Amyloid Antibodies and the Role of the Geriatrician: Nate Chin, Sharon Brangman, and Jason Karlawish

Eric: Welcome to the GeriPal podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: And Alex, who do we have with us today?

Alex: We’re delighted to welcome back to the GeriPal podcast, Jason Karlawish, who is professor at the University of Pennsylvania School of Medicine, co-director of the Penn Memory Center, and associate director of the Alzheimer’s Disease Research Center, and author of The Problem of Alzheimer’s Disease. Welcome back to the GeriPal podcast, Jason.

Jason: Great to be back, Alex and Eric. Thanks so much for having me on.

Alex: And we’re delighted to welcome back Sharon Brangman, who is a SUNY Distinguished Service professor and chair of the Department of Geriatrics and director of the Center of Excellence for Alzheimer’s Disease. Welcome back to GeriPal podcast, Sharon.

Sharon: Thank you for having me again.

Alex: And we’re delighted to welcome Nate Chin, who is associate professor at the University of Wisconsin, where he is medical director of their Alzheimer’s Disease research center and runs a large study in Wisconsin called the RAP Study studying Alzheimer’s Disease.

Eric: Yeah, he is the host of my favorite dementia podcast. Dementia Matters. If you haven’t checked out that podcast, please do. Dementia Matters. Just type it into your favorite podcasting app, and it’s the first one that pops up.

Nate: Thank you guys for having me.

Eric: We have another podcasting host. [laughter]

Nate: Podcast competition. [laughter]

Alex: That’s right.

Eric: So we have an exciting episode today. I think the general theme of this is going to be what’s the geriatrician role in prescribing these new monoclonal antibodies for Alzheimer’s disease? We got a lot to talk about, including redefining dementia, which we’ll talk about where there’s a draft proposal from the NIA and Alzheimer’s Association on redefining Alzheimer’s disease as a purely biological marker definition. But before we jump into all of that, I think somebody has a song request for Alex. Nate, is it you?

Nate: No, it’s Sharon.

Eric: It’s Sharon.

Jason: Yeah. Sharon won.

Sharon: Well, yeah. I would like to hear Doctor My Eyes. I thought it was appropriate for the subject and all of us being docs. So hit it, Alex.

Alex: Great.

(singing) “Doctor my eyes have seen the years and the slow parade of fears without crying. Now I want to understand. I have done all that I could to see the evil and the good without hiding. You must help me if you can. Doctor My Eyes. Tell me went wrong was I unwise to leave them open for so long.”

Eric: Nice.

Alex: That was wonderful. Sharon, why did you pick that song?

Sharon: Well, we’re in geriatrics and most of my patients have had their eyes open for a very long time and have seen the evil and the good. So just thought it was-

Eric: Well said. So let’s jump right into the topic. We’re going to be talking about amyloid antibodies for Alzheimer’s disease, monoclonal antibodies towards the treatment of Alzheimer’s disease. The field of geriatrics has been, I would say, somewhat negative on these drugs. I think in large part it’s to a terrible launch, probably the worst drug launch of all time, which was aducanumab, which is now really out of the market.

But we have two new drugs, lecanemab and donanemab, both now published. One, lecanemab is FDA approved now. Likely donanemab will become FDA approved. I’m wondering, I’m going to start off by asking all three of you geriatricians, are you going to be using these drugs and do you think we as a field should be using them?

Jason, you’ve been both a loud opponent of aducanumab, but more recently somebody who’s been pushing more for us to think about use of lecanemab. What do you think about this?

Jason: Oh, I plan to prescribe lecanemab and donanemab or lecanemab because it’s FDA approved. Assuming donanemab is FDA approved, I will be a prescriber. And I do think geriatricians need to as individuals make that decision, largely based on their comfort with the diagnostics and the specifics of the therapeutics.

If anyone’s wondering, now wait a minute, what about aducanumab? My answer to that is aducanumab was just a failure of regulatory science. It wasn’t about the drug itself, it was about the decision and the drug. It’s quite possible actually, aducanumab is as effective as lecanemab and donanemab, but we just don’t know that. So this is about lecanemab, donanemab, two well done phase three trials. I’m a prescriber. I think geriatricians seed to decide whether they want to get on board as individuals.

Eric: What’s convinced you, Jason?

Jason: Well, let’s say two well done. Well, each one, I think… Again, only one phase three trial. That was an FDA decision. We could debate that as a matter of public policy, but I found the trials to be well done, well-designed, generally well analyzed, and the data across clinical and biomarker endpoints are consistent and compelling that the drug is effective and the benefits are there. And so too are the risks.

Eric: Yeah. And we’ll talk more about the benefits, but I wanted to hear from Sharon. Sharon, what about you? Where do you fall in line with this? Are you going to prescribe?

