Alzheimer’s Defintions, Biomarkers, and Antibodies: Halima Amjad, Barak Gaster, and Heather Whitson

Eric 00:13

Welcome to the GeriPal Podcast. This is Eric Widera.

Alex 00:17

This is Alex Smith.

Eric 00:18

And Alex, I love this episode. We’re going to be talking about all things Alzheimer’s, amyloid and antibodies today. Who are our guests who are going to be talking?

Alex 00:29

We have all returning guests today. This is terrific. We’re delighted to welcome back Heather Whitson, who’s a geriatrician and researcher at Duke, and she is co director of the Duke UNC Alzheimer’s Disease Research Center. Heather, welcome back to the GeriPal Podcast.

Heather 00:47

Thank you. I’m glad I made it back.

Alex 00:49

And we’re delighted to welcome Halima Amjad who is a geriatrician, researcher and dementia specialist at Johns Hopkins. Halima, welcome back to the GeriPal Podcast.

Halima 01:00

Excited to chat today.

Alex 01:01

And Barak Gaster, who joined us pre Covid when we were an audio only podcast back in the day. Barak is a primary care clinician and dementia expert at the University of Washington and director of the Cognition and primary care Program. Barak, welcome back to the GeriPal Podcast.

Barak 01:21

Happy to be here.

Eric 01:23

Can I just say how awesome it is? We have three dementia experts, two of them geriatricians, one of them primary care. I just want to highlight how cool that is. But before we get into this topic, Heather, I think you have a song request for Alex.

Heather 01:40

Yes, I’m going to request my favorite song, Harmony hall, normally sung by Vampire Weekend, but today sung by Alex.

Alex 01:48

And why this song?

Heather 01:50

So I figured we would probably be talking about blood based biomarkers. So Vampire was part of the inspiration. But also it’s my favorite song right now.

Alex 02:00

It is a great. I had not heard this song but I had so much fun I went to town. So those of you who are listening to the audio only version of this, you’re going to get my version with many instruments. It was a lot of fun. So thank you so much for this request. Heather, here’s a little bit.

Alex 02:25

(singing)

Eric 03:53

Lovely. Thank you, Alex.

Barak 03:56

That was great.

Alex 03:57

That’s a jam.

Heather 03:58

Love that one.

Alex 03:58

Thank you.

Heather 03:59

Love it. You did it. You did it proud. Thank you, Alex.

Eric 04:02

All right, I’m going to start at the top.

Eric 04:04

And again, I. We’re going to have links to past episodes that we’ve done on amyloid antibodies. Thinking about how to diagnose somebody in primary care with Alzheimer’s disease. But you don’t have to listen to that. We’re going to actually start from the very top. I’m just thinking, Barak, you do a lot of teaching of primary care providers, right, on how to diagnose dementia, how to think about Alzheimer’s disease.

There’s a lot of competing definitions out there right now of what is Alzheimer’s disease from, you know, the more traditional, like, it requires both clinical and a pathological diagnosis versus just it’s all biomarkers. How, how do you talk about Alzheimer’s disease to the primary care providers that. That you see?

Barak 04:53

Yeah. And, you know, we’re still in such an area of flux where everybody’s still trying to figure out what do all these words mean? And, you know, and I, I really sort of in terms of what we sort of the training we do for primary care doctors and as part of the cognition primary care program, really focusing sort of absolutely. At the center first is identifying somebody who has cognitive impairment. You know, like that. That is the sort of most important giant first step, you know, making a diagnosis of either mild cognitive impairment or dementia in the primary care space.

And then after that, there is the question of, you know, what might be the etiology of somebody’s cognitive impairment. And, you know, we are really sort of, you know, make it clear that it is often difficult to make a precise diagnosis, you know, that most people have mixed forms of dementia and that we really encourage primary care to use the A word, you know, because that is the word that sort of patients and families know.

And if they Alzheimer’s and if they walk out of the exam room only hearing mild cognitive impairment, they may be thinking like, phew, you know, thank God I don’t have Alzheimer’s. You know, people have never, you know, most people haven’t heard the term mild cognitive impairment. And so we do encourage use of the word Alzheimer’s and how much uncertainty there often can be in and identifying that as an etiology for somebody’s cognitive impairment.

Eric 06:26

Can I ask, because there’s more and more push to say Alzheimer’s is both again, clinical and pathological. So actually knowing there’s amyloid in the brain on top of just having MCI or mild dementia or dementia, versus saying somebody has Alzheimer’s but not really knowing if there’s amyloid in the brain, how do you think about that?

