postponing I think what we're saying biologically is that we are reducing the accumulation of the pathology in the brain, or slowing down the pathology, which then translates to delaying the onset or appearance of symptoms. But your point about cognitive resilience or creating that buffer, it comes from the healthy lifestyle interventions I think that is so important. And thinking about the disease, a life perspective of the disease course, and improving health throughout the life span, educational opportunities throughout the lifespan, to create more of that cognitive reserve or buffer for greater percentage of the population.

Nathaniel Chin: So what is the next study?

Jessica Langbaum: The next study is going to be, we have a few in the pipeline, a few ideas. It would be remarkable to continue to move these studies into earlier and earlier in the at-risk population. So perhaps in individuals who are at the highest genetic susceptibility but don't yet have evidence of disease in their brain, such as amyloid, having elevated brain amyloid, but yet being at very high genetic risk, but no evidence of amyloid in the brain -- that would be a remarkable study to do as well as in younger and younger mutation carriers, and non-carriers. So we have a few studies in various stages of planning that we can't wait to announce in the coming months or a year.

Nathaniel Chin: I look forward to that. And I would say that I've been to your Generation's website many times, and it is by far the clearest and most visually appealing website in Alzheimer's disease research that I've seen.

Jessica Langbaum: Thank you very much.

Nathaniel Chin: I think we could all take a lot of cues from you guys. And so with that I'd like to thank you for being on Dementia Matters, and we do hope to have you the next time you're back in Wisconsin.

Jessica Langbaum: Oh, it's been great being here today. Thank you.