Sharon: Yes, I’m going to prescribe lecanemab as well as donanemab when it becomes available. I direct a Center of Excellence for Alzheimer’s Disease, so we have to offer FDA approved drugs. But we’re going to use a shared decision making process so that patients have realistic expectations. I’ve already been fielding questions from adult children whose parents have advanced Alzheimer’s disease and clearly would benefit. So there are people who are out there looking for something that’s going to make their loved ones better. And we know that these drugs are good at clearing away amyloid and they give a modest benefit in less cognitive decline, but we don’t have anything that stops the disease process yet. And I think that’s what’s important for families to know because everyone wants to stop this disease and roll back the clock to make their loved one better.

Eric: And my understanding of the literature is that these drugs compared to placebo, modestly slow down the reduction over 18 months in cognitive decline, on a over a hundred point scale, like four or five points, over 18 months, with some real risks associated. Is that kind of how you’re thinking about this, Sharon?

Sharon: Yeah, they have to understand the risks. And there are a lot of questions that we don’t know. So these folks who are taking it for the first time are going to be part of the new information that we have. How long do we need to give it? We know the trials were 18 months. Do people need to take it longer? Are they going to need a touch-up? Do you stop after a certain amount of amyloid is removed and then monitor them and then maybe give them another dose periodically?

Jason: And the donanemab data are very interesting because Lilly’s design for donanemab was once amyloid positive obviously got the drug, and then once their amyloid measure fell below a cutoff of centiloids, the drug was stopped. The patients continued to be followed. So they’ve introduced an interesting practice here, which is reassess amyloid after a certain period of treatment, and if amyloid is cleared, cease drug and follow. And that’s going to be very interesting to see how that unfolds in healthcare practice. So it does give us an endpoint and also gives us a biological endpoint, which is very interesting, as opposed to a clinical endpoint for that decision about whether to stop the drug.

Eric: Yeah, payers must love that, but we also are not sure. Are they going to have to restart the drug if their amyloid rises to a certain percentage?

Jason: It will be known, but we don’t know what Nate would do.

Eric: Nate, are you going to take the devil’s advocate approach here?

Nate: No, no, I too will be a prescriber. And I think what Sharon said is really important, shared decision-making and making sure we find the right population because not everyone is going to be right for this drug. And certainly geriatricians I think will be experts in being able to discern who’s the right person, when is the risk benefit ratio in the right direction. But I too, I think the science and the data really are there to prove that not only does it lower the amyloid and make it to the point where it’s not present, but then there was roughly, Eric, a four-month stability or delay in progression over an 18-month period. And that could extend beyond 18 months. We just don’t know that. But all of this has to be understood by the patient and the families and so that they’re comfortable of that. Certainly some people, it’s just not going to make sense.

Eric: Who are the right people? Nate, when you think about this for your practice, who fits the bill for these drugs?

Nate: Well, so this is where I think staging is so important and often overlooked. These drugs are indicated for people of mild cognitive impairment. So those who are having symptoms, changes on cognitive tests, but not functionally impaired, they can have subtle changes or I’m sure Jason will have a comment about that. But they’re actually doing really well and they’re very capable.

And so if they had pure Alzheimer’s disease, truly just amyloid and maybe tau in their brain or low levels of tau, they potentially could have this great benefit of stability and prolonging this current stage, which I would say is a high quality level of stage for longer in their life, mild stage dementia. I think there’s more discussion that needs to happen there because we’re not sure if the risk of bleeding and confusion is worth it to those individuals, but certainly known with moderate stage dementia. They’re not indicated and I think the priorities are different. That’s more of a palliative care approach, and I don’t think the drugs, and I agree that the drug shouldn’t be indicated in that stage.

Jason: Yeah, the studies enrolled people met criteria for MCI, cognitive impairment with inefficiencies in daily activities. So some mistakes, but you caught them and/or mild stage dementia, which is some disability in instrumental activities of daily living. The mean mini-mentals in both studies was around the mid-twenties, don’t quote me, but like 24 or so. The cutoff lower end of mini mental was again, 20 or so. So that’s the kind population described.

Had to have elevated amyloid by some measure CSF or PET scan. Donanemab also required a tau scan value, namely at least low tau. Although the question is whether that would make it into the label. And I think depending on who you talk to, it’s very interesting. What would you do for people with below low tau or high tau? We can get into that, but those are the basics for the drug. So got to meet a clinical criteria, which is pretty well described and have this positive biomarker test. And then there are some safety issues that need to be assessed as well.

Sharon: Well, the other thing is the ApoE value, and I’ve talked to colleagues who say they’re not going to check for ApoE.

Jason: Absolutely.

Sharon: But I think abalee is important to check for because if you’re homozygous, you have an increased risk of bleeding. And even if you’re heterozygous, meaning you just have one strand, there’s an increased risk. So I think that’s an important thing to check.

Jason: Absolutely. Sharon. Sharon, you’re totally onto it. Lecanemab has a FDA… They don’t like the term, but they put it in the black box. It’s the black box warning, it’s the top of the label. The label leads with a warning. And the warning is on the risk of what? I don’t like the term, I find it odd ARIA, amyloid related imaging abnormalities, H and E. H for hemosiderin or hemorrhage, E for edema. And exactly as Sharon said, it is well associated with abalee four status. One copy of abalee raises your risk, two copies, increases it more. And maybe we should talk more about this risk. What do you guys think?