Barak 06:48

Yeah, so I mean, I acknowledge that there’s just a lot of uncertainty about it, you know, and that somebody can have Alzheimer’s and have a negative biomarker blood test, you know, like that. I mean, it doesn’t have a hundred percent sensitivity for Alzheimer’s disease. And so I really do think that it is important for us to stay grounded in the clinical syndrome of MCI dementia and the clinical syndrome of Alzheimer’s disease with the overlay that, you know, we are gaining sort of better understanding of, you know, possibly being able to identify the presence of amyloid plaque in the brain, somebody with cognitive impairment, which is a more robust diagnosis of Alzheimer’s disease.

Eric 07:32

Now, Heather and Halima, you work in specialty dementia clinics. How do you think about like defining Alzheimer’s disease? How should we talk about it? Like when we’re talking to primary care providers or with patients, Start off with you, Heather.

Heather 07:47

So, you know, I, I feel like we’re in such a moment in this disease that the field is moving so quickly that I usually start by just acknowledging that there’s not agreement amongst the experts in the field, acknowledging that there are schools of thought that don’t agree that Alzheimer’s disease should ever be diagnosed without clinical symptoms. And there are others who feel really strongly that if we’re going to get to a point, especially if we’re going to talk about risk reduction for people who don’t yet have devastating cognitive changes, that moving to a purely biopathological understanding of Alzheimer’s disease is the right thing.

And so I kind of start by acknowledging that we’re at such a fast moving point in this field, making so much sort of disruptive progress, if you will, that there are experts, card carrying, bonafide experts that don’t agree on that point. And I just think we have to sort of acknowledge that. Personally, I’ll sort of put my cards on the table. I fall in the school of thought that I’m okay with calling it Alzheimer’s disease without symptoms. I’m okay with if somebody has amyloid

Eric 09:03

in the brain, that is Alzheimer’s disease.

Heather 09:06

So for me, it’s not just having amyloid in the brain, but it’s having amyloid in the brain and the pattern that is consistent with Alzheimer’s disease. The problem is our current biomarkers or tools can’t always tell us with that level of granularity. But if we could know that the person had amyloid in the brain that was because of the Alzheimer’s disease pathology, I’m okay, I think that there’s value in calling that Alzheimer’s disease, you know, so, so preclinical Alzheimer’s disease exists in my world.

But, but I also acknowledge that the problem with the fact that right now we don’t have full agreement on that is that if I tell a person that they have Alzheimer’s disease and then they go tell their friends and families that they have Alzheimer’s disease and then they maybe their insurer catches when that they have Alzheimer’s disease or their employer catches when and they don’t understand or

Eric 09:59

they just Google what Alzheimer’s disease is. It’s. Alzheimer’s disease is a dementia. Like you read it everywhere. It’s a dementia, it’s cognitive, like it’s progressive disease. It makes it seem like if you have amyloid, you are absolutely going to develop. Well, you’re not absolutely going to develop Alzheimer’s disease. By definition, you already have Alzheimer’s, you have Alzheimer’s disease.

Heather 10:18

And that’s what I mean. Depending on, if you Google it, depending on maybe your search engine and how the, how the functionality is working, you might land on a page that tells you it means one thing and you might land on a page that tells you it means something else.

Eric 10:30

Right now, Halima, where do you fall?

Halima 10:33

So I appreciated hearing that comment about there’s not agreement because I was going to say I actually fall into the. Whether it’s in my clinic or when I’m talking to primary care providers about this topic saying that yes, we’re at a super exciting time. When I was a fellow, we did not have these. Right. Just within the last two years we’ve started using these tools for more specifically diagnosing Alzheimer’s. But to me, the basics haven’t changed. And that’s that idea of the clinical syndrome that unless you have mild cognitive impairment or meet sort of all cause criteria for dementia, I’m not necessarily comfortable doing the testing.

So ordering biomarkers going down that path, I can see that perspective of. Right. From that research perspective calling it preclinical Alzheimer’s disease. But I don’t think we’re there in the clinical realm yet and publicly knowing the weight that that word carries, right, that someone’s like, I feel totally fine. And now someone is telling me I have Alzheimer’s. So I think we’re moving that way. But I am still in that, you know, unless you have objective evidence of cognitive impairment, we’re not necessarily going to go down that path yet.

Heather 11:44

So I want to just completely agree with Halima, and our clinical practices don’t differ on this at all. So when I’m a. When I’m in my clinical world, practicing clinical medicine, I don’t order biomarkers on cognitively unimpaired people. And so because I don’t order the biomarkers, I wouldn’t make the diagnosis in a. In an cognitively unimpaired person.

But I do a lot of research in risk reduction. And so in, you know, I believe that the leading edge