The Case for Disclosing Biomarker Results to Alzheimer’s Research Participants

Image
Photo of podcast guest Josh Grill, PhD
Josh Grill, PhD
Image
jason karlawish
Jason Karlawish, PhD

Though several validated biomarkers are studied and used in Alzheimer’s disease research, most research participants don’t have the opportunity to learn their biomarker results afterward, even if they have cognitive impairment. Drs. Jason Karlawish and Josh Grill join the podcast to discuss the debate over sharing biomarker results with research participants, how these powerful disclosures can be made ethically, and why it's as important for the field to study biomarker disclosures as it is to study the biomarkers themselves.

Guests: Josh Grill, PhD, director, Institute for Memory Impairments and Neurological Disorders, associate professor, University of California, Irvine, and Jason Karlawish, PhD, co-director, Penn Memory Center, professor of medicine, medical ethics and health policy, and neurology, University of Pennsylvania

Show Notes

Read Dr. Jason Karlawish and Dr. Josh Grill’s viewpoint piece, “Disclosing Alzheimer Disease Biomarker Results to Research Participants,” from JAMA Neurology’s June 2022 issue.

Listen to our episode with Dr. Daniel Gibbs about his book (mentioned by Dr. Karlawish at 34:21) on our website, Spotify, Apple Podcasts, or wherever you listen.

Listen to our past episode on amyloid disclosures with research participants on our website, Spotify, Apple Podcasts, or wherever you listen.

Learn more about Dr. Josh Grill at his bio on the University of California - Irvine website.

Learn more about Dr. Jason Karlawish’s work at his website.

Connect with us

Find transcripts and more at our website.

Email Dementia Matters: dementiamatters@medicine.wisc.edu

Follow us on Facebook and Twitter.

Subscribe to the Wisconsin Alzheimer’s Disease Research Center’s e-newsletter.

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. Alzheimer's disease research is advancing and the scientific community is finding new ways to predict and diagnose Alzheimer's disease. While much of this information could potentially be useful to a research participant, historically the research community has not shared this information with research participants. But now, things are changing. Joining me today to discuss when and how to share Alzheimer's disease risk data and its impact on research participants are two returning guests. Dr. Josh Grill is the director of the Institute for Memory Impairments and Neurological Disorders at the University of California–Irvine and Dr. Jason Karlawish is co-director of the Penn Memory Center at the University of Pennsylvania. Together, they penned a viewpoint piece for the June 2022 issue of JAMA Neurology on the importance of disclosing biomarker results to some research participants. Welcome back to Dementia Matters, Josh and Jason.

Dr. Josh Grill: Thanks very much, Nate.

Dr. Jason Karlawish: Yeah, Nate. Great to be back. Good to see you, good to hear you.

Chin: Before we proceed in the podcast, I have a disclosure of my own for our listeners. I'm a co-investigator with Drs. Lindsay Clark and Sterling Johnson in disclosing amyloid PET scan results to participants with cognitive impairment and those without any impairment. These are all done within an IRB protocol and at a research center, but I am the study physician doing those disclosures so clearly I have a bias of my own. So with that out, today we're here to talk about returning Alzheimer's disease biomarker results to research participants. To be clear, these are not clinic patients who are using insurance and copays to pay for the visit, receive a diagnosis, or get prescriptions. These individuals are volunteers and they have a research diagnosis, possibly a clinical one, of either mild cognitive impairment or dementia. Today, we are not discussing research participants who are cognitively normal. Jason, I'd like to start out with you telling our listeners what information the Penn Alzheimer's Disease Research Center shares with its volunteers who join the longitudinal Alzheimer's disease research studies.