Eric: Yeah, what risks are we looking at?

Jason: Yeah, so the risk that’s most concerning is ARIA is the edema, the swelling. That’s what causes symptoms and if not caught, disability. And in lecanemab, there were deaths. And in donanemab, there were deaths. So that’s-

Eric: Three in lecanemab, I think largely post-study period and three in the study period with donanemab.

Jason: That’s correct. Right. So ARIA, hemorrhage and edema is very common. About 50% of abalee homozygotes in the lecanemab study had that. ARIA with edema is not as common. About 2% of E-4 homozygotes had it. And then serious ARIA for any E-4 carriage was about 3%. So ARIA is common. Often it’s not symptomatic and not a problem, but it requires being detected because if you don’t detect it, it can become symptomatic and a problem.

Eric: Well, I got a question for you or anybody else. So do we know, has there been studies looking at the folks who got ARIA or EREH, and do they look different as far as their outcomes versus those who didn’t? Is there a longer term issue with if you develop this, is your cognition going to worsen over time? More so than the folks who didn’t?

Jason: So in the studies, it required either dose adjustment or dose cessation, but many continued if all they had was ARIA-H or low grade ARIA-E and/or got resumed on dose. So I haven’t quite answered your question, but I think that the data are seen, you can look at who dropped out or who discontinued drugs, but the data on the primary endpoints are all-comers, everyone in the study.

Eric: And certainly if you’re dead most cynically, your cognition has certainly worsened. So for those people.

Jason: I want to hear… Go ahead, Sharon. Go ahead.

Sharon: It’s going to be part of what we find out. And many people, many geriatricians and colleagues are going to be participating in databases where we collect information about people who are on these drugs. And that may be one of the questions that we find out an answer to that, if somebody does get an ARIA side effect, what does that do to their cognition and function moving forward? So we’re actually still in the clinical trial period in a way because we only have 18 months worth of data. And one question I’d like to ask, Nate or Jason, is what are you going to do if somebody is in their nineties? Because the cutoff for these drugs were, I think 85.

Eric: I think 85 for donanemab and 90 for lecanemab, with no explanation of why they used that cutoff.

Alex: Nate, why don’t you take that one?

Nate: What I would say is I would look at their function in this regard like cancer. I would look at their functional ability. If someone is 90 and has mild cognitive impairment. Someone is 90 mild stage dementia, but they’re only impaired in their managing of a checkbook, that person still could receive this medication. I guess I would remove the number itself and look at the individual person and ask the question, is there current state, are we trying to maintain that? Are we trying for stability? Is it worth the risk of doing it? And certainly if that ratio favors a person willing to try this, then I would certainly be comfortable doing it. I would not want someone who cannot move, that’s having a lot of other medical problems, that their quality of life is already questioned to be put on something that might worsen that. But that would be the discussion with the person.

Eric: Yeah. This other issue too, which was another great paper about cancer treatments that just came out in Jags, but it was talking about time toxicity. So when we think about cancer treatments, it’s not just the toxicity from the cancer drugs, but the amount of time that you’re going to have to use on the workup, the diagnosis, the following, the MRIs, the PET scans, the infusions.

Jason: So this drug upfront is a bit of work. MRIs prior, genetic testing prior.

Eric: PET scans.

Jason: Cognitive assessment, amyloid testing prior. And then a schedule of MRIs following. And if it’s lecanemab, it’s Q2E infusion. If it’s donanemab, it’s every month infusion. So it’s a bit of work. For example, it pretty much says you need someone else because you got to get in there to get the infusions and whatnot. I’d be very reluctant to prescribe it to someone who, I don’t know what it means to live alone, but who didn’t have anyone around them to watch over and whatnot, given the side effects of are and the upfront infusion.

So I agree. The drug’s a lot of work. I personally don’t have a strict age cutoff based on the eligibility criteria. I will say that on my geriatrics colleagues, anyone coming in with cognitive impairment, that’s incipient occurred in the last several years, who’s 75 80, 85 plus think about late TDP-43. I think every geriatrician needs to know about TDP-43 disease. It’s probably the most common cause of dementia in that 80 plus crowd. And oftentimes, I think in my own career was mislabeled as Alzheimer’s.

Eric: Tell me what that is, Jason.

Jason: Well, late TDP-43 is a well-described pathologic entity in frontal temporal lobar disease. That is one of the primary pathologies in FTLD along with ubiquitin. And it was in the last several years that autopsy studies showed that this 80 plus crowd of individuals with a densely amnestic form of dementia, who one who labeled them as having Alzheimer’s actually had TDP-43 disease as the driving pathology.

And we have emerging blood biomarkers for it, but the characteristic hallmark is an MRI imaging finding a very profound hippocampal atrophy blown medial temporal lobes, excuse my highly clinical term, but really enormous atrophy in the medial temporal lobe area, with relative preservation of the cortex otherwise. And we’ve been diagnosing it at Penn. In days of old, I would’ve called them Alzheimer’s. The question of course is if someone’s got clear TDP disease but elevated amyloid because the two-

Eric: I was just going to ask you that, Jason… [laugher]

Alex: Yeah there you go-

Eric: Jason, because there’s a pretty good odds that their amyloid levels are also going to be up.

Jason: You know what the next test I’d get is a tau test. Now, of course, Medicare doesn’t pay for them. I think they should now start a demonstration project for tau tests because we really, really, really, I think that could help inform. Bottom line, you have someone who meets criteria for late elevated amyloid negative tau. I would be very… I’d have a long conversation about the upsides and downsides of taking an antiamyloid agent. I would be, that’s an experiment in my view.

Nate: I just want to say to Jason, we don’t know that the anti-amyloid would have a negative effect on TDP-43 because they excluded all those peoples in the trial.

Jason: And I don’t know. I don’t know if they were excluded.

Nate: In the exclusion criteria for lecanemab, and I know this because I’m going through how to build a protocol for our own program, it says, any other neurological disease that may contribute to the cognitive impairment was excluded. Lewy body disease, severe vascular disease-

Jason: [But I wonder if it’s such an emergent diagnosis. But again, if there’s one takeaway, this our conversations about anti amyloid therapies and the biomarker transformation of Alzheimer’s, I urge my colleagues in geriatrics though learn about LATE, L-A-T-E. Horrible nickname. It’s not a name. It’s an acronym. Limbic associated TDP encephalopathy. I didn’t make it up.

Eric: Wonderful. Well, this brings up so many issues including what geriatricians have to know going forward. But before we do that, two other risks I want to talk about. One is, are you worried at all about increased brain atrophy with these drugs? Because both lecanemab and donanemab, we see worsening brain atrophy, global brain atrophy.

Sharon: So that’s another thing that has to get followed with time because it does appear that there’s a significant shrinkage of the brain, but you don’t know if that’s just a point in time and that maybe the brain recovers after the amyloid is removed. So this is another point of interest that we’re going to have to collect data on.

Jason: Yeah. What you don’t know… And what we don’t actually know is, and what doesn’t line up is that change in brain volume reflecting neurodegeneration or not, because the neurodegeneration markers don’t move in the direction of worsening neurodegeneration. So your P-tau measures and other measures of neurodegeneration go in the direction that you’ve reduced neurodegeneration. But yes, you’re right. The MRI measures for atrophy don’t go in that right direction. I think it’s a question still to be studied, but I don’t think the data say that is worsening neurodegeneration. The data say that’s the effect of the drug and removing amyloid on brain volume. And we haven’t figured out what that means physiologically or pathophysiologically. It’s a very interesting observation.

Eric: And Nate, what are you going to do about anticoagulation?

Nate: I don’t want my patients to be on blood thinners if they’re going to be taking this medication, at least this initial round of it, this first time use because I’m worried about the hemorrhage piece. When we talk to our patients about what’s happening, what are the side effects, what is ARIA, bleeding in the brain sticks to a person’s mind. And so that’s a huge factor.

Eric: No pun intended.

Nate: And so it makes sense that… I know donanemab is going to come out and they might have some data that would speak otherwise, but being on the blood thinner increases risk of bleeding. That’s a hard stop. That’s just the fact. And so I would be hesitant, and I’m certainly, in this regard, I’m looking to institutions and appropriate use to let us know-

Eric: If a patient says, you know what, Nate? I know I got AFib and I’m on my anticoagulation, but I’m so much worried about Alzheimer’s disease. I want you to stop my AFib medication, my anticoagulation and start me on this drug.

Sharon: Then they’ll get us-

Nate: I anticipate that’s going to happen.

Sharon: …Even if they stop and they get a stroke, they’re not ahead of the game. So I’m with Nate. I’m going to use that as a hard stop in our shared decision-making process because people have to put things in perspective.

Eric: Jason, what about you? Aducanumab was a hard stop. Nobody can enroll in the study. If they were on anticoagulation, lecanemab and donanemab, you were allowed to, but the numbers were relatively low.

Jason: Yeah, well, they were for no, but what do they called-

The DOACs.

Eric: Yeah. So I think that’s the conversation to have. I think I’m seeing the field go on either side on the DOACs. I’m one that would say E-3, E-3 non abalee 4 carrier, otherwise well-controlled cardiovascular disease on a DOAC, zero micro hemorrhages on susceptibility weighted imaging scanning. I would be open to that, but three micro hemorrhages, E-4 carrier, I think it’s just not a question of whether but when they’re going to have a bleed and edema. So I’d be a little more contextualized than having a hard stop no matter what about the patient.

I think the other issue as geriatricians and we need to educate our patients about is now you’re not on one, but six months later on this drug, you go on one. Before you go on it. We need to have that conversation. So leaving the office with the script is going to require some education around subsequent medication taking as well as education around the symptoms of ARIA. What we found at our site was visual changes, headache, gait changes. And so patients need to know, and this gets back to you have to have someone help with you. If you’re experiencing these, give a call again and get an MRI.