Karlawish: If someone signs up to be in our Aging Brain Cohort study, otherwise known as the ABC study, and they want to know what you find out about my cognitive health, we'll let them know that we didn't find any evidence of cognitive impairment or we did. If we do find evidence of cognitive Impairment, we'll drill down to what we think the cause of it is and whether it's causing disability, that is to say dementia or just inefficiencies in daily activity, MCI. Most people want to know that. They want to know what you find out about, you know, how my cognition's doing. If they want to know the cause, and because of our research study we were able to get biomarker data, and they want to know the cause from biomarker results, we'll tell them the biomarker results if they have cognitive impairment. If they don't have cognitive impairment, we do not offer them the biomarker results and if they ask we don't provide them.

Chin: Is there any other information besides the biomarker results that Penn offers participants?
Karlawish: Measures of cardiovascular health because they're so relevant to brain health and then any incidental findings, of course. I think what you might be saying is, we don't routinely offer and, if they ask, don't typically offer the results of ApoE testing.

Chin: All right. Josh, what does UC-Irvine’s center share with its participants?

Grill: It's quite similar here. We will certainly give people back information about pertinent diagnoses if they suffer from cognitive impairment. Our neuropsychology team is really outstanding and devotes a lot of time to producing reports and going through those reports with patients and their families who suffer from impairment. For the last several years, we've had a relatively large emphasis on cerebrospinal fluid biomarkers. Those are primarily run locally and so we have not made a practice of sharing the results of those biomarker tests because they're deemed investigational and not done in a laboratory setting conducive with giving it back. We're quite pleased that there's been some funding acquired over the recent couple of years that's allowing us to do more PET imaging. We had these very same discussions locally, and I'm heartened to say that we arrived at the same decisions as are articulated in the essay, that people with cognitive problems – that is meet criteria for MCI or dementia who get these biomarker tests – and want this information back should be provided it if they have, you know, an amyloid PET scan, for example.

Chin: At Wisconsin and our ADRC, we share what we call a research diagnosis because it doesn't go into a person's medical record, even though the process of evaluation is similar. We will share our clinical suspicion for what the cause might be, but we don't share or we haven't been sharing the biomarkers until recently for those with impairment. We have standard blood work so something that Jason you had said – lipid panels, things like that. We'll share that but we don't share MRI scan results, unless there's an incidental finding like you mentioned, and we do not share ApoE results. I think similar but there are some nuances and I think that's an important thing that I wanted our listeners to know – that each center is different and they are bound by their own institutional review board but also their own philosophy and belief systems. I think that part of it is what is being challenged at certain centers or at least among the field. I find it interesting that while many in the field can share a diagnosis or at least what they think is causing a change, maybe sometimes testing results depending on who you talk about, not all things are shared – biomarkers, genetic information like ApoE. Why do you, one, think the field treats biomarkers differently? And why are biomarkers really more palatable than genetic testing at some places that do share information?

Karlawish: Well, Josh, why don't we ping-pong this one? 

Grill: Sure.

Karlawish: I think one issue is that not yet even have biomarkers of Alzheimer's disease arrived in clinical practice. While many are FDA approved – PET ligands for example – they're not used widely in clinical practice largely because of the reluctance of insurance to compensate, to pay for them and I think that's an interesting story. So clinicians really haven't gained comfort with how to disclose them. You know, the odd thing is in a research setting we've been getting them and yet we still don't disclose them. I think their things get more interesting. I suspect there's issues around labor, effort. You know, it's work – number one. I suspect also they've sort of rolled out in a kind of slow way, you know. Amyloid, but not tau. Now there's tau but the tau ligand hasn’t been validated, etc. There's been kind of a learning-curve, comfort-curve. I think the point that Josh and I arrived at though is the comfort-curve has crossed a threshold. There are well-validated biomarkers out there – imaging and soon blood – that measure the ATN framework and in expert centers where expert clinical diagnoses are made, it's time to start giving those results up. Josh, what do you think?