I have a question before-

Sharon: But this is just-

Eric: We move on. Go ahead, Sharon.

Sharon: I was just going to say this is another example of the actual burden of work that’s going to be on our shoulders as geriatricians, because the conversations that we already have are pretty long and they’re going to get longer. And we know we don’t get reimbursed for these long conversations, but they are necessary for us to have in order for patients to make good decisions. And then we have to monitor them, but we also have to get our other colleagues along the way up to speed.

So if somebody is on an anticoag and they are taking lecanemab and they go to the ED, does the ED doc know what to do and what are the implications there? There’s a lot of stops along the way for education. The other thing that I have a concern about is the neuroradiologist and how good they are at reading ARIA. Because in our clinical trials, we often had central reads that showed ARIA, but the local read did not. So I am not completely confident that I will be able to know if somebody really has ARIA and needs a dose reduction or maybe even a break from the drug just from our local neuroradiologist. And we’re in an academic-

Eric: Yeah, that’s if your center has a neuroradiologist.

Sharon: Well, that’s the thing. There’s a lot of places that just have a kind of general radiologist and if we are in a center with neuroradiologist, and that’s a challenge. That’s another level of concern is-

Jason: This is why I think FDA should have put a risk evaluation monitoring system in on these drugs.

Eric: Yeah. You advocated for REMS before FDA approved. Briefly, what is a REMS and why do you think it would’ve been important?

Jason: Well, they can still do it. And if things go south with the drug and they start making it in the papers because of the prescribing and whatnot, FDA could step in and say, look, let’s tighten up the system here for prescribing. Or REMS is a risk evaluation monitoring system. FDA has done about 300 of them. There are a way to put a drug out there that’s effective, but has concerns related to risks or complexity of prescribing to assure that the drug is prescribed in a way that maximizes efficacy and minimizes risks, maximizes safety.

It’s not intended to say a drug is risky. It’s just intended to say it’s a complex drug for which things could go bad quickly. And, Sharon, you’ve outlined it. You’d like to have each healthcare system go through a checklist of do we have a neuroradiologist and if we don’t, how are we going to get one? Et cetera. And what I’m worried about with these drugs is not the drugs, it’s the drugs in the system, and is the system ready for them? We could have gotten the system organized for these drugs. We had decades to get a good memory care system going in America, but that’s another story for another podcast. But anyway, a REMS would be a way to assure the drugs get out there in a way that maximizes efficacy and safety. FDA chose not to do that. They do have the black box warning. We’ll see. We’ll see.

Eric: Well, I know we have a lot to get to. I want to ask this question because I’m hearing from all three of you who are directors in various capacities of Alzheimer’s centers that you’re ramping up to prepare to prescribe these medications, to evaluate patients for these medications, and to monitor patients who are on these medications. I am seeing nodding. So that is remarkable to me.

That is this moment here that we are in that three geriatricians are planning to take the lead or are taking a leading role in their institutions in the evaluation, administration, and follow-up for these anti Alzheimer’s disease drugs, which are infusions and sort of different from what the types of drugs that geriatricians have traditionally prescribed. So that’s a lot we could talk about there. But any quick thoughts before we move on to the other things we need to talk about?

Jason: Welcome to the biomarker revolution of Alzheimer’s disease.

Sharon: It’s a heavy lift and geriatricians know how to make sure their patients are getting the best kind of care and not marginalized in our healthcare system. That’s what we fought for our whole careers, and here’s a perfect chance for them to fall through a crack if we are not careful. So that’s part of the struggle to get different specialties and everybody aligned. Even getting an infusion chair is no easy task. There’s a lot of people getting infusions now, and so we have to make sure that somebody can get an infusion chair, a seat in a chair for about an hour twice a month.

Jason: I eat two chairs. Remember, family member.

Nate: That one’s not hooked up though, hopefully. Alex, I would say to you, it’s about time geriatrics was involved. If you think about Alzheimer’s disease, remove the biology, amyloid, tau, all of that, it is not just the disease of the brain, it’s the disease of every part of a person’s identity and their function. There’s multi-morbidity that influences it. There’s medications, there’s palliative care, there’s working in a team, there’s frailty. All of this is the patient living with Alzheimer’s, but we would call it MCR dementia. And who’s an expert in that? That’s a geriatrician. And so why hasn’t geriatrics been more vocal up until now? And I don’t have an answer to that, but certainly-

Eric: We’ve been vocal, we’ve been kind of anti, well, part of that again was the aducanumab debacle, but I also-

Nate: And it was a debacle.

Eric: Yeah, it was a debacle. I wonder, Nate, thinking about that. Because these are, I hear from all three of you. These are incredibly complex decisions too, whether or not to start these drugs, which is perfectly set up for geriatrics. I guess the question to you, I’m going to start with Nate. We’d love to hear all three of your opinions. What does geriatrics have to do to be ready to be an integral part of this process of diagnosing, prescribing, and monitoring for side effects from these drugs? What do you think, Nate?

Nate: Well, there have to be more geriatricians, but that’s more of a systemic issue. I guess I would say. Speaking to what Jason was talking about, education. Geriatricians are excellent in certain things, which I think are really critical. They need to become experts in understanding the biology of Alzheimer’s or all cognitive conditions and marry those two things because we are going to be either in the primary care clinic doing this or in the specialty care clinics doing it because geriatrics is in both. And so I think they need to provide-

Eric: So fellowships need to change.

Nate: Yes, I think there needs to be more emphasis on memory care in all fellowship programs, but I think geriatricians have to have that interest too and at least incorporate that into their practice. Because yes, falls is really important. Inpatient is incredibly important, but memory is going to transcend all of those different spaces. And a geriatrician needs to know memory just as much as they know adult medicine.

Eric: It’s one of those M’S.

Alex: And we’ll go to Sharon next, but before we do, just to briefly plug that, I heard you say we need more geriatricians and we are well aware of Jerry Gurwitz’s article and JAMAs about the decline and fall of geriatrics. And we will have him on a podcast. Jerry, that’s an invitation. We will get to you formally. And so listen for that coming up. Sharon.

Sharon: So geriatricians are very influential in helping health systems adjust to the needs of older adults. And that’s what we’ve done for decades. And here’s another example, but I agree with Nate. We need to understand biomarkers and we also need to understand how to help navigate someone through this system because it’s a whole different universe to get someone through the healthcare system who’s going to be on these meds.

And that just compounds what we already do to take care of the whole person, make sure that they have the family support, make sure that they have somebody who can monitor their care. I also think that most of my colleagues already have a full plate. We already have new patients who are waiting several months to get in. And so I’m just wondering how we’re going to build the capacity to do what’s going to take longer than our usual visits in terms of explaining and monitoring, keeping track of MRI results, so that nothing falls through the crack. So it is going to take a new set of skills, but we are up for the task. We have always been mission-driven as geriatricians.

Eric: Yeah. Jason, what do you think?

Jason: I think a geriatrician of the future should be comfortable with the workup and diagnosis of cognitive impairment, able to decide whether someone has impairment. If they do, is it causing inefficiencies or disabilities in function? And then to be able to noodle down to what diseases might be causing it. Alzheimer’s, lewy body disease, PSV, CVDE, frontotemporal lobar disease, LATE, and have comfort with the imaging tests, the other biomarker tests that could help get to that. I don’t see… I think geriatricians can do that. I know many who are. I’m one of them. And I think that should be part of our future, and I think we’re well equipped to learn how to do that.

Eric: And I know many of you work closely with neurologists. Oh, go ahead Sharon.

Sharon: I was going to say there’s still a lot of questions about biomarkers because I don’t think they’ve been really studied in people who aren’t white. They haven’t been studied in African-Americans, Asian populations. We know that what they do in people who are Caucasian white people, but we don’t know in other groups.

Eric: Sharon, I was shocked reading some of these biomarker studies and PET studies that they come out of Minnesota or Wisconsin. I’m not sure if they come out of Wisconsin, but they don’t even mention demographics because I think they’re all white. And it’s shocking that a lot of these are a very homogeneous population that we’re making these huge decisions on.

Even these drugs, in these drug trials, if you tally up the folks in the aducanumab, lecanemab, donanemab style, you have several thousand patients, I think 50 of which were Black.

Sharon: So this is the nature of medicine even beyond Alzheimer’s drugs. We tend to enroll people in clinical trials who we care about. And the other problem is is that we don’t know from these trials, even the skimpy numbers, who was turned away because they didn’t have enough amyloid versus who wasn’t even recruited in the first place. So I think there’s a lot of information that we need so that we can take care of broad groups of older adults appropriately. And especially since everything is going toward making a decision based on biomarkers. That’s going to whole groups of people excluded from formal diagnosis.

Jason: And this is where the revolution is really going to rev up. It’s not about imaging, it’s not about spinal fluid, it’s about blood. It’s going to get really bloody.

We have the ability with plasma measures now and serum measures to measure tau and amyloid as well as other markers such as markers of neurodegeneration and neuro inflammation. One of the most compelling moments I thought, at the Alzheimer’s meetings in Amsterdam this past July, was a presentation that showed that a blood spot, meaning you stain in a piece of paper and go analyze that within ELISA, a blood spot test could measure P-tau 217 as well as the blood test could, which has been as well shown to be as good as the imaging. So we are at the ability now to measure-

Eric: Let’s talk about that, Jason, because Quest just is releasing an amyloid blood test. So I could walk into Quest, get my amyloid tested, and the big revolution is NIA and Alzheimer’s Association is putting together draft or put together draft guidelines on defining Alzheimer’s disease, not just from a research perspective, from a clinical perspective. And that includes stages, I think, what, zero to five or six, with stage one being you have Alzheimer’s disease just based on having one of the two core biomarkers for Alzheimer’s disease, either positive amyloid or positive tau. So I could in the future, in a year from now, get my Quest test and then be diagnosed with Alzheimer’s disease just based on that positive biomarker. .