Grill: I think those are really important points. I think there's also just sort of inertia. This is the way it's been done. Remember that these same centers really deserve a great deal of credit for helping us get to this new place in the use of biomarkers, the availability of biomarkers, the development of the biomarkers themselves. So the way it's always been done ultimately does need to change at some point and we think we've arrived there. I think another thing that's really quite interesting is that I think many centers are still using the ligands that ultimately didn't get FDA approval. You know, the PiB ligand that really was so key in accelerating research in Alzheimer's disease is still utilized quite a bit. It's not FDA approved. And so, you know, there is a logic that can be applied that because it's not FDA approved, we shouldn't use the results but in fact the data for PiB are more robust than for really even any of the FDA approved ligands.

Karlawish: Lots of medical practice happens about drugs and tests that don't have FDA imprimatur on them. I think another issue is also the fact that the research studies reflect designs that were done in the pre-biomarker era. In other words, the diagnoses in the UDS system still are sort of clinical diagnoses. They're not caught up to biomarkers and the fields that are being collected – and I think one of the key arguments in our essay is, you need to tell people. If they want to know these results, you need to tell them the results and you need to record this in the database. Did they learn it? What – did they want to learn it? Did they not want to learn it? Et cetera. And we'll talk more about that. You know, if you look at the UDS – uniform data set in a database – it's just clinical diagnoses according to old standards and so there's these sort of built-in disincentives, if you will, to sort of do this because it's sort of extra supernumerary work to the research project as opposed to embedded in the research and part of the research. I think that's where Josh and I want to take the world. Go ahead, Josh.

Grill: Yeah, and I think that we also have for a long time really tried to take a participant-centric approach to thinking about the way we do research. I think that it's high time that we think about the place a participant might be at. In particular, if they have a diagnosis of MCI and they know they're getting this result and they want to know it, if they can't get it through the study then they might face the alternative of going to get another scan, which really is just kind of inexcusable in our minds. There's cost and risks that come with that and so it's high time that we find a way to show our appreciation for the people who helped us make these tremendous advances and give this information back to them in these circumstances.

Chin: But there's a history to this, to not disclosing information in longitudinal studies. I think you both hinted at part of it. You know, to me, we've been collecting cognitive testing information. We've been collecting ApoE for decades. Most centers – I think a study that both of you have been a part of – showed that ADRCs don't share that and I'm sure they have good reasons for that, but I mean how do you slice this to say, well we can share PET scans but we're not going to share your ApoE, which you could get privately?

Karlawish: I think it's about diagnosis. I mean, you know, I don't know what my ApoE genotype is but whatever it is I have had it since my zygote implanted right on my mother's womb. I don't think I had amyloid and tau when I was eight years old, but I think if someone comes in at the Penn Memory Center and has been diagnosed with cognitive impairments causing inefficiencies or disabilities in daily life – MCI or dementia – I feel more and more a need to say, look I have available tests that can tell you if this is being caused by Alzheimer's disease. Also if not, they will say that it's not but I don't have tests to tell you what it's not, which is interesting. I just think it's high time that people have the opportunity to learn what their diagnosis is if they have cognitive impairment. I think ApoE is just different. It's not about diagnosis. It's about – I don't know what the value of it is for MCI and dementia for that individual. Oh, I know what it is but I think that's this completely different clinical set of issues around the value of genetic testing to inform family risk, etc. It's just different.

Grill: And once upon a time, we really didn't know what to tell people about these tests and now we do. There's a dramatically growing, robust evidence base around what these tests mean, and what they mean to participants, and what actions they can result in on a clinical scale. This too was really a key component of our argument, that there is now an evidence base to support the clinical utility of these approved biomarker tests. Withholding that information from people who might value from it skirts some ethically challenging areas.