Jason: Yeah. So a couple things in the table here. First point, just in general is there are several different blood tests out there for several different biomarkers. Quest is one of them for markers of amyloid. I was talking about the P-tau 217 test, which is a different test. There are several out there. I do think the future is going to be these tests because there are efficiencies are spectacular compared to imaging. Imaging is extremely expensive and resource intensive. All right, that’s one point. Second point, Quest did what Quest did their test has its sensitivities and specificities. They have access to physicians for people to talk and whatnot. I think they probably want to bridge too far, but I do think it’s only a question of whether or not when home testing becomes part of our world because this disease is a lot like other diseases where home testing is available, HIV, et cetera.

Highly identity transforming diseases tend to lend themselves to people to want to get the information on their own time and their own speed. All right, let’s set that aside. I think the big issue here is just what you cited, which is the move, which has been going on now for a good seven years as the science has advanced to define Alzheimer’s disease on the basis of biology period. In a way to try and resemble other diseases such as cancer, diabetes, et cetera, that defined quote on the basis of biology.

I can’t quarrel conceptually with it. I think where the debate occurs is some of the, if you will, edge criteria, like as you said, what is the initial label that says this is Alzheimer’s as opposed to not. And right now it looks like amyloid alone would make that criteria of you’ve got Alzheimer’s. The explanation for that is because amyloid is the initial biological event which leads to the cascade of developing tau and subsequently neurodegeneration. So that’s the logic.

I get it. It’s coherent. But I think where I felt at the meeting when I watched the presentation of those criteria, I think what people were struggling with is amyloid or risk factor that would lead to subsequent development of the pathologic cascade, whereas amyloid a disease marker.

And what I found in the conversation that had me confused is, sometimes amyloid was talked about like cancer. Mitotic figures was spread beyond the basement membrane and necrosis. That is abnormal. That is pathophysiology. Other times amyloid was talked about like hemoglobin A1C. Glycosylated hemoglobin is a measure of physiology. We all have glycosylated hemoglobin level, but it can go above a certain level that then becomes pathologic based on criteria of cutoffs that would then define diabetes. And so I can’t tell is amyloid alone a risk factor like hemoglobin A1C that crosses a threshold or is amyloid alone in the brain like a tumor?

It is by definition pathology. This is just a normal about mitotic figures with necrosis and spread beyond the basement membrane. That is cancer. And I think what it comes down to is what measure of amyloid is that? Is it the plaques? Is it the toxic oligomers, which we cannot measure? Is it the monomers, which we cannot measure. And so that I think is where we’re struggling. And I feel that that early definition of amyloid positive is Alzheimer’s. I don’t get the conceptual model. Is it tumor or is it hemoglobin A1C? Those are very different concepts.

Eric: Go ahead, Sharon.

Sharon: But we also don’t know when the disease might present itself. There are clearly people who have amyloid for years and they’re cognitively intact.

Eric: The majority of people-

Jason: That’s fine. There are people who have tumors that are clearly pathologic who have no symptoms or signs.

Eric: It feels like prostate cancer. You can have an elevated PSA, which puts you at risk, but an elevated PSA does not define, it’s not stage one prostate cancer.

Jason: But then it’s like, okay, well what is the Gleason score, et cetera? And exactly. And I think these aren’t just metaphors. They’re important conceptual models. And I think I found that the presentation in Amsterdam at one… Again, sometimes it was hemoglobin A1C, sometimes it was colon cancer and even sometimes it might be a PSA. And so I kind of think we’re still struggling as a field. What is this conceptual model that embraces the field?

Eric: What do think?

Jason: But in principle, I think defining the disease biologically makes sense because it is a biological entity.

Eric: I feel like we’re not there yet. I don’t know. What do you think, Nate? Is this putting the cart before the horse or?

Nate: So I agree with everything that Jason just said. I like the idea of defining Alzheimer’s disease itself by its biology. I think in a clinic, and this is where I struggled with this, was clinical criteria. In clinic, we don’t have the ability, as of now, to do the biological identification on everyone. And that’s because to Sharon’s point access issue. We’re not at that point where every person can have blood or that we all trust the blood. So the syndrome still matters. So we still have MCI. We still have dementia.

But I do like this idea of diagnosing, or defining, I don’t want to use the word diagnosing, defining Alzheimer’s biology. Where I don’t think we’re there quite yet is we really need our longitudinal studies to tell us that there is no such thing as benign amyloid. If you could tell me that every person with elevated or considered abnormal amyloid progresses to tau, then I would say it makes sense to me because then amyloid and tau do really come together these hallmarks pathologically as Alzheimer’s disease. But I just haven’t seen that. I haven’t seen this clear direct relationship that all abnormally high levels of amyloid lead to tau. I think there’s probably that building data. But until you show me that as a clinician, I feel like we’ve gone out on a limb here and just said elevated amyloid is eventually going to lead to disease.