Karlawish: To build on the clinical value issue, I mean, let's face it. The field is haunted by the MEDCAC meeting of – whatever it was – 2011, when Lilly really had been boldly pushing florbetapir forward, got FDA approval with an elegantly designed study that did clinical-pathologic correlation, and then goes to medicare to make the case to pay for it and MEDCAC shoots it down. When you read the story of the MEDCAC hearing, essentially what they were saying – either explicitly or implicitly – was in principle we get that there are some clinicians out there who could use this study wisely, but if it's made available widely it's going to just be used for any older adult with a memory complaint. It reflects larger problems with this infrastructure in America for cognitive assessments. I think that haunted the field. Medicare said, we're not paying for it. We can't see how it's reasonable and necessary, which is Medicare Par’s loss. I think an Alzheimer's Disease Center researcher, clinician, investigator is capable of deciding that this research study result is reasonable and necessary for a patient who wants it and on that basis be able to give it to them where cost issues are off the table now because the test has been obtained in research settings. That is to say, it's been paid for by the research budget, just like the cognitive testing has been, just like the neurological exam has been, which we're telling them.

Chin: Well, so let's get to your viewpoint. This is in JAMA Neurology and it's really highlighting an argument – and Josh you used the word argument so I think that's fitting – that research participants who have MCI or dementia ought to have the opportunity to learn their amyloid and their tau results. My first question to you is, why should a research participant be allowed to learn something that is not widely available in a medical practice?

Grill: Well, it's widely available. It's just not widely utilized for a variety of, I would argue, practical reasons including that it's not typically covered by insurance but, you know, the tests are valuable. They’re valuable to our research but they are increasingly understood to be valuable clinically as well. They are also expensive. They also have small risks associated with them and so there are practical reasons that their clinical uptake has been perhaps less than what we might have expected when they were being developed. Again, you know Jason makes the point. In the case of a longitudinal observational study the test has already been paid for. It's already been ordered. In some cases it may have already been performed. The real question is, is there adequate reason to not give that information back? I think for these folks with MCI and dementia, there simply is not. There's a lot of rationale for giving it back to them including that the alternative for them is to go get a second scan.

Chin: What is the clinical utility of learning your MCI or dementia that it's due to Alzheimer's disease through these PET scan results when we don't have a disease-modifying therapy for it? In essence what I'm asking is, is it enough that people want their information and that we have it that we can share it with them? Jason, I'll start with you.

Karlawish: Absolutely. I think that if I've got a test that validly measures a measure of a disease and I think based on what I know about you, the patient, that this measure is reasonable for you and you want it to explain the cause of your cognitive impairment, boy that strikes me as a very personally valuable set of information to give someone to explain the cause of their cognitive impairment. That, to me, is an ethical reason enough to tell someone that information if, of course, they want it. If they don't want it, they don't need to learn it.

Grill: And I'll just piggyback that. A few years ago we did a study of people undergoing clinical amyloid PET imaging and interviewed them after having the test. One of the more common reactions to getting the information, regardless of the result of the scan, was relief. So for people with symptoms, the opportunity to get more information – be it whether Alzheimer's is the cause of their impairment or whether it's something else – they do derive value in that. They do derive relief from the opportunity to learn more about their disease, and I think to move from a diagnostic phase of their experience into more of a treatment- or action-oriented phase even if it's simply around planning.

Karlawish: And to build on this, I get the perspective of CMS – Center for Medicare Services – which is, help me articulate that value into things that we can translate across hundreds of thousands, if not millions, of people. I see the challenge there. I think that topic is off the table if the issue is I've obtained this test already, cost issues are not a matter here, and I'm doing it at a place that is on the forefront of studying the diagnosis and clinical experience of these diseases, which gets to sort of our other half of our argument which is it isn't just handing out this information to people and saying great. You've got – it's put this into the database about what you told them, what you didn't tell them, and also other measures of what people do once they get this information. I think this is the new wave, the new era of the biomarker-based definition of these diseases and what better place to sort of study that and learn about it than the centers that have been dedicated since 1984 under congressional mandate to study and to figure out what is this thing called Alzheimer's disease.

Chin: Well I appreciate that context too because you're absolutely right. In a research setting, these things have already been done or already paid for and now it's a matter of what do we do with that information. But I also appreciate Josh what you said about sense of relief because oftentimes people will make this argument of, ‘Well there might be personal utility but there's no clinical utility in the absence of a drug’. Sense of relief and addressing mental health certainly feels clinical to me and so to be able to show the evidence that people regardless of the result have a sense of relief seems to argue that even personal utility ends up being clinical utility.

Karlawish: Yeah, and scientific value because, I mean, the complete disease experience is knowledge of what is your diagnosis. You know up until recently it was the skull that kept that from being known clinically. Namely, you couldn't easily figure out what was causing someone's brain disease because the skull keeps you from getting tissue biopsies or whatever else. I'm joking, almost. Things have changed since 2002, slowly but all at once. Our obligation scientifically is to study this disease according to the best standards of diagnosing it. We have that ability now with imaging and soon blood tests to tell someone you do or don't have these pathologies. That's the 21st century for Alzheimer's research, which is what it's like to know, ‘I’ve got cognitive impairment and it's caused by or not caused by the following diseases’. That's where we're going to go as a society and it needs to be studied at Alzheimer's centers.

Chin: And that was a perfect lead into my next question which is, what if it's not a positive result?

Karlawish: (laughs)

Chin: So the Alzheimer's disease biomarkers – they're very specific to Alzheimer's disease and they cannot tell if a person has any other brain disease. We know from great research that Alzheimer's coexists with many other brain pathologies. Is it appropriate to share an incomplete picture with someone who already is experiencing cognitive impairment – be it MCI or dementia? Is it okay to share partial information when we don't have the rest of it? Josh, I'm going to start with you.

Grill: I think it is okay to share that we have partial information, but it needs to be shared with education and counseling about what we can offer. That includes helping patients and their families understand that we're going to get one piece of information about whether Alzheimer's disease changes appear to be present in the brain and are a contributor to the person's cognitive problems. It doesn't mean that there's not anything else going on. If the scan is negative or if the results don't support Alzheimer's disease, it's not going to give us information about what is going on. I actually think these are areas of research that still are greatly in need for our field. We haven't done a lot of work around giving this information back to people with MCI and dementia. In particular, we haven't done a lot of work around giving negative results to people who have MCI and dementia. What are we really telling them and how should they be reacting? Obviously the way we counsel them, educate them, prepare them for the test and learning the results will have a big impact on their reactions to this information, but if it's not Alzheimer's disease in all probability there's something else going on that's causing the cognitive problems. Ultimately, we certainly hope to have other tools to get at what those problems are but right now they're pretty limited.

Karlawish: Yeah, let me plus one what Josh said, which is part of the education has to be – we can tell you whether you have Alzheimer's but if the tests are negative, we can't tell you with the same kind of certainty what the other diseases might be. That's part of the education about alpha synuclein, TDP43, vascular disease, ubiquitin, and as yet undefined pathologies. We actually – I had a meeting with Eddie Lee, who's our lead neuropathologist at Penn, and he said, ‘You guys made the first pre-autopsy diagnosis of TDP43-late.’ We did it on the basis of MRI atrophy showing really severe hippocampal atrophy, et cetera, in a clinical picture that otherwise fit. The person died and, sure enough, they had TDP43. It's this kind of information that we're giving back to people that I think is very valuable. We were thrilled to have it validated clinically, but let's embrace the uncertainty. Let's convey it to people, and again, let's study it. That's my point and Josh's point, which is let's make this part of what we gather and develop best practices around it.

Chin: So education, preparation. In essence, informed consent is really critical before even learning one's result.

Grill: Without question.

Karlawish: And if you had to pick one group of patients – granted they’re research subjects, but essentially they are patients. We're talking about people who have MCI or dementia. These are high-octane diagnoses who probably would be on the forefront of wanting to learn this, et cetera. It's people who are coming to an Alzheimer's center to participate in a longitudinal cohort study. I mean, they’re here because they want to contribute, help, learn and know. Are they quirky compared to the general population? Yeah, but – and I view them as the least vulnerable in that sense though because they're there because they want to be there.