Eric: The other thing with Alzheimer’s Association, NIA draft definition is it’s either amyloid or you can be tau positive, amyloid negative. Is that right?

Jason: No. That would not define Alzheimer’s.

Eric: No? I thought it was. I thought it was one of the two core biomarkers.

Jason: Yeah, I just was reading this over the weekend, but I believe amyloid is essential for the definition. But you then had some very interesting side cases. One of the cases presented with someone with moderate dementia, elevated amyloid, obvious MRI changes consistent with TDP history consistent with that as well. And that individual was called as having Alzheimer’s and TDP. My reaction to that was, and oh, negative tau, that was the other thing. Negative tau. So negative tau, elevated amyloid, TDP on M R I. I’m like, well, now wait a minute. You really want to call that Alzheimer’s just because there’s elevated amyloid. And again, say, well, that’s the biological definition. That’s the biological model. So we’re going to struggle on this.

Sharon: And again, I just don’t want us to forget how we’ve created a built-in disparity right here in making a diagnosis of Alzheimer’s disease. And I’m not sure how we rectify that until we start broadening our research base, because we’re talking about a real small percentage of the population right now with Alzheimer’s disease. And there may be other entry points, but we’re just focused on amyloid. That’s the only thing we’ve looked at.

Jason: Well, here’s what people really want. The biological definition, is to some degree, insider baseball. No one wants to develop dementia. And if you think about it, the future I see for the field would be it’s about telling people what’s your risk of getting dementia? And you do that with cardiovascular disease with respect to what’s my risk of getting a heart attack in 10 years? We do it with osteoporosis. What’s my risk of major osteoporotic fracture? I kind of see the field going in that direction.

There was a moment at the Alzheimer’s meetings in Amsterdam where someone said, “Look, just like we have pediatric growth curves, we need older adult dementia curves for predicting one’s risk of developed dementia. And then based on that, obviously intervening with these various anti-amyloid drugs.”

I guess my dream of reason would be, nevermind these disease labels, Alzheimer’s, Lewy Body, et cetera, let’s just embrace the pathology labels and say, look, I’ve got a synucleinopathy with amyloidopathy, but no tauopathy. My lifetime risk given my age of developing dementia is 10%. I’ll take the therapy to reduce my amyloid, et cetera. I would find that conversation to be kind of a dream of reason that just addresses the core problem.

Sharon: But we’re still excluding a lot of people because we do not know what amyloid looks like across different racial groups.

Jason: I agree. And the blood tests become promising because there are bigger cohort studies with more diversity where there’s tubes of blood in freezers so we can better understand what goes on with these diseases. I think studying these diseases with imaging is a huge resource lift, but blood allows large cohorts to be studied.

Eric: Okay, final question to all three of you. You got a magic wand. You can do one thing around geriatricians and the use of monoclonal antibodies for Alzheimer’s disease.

Alex: But try not to do the same thing as another person.

Eric: Yeah. Nate, what is it? That all geriatricians listen to Dementia Matters? The best dementia podcast out there.

Nate: I would say I would want every geriatrician to weigh in on the conversation and to take a lead in being a part of memory care, whether it’s in your primary care or in a specialty care, that they would have a seat at the table with every other specialist.

Eric: Sharon.

Sharon: I would want us to weigh in on what building this infrastructure is going to look like and how we make it inclusive.

Eric: And Jason.

Jason: Let’s be leaders in the United States effort to tackle the problem of Alzheimer’s at large. And that means being part of the biomarker transformation and delivering our great expertise in care for the patient and their family.

Eric: And I’m going to throw in one already, because I said one before, which is I do think geriatricians should listen to the Nate’s podcast, Dementia Matters, because as for me, I think it helped me really learn a lot more about this disease that I don’t think we trained well enough in geriatrics for. So if you’re a geriatrics fellow, listen to that.

I think my second one is now is the time to give feedback to the NIA and Alzheimer’s Association about this Alzheimer’s definition. So take the lead. As Jason was saying, we got to jump in the conversation. As Sharon was saying, and Nate was saying, jump in the conversation and give your feedback. We’ll have a link to the feedback form on our show notes. And with that, let’s turn it over to Alex.

Alex: (singing) ” ’cause I have wandered through this world and each moment has unfold. I’ve been waiting to awaken from these dreams.

People go just where they will. I never noticed them until I got this feeling that it’s later than it seems, Doctor my eyes. Sorry, I was scrolling.

Here we go. Tell me what you see. I hear their cry. Just say, if it’s too late for me.”

Eric: I think I may have to do an amyloid blood test on Alex. His functional status seems to be declining. [laughter]

Alex: Fortunately, for our listeners, if you’re not watching this on YouTube, you get the version I recorded last night, which did not have that interruption in the middle. Thank you.

Eric: Sharon. Nate. Jason. Thanks for joining us on the GeriPal podcast.

Jason: Thank you so much, Eric and Alex.

Nate: Thank you.

Sharon: Thank you.

Eric: Always a pleasure. And to all of our listeners, thank you very much for supporting the GeriPal podcast.