Chin: So you mentioned in this article that learning about Alzheimer's disease biomarker results may help people plan for the future – “plan for the future” being the key phrase there. Does learning about these biomarkers add that much more than already just being diagnosed with the syndrome of mild cognitive impairment or dementia when really talking about advanced care planning and what someone should do? Josh?

Grill: Well, I certainly think it can. You know, for the person with MCI who lost their mother to Alzheimer's disease and is really worried about it, getting this scan result if it's positive can be challenging but it can also help them move to a phase where they're going to take important next steps that they might not otherwise take. We know that giving this information to people does spark thoughts and conversations and actions around long-term planning, financial issues, residential issues. It sparks changes for their doctor too. Change in the diagnosis, change in the treatments; these things are also extremely important and might not occur for the person in the observational study who doesn't get that result back.

Karlawish: I think for someone with MCI who learns they have not elevated amyloid and negative tau, it's a very different story than if they learn they have elevated amyloid and positive tau. I mean the data about change over 5 years are very compelling. I think people knowing what that information could mean, there are some who would value knowing that and want it for all the reasons Josh said – I won't reiterate them – and others that say I wouldn't want to know that, but that's their choice. I think there's tremendous value. Again, they're hard things to articulate under standard measures of health utility. I mean, standards measures of health utility are about disability and they typically capture physical disability. If you look at the Huey and all these other disability measures, they're about physical disability issues. They're not about losing one's ability to self-determine one's life. But you know what? That's what matters to older adults. It matters to all adults. It's just self-determining your life. If you know you're going to have a disease that's going to take that away because you already are beginning to experience it, I think a lot of people would want to know that.

Chin: Jason, my next question is for you, as someone who's in a memory clinic and talks to people about diagnosing and risk of Alzheimer's disease or pathology that one you would suspect based on a history. This is kind of a long question so bear with me. When you tell someone they have amyloid in their brain – just amyloid – the conversation is about risk of having Alzheimer's disease, developing Alzheimer's disease, and perhaps progression from MCI to dementia. When you tell someone they have both amyloid and tau, you are in essence telling them they have Alzheimer's disease, very definitively. If Alzheimer's disease is in their brain and it's causing their MCI and dementia, there really isn't any conversation of risk. There's no conversation of, well it could be something else. It could be something in addition, but you're not really wavering. How do you think people are going to respond to such a definitive information-sharing, and are you worried about negative consequences of doing so?

Karlawish: So it is. You're right. You're conveying a diagnosis. The information I'm conveying is, I think that the cause of your cognitive problems is Alzheimer's disease. In my clinical experience, that certainly is high-octane information. Again, people have come to the Penn Memory Center in a waiting room that has information about Alzheimer's disease, having undergone an hour-and-a-half long assessment, having come back one month later to go over the results, and that – I think that kind of clinical experience has a host of steps that allow people to sort of walk away from that process. By the time I've told someone that based on results of biomarker testing, my experience has generally been that, A, they wanted to know it and, B, that they make sense of it and use it. It's not pleasant information, to be sure, but they've come there wanting it and received it. I agree, though. I think one of the areas of concern that many of us have, particularly now that blood tests have made the economy of scale of these tests very easy, is this sort of blithe handing out of these results. Come on in and get your Alzheimer's test even before you've done anything else other than come in. I'm very bothered by that, very bothered by that. But again, that's why Josh and I think the place to get going here are Alzheimer's centers to set the standards because that's not what we do.

Chin: I think that's a key part. This is all a research context, research participant, research setting. Lots of staff and support, ideally. How might a research participant learning their result, how might that help them within the research context? How might that help the actual research center itself in being able to share this result with the participant? I'll start with you, Josh.

Grill: Well, it's not well studied but I think it certainly could have ramifications for the retention of research participants. On one hand, I think it is a demonstration of our appreciation for their contributions, respect for those contributions, and our desire to make the experience valuable for them. I don't think that this has been studied per se but it makes sense to me that this will help us keep people in studies longer if we do this and if they know that, to the best of our ability and to the extent to which we think it's reasonable, we're going to try to give information back to them. Numerous studies have shown that people want information about themselves when they participate in research. I think that there is potential value in that. Again, I think we've made this point several times already but I'll make it again. This is part of our work. This is research that needs to be done. As the field evolves in clinical practice, research must guide it. Understanding people's reactions to this information, what it means to them, who's likely to want it, who doesn't, et cetera; all of these things are very important research questions unto themselves.

Chin: Jason, why is it advantageous, from a logistical and ethical perspective, to disclose in a research setting versus in your clinic?

Karlawish: The point of research ought to be that it is revolutionary. It's designed to change the standard of care. Right now biomarker disclosure is not part of the standard of care and clinical practice, but in a clinical research setting it can be. Much like a drug trial that changes clinical practice, I think we have this opportunity in research settings, in our Alzheimer's disease research centers, to develop the evidentiary base to change clinical practice around disclosure of biomarkers of Alzheimer's, and so that's the right place to start this and roll it out.

Chin: In this commentary you mentioned ethical criteria that must be met in order to share results. For our listeners who haven't read the article yet, what is the criteria and how did these biomarkers fit those?

Karlawish: So I'll start with one and then Josh will do another. The first one, first of all, is validity. If the test does not meet scientific standards for validity to accurately and reliably measure what it says it's going to measure, further discussion of disclosure is off the table. It's not even worth proceeding. But if it's valid, then the next steps are… Josh? (laughs)

Grill: It needs to be interpretable. You know, the biomarkers are intense areas of study but for the FDA approved ones there is an indicational use that's been approved to call someone positive or negative, for example. So we think that biomarkers must be valid but they must also be interpretable. Ideally there's an approach that's been recognized as clinically useful and that researchers should try to use those approaches that have made it to the point of a wide-scale acceptance.

Karlawish: In short, a competent clinician capable of doing it, as well.

Chin: And that's my next question is, who should be doing the disclosures in a research setting? And what resources do you two think should be mandatory in doing a disclosure?

Karlawish: Well, a competent clinician to disclose it. In other words, he or she should feel comfortable with telling someone with cognitive impairment, explaining the test, answering questions about the test, and then being able to obtain a test and interpret the result and explain it. If someone's not comfortable with all those steps, they shouldn't do it. Period. End of story, full stop. If they are, great. Again, you know, if you had to pick one place where you're probably going to find clinicians capable of doing that, it's Alzheimer's disease research centers. All the better to pave it. I will say it raises a resource issue though as you said, which is do the clinicians have the time and support to do that and is the center able to routinely get those results as well. Right now, a lot of centers rely on substudies, ancillary studies, philanthropy, double billing for MRI, et cetera, to be able to get these. I think the field is going to have to start to ask questions around resources. In other words, does it make sense to not routinely gather these measures in a cohort study to understand these diseases? I think the blood tests are really going to transform that – the answer to that question because, I mean, it's a tube of blood and it's just the cost of the analysis, which is magnitudes less than imaging.

Chin: What about infrastructure, though? So you have a competent clinician scientist doing the disclosure. What is needed in order afterwards with the disclosure? Josh, from a systems perspective, what else should be there, if anything else should be mandated?

Grill: No, certainly I think ideally time is key. There is time involved in going over what we understand and what we don't understand, what the results are possibly going to be, and helping families make a decision that this is information they want to acquire given its limitations. Then there is obviously going to need to be time on the other side of the actual biomarker test to make sure a person still wants this information and hasn't changed their mind, that they and their family still understand the limitations of the test, and then explaining the result to them and taking the time to answer their questions. I agree with Jason ADRCs are chock full of individuals who are adequately skilled and capable to anticipate those questions and then answer them, but it is a resource of time. I think, too, given that we are really strongly lobbying for the science of this disclosure following people over time, performing telephone follow-up to understand how they're doing, how often are they thinking about this, has it resulted in them making changes at home or in their lives otherwise? This will, of course, also require resources. Maybe it won't need to be the skilled clinician who's making those follow up calls, but it's time and effort nonetheless.

Chin: In your commentary, you state that returning Alzheimer's disease biomarker results is care. That's not something you hear frequently particularly in a scientific research journal where we like to draw a line, whether it be arbitrary or not, between research and care. Can you explain this viewpoint for our listeners?

Karlawish: It's about the value of information. I mean, doctor means teacher at the most fundamental level. I've realized that the 21st century advances in therapeutics, antibiotics, chemotherapeutics, you know – clot busters, aspirin, you name it – transform doctors into pretty darn good healers sometimes for some diseases but fundamentally our job is to explain to someone what's going on. Make sense of my problem, make sense of what worries me. In that sense, I think the value of this information that's gained in research and why it is care is, I'm going to explain to you why it is you don't feel as sharp as you used to, why it is that you know your husband seems like he's not listening to anymore. It's because he's got cognitive impairment and it's caused by Alzheimer's. You know, I think Dan Gibbs in his book lays this out very nicely. He's a neurologist who's been diagnosed with Alzheimer's and obviously very public about it. For him, making sense of why he was not able to smell his wife's apple pie, a rose, why he shredded the cucumber shavings in the salad and not the garbage, it's because of this disease. He makes sense of it. His wife makes sense of it. They carry forward with it.

Chin: You both have been involved in risk disclosure, genetic disclosures, biomarker disclosures in this field of Alzheimer's disease for many years. I'm hoping you can share, what insights do you have from your experience and then where will we be in the next five years, the next ten years?

Grill: Well, clearly blood biomarkers are coming at us fast and look incredibly promising and will enable use at a scale as yet unseen. I think there's going to be tremendous opportunity that comes from that as well as some real risks. I think that, you know, Jason and I both have concerns around the potential impact of those tests going, if you will, public or direct-to-consumer before we have time to adequately study them. I think there's concern, at least for me, that people are going to start walking in with results before we can adequately educate them, counsel them, help them make a decision about whether this is information they wish to have. That could pose some real challenges for our research, but for people themselves. We don't yet live in a dementia-friendly society and the implications of this information being out there in the medical record or beyond, while I wish it weren't the case, there could be real negative ramifications for people who perhaps make a quick decision. ‘Oh sure, I'd like to know if I'm ever going to get Alzheimer's disease.’

Karlawish: I think the next ten years are going to be a wild ride in autonomy on trial because in the end, why do we care about this disease? It takes away, bit by bit, slowly your ability to self-determine your life. Others step in and help make it possible. We call them caregivers. Until not that long ago, a lot of that happened in the wild until people finally came in because something was really wrong. I think the earlier and earlier we make these diagnoses, the more precision, no matter where you are in the continuum. We're making these diagnoses – for good and for bad, intended and unintended – medicalizing the experience of losing one's autonomy. Josh is right on. I mean, we don't have a dementia-friendly society set up, so that's why I use the phrase “wild ride.” Again, you know, I'm being a one-note Jason here in some sense. Let's get on top of this and start studying it at centers paid for by the taxpayers, which are here to help implement a national Alzheimer's plan. I think we can do this. I'd rather us doing it in that way than, you know, letting various and sundry private interests kind of sort it out the way things often happen in America. I'm cautiously optimistic by the future. I'll leave you with my one – not leave you but – I think it's only a matter of time before one of these tests becomes direct-to-consumer though because anything that's such a threat to intimate personal wellbeing invariably makes it pretty quick into the DTC market because there's a crowd there that wants this information and they want it right away, and now, and personally, and privately. You can see that you know the history of several different kinds of tests like genetic tests and pregnancy tests, for example.

Chin: So a lot of excitement in the research and the possibilities within research, but some words of caution from the two of you. I appreciate that. I thank you for your time and your candidness in this discussion. I'm certain we'll be having you both on as things progress within the field.

Karlawish: Yeah, we'll meet again. Thanks. (laughs)

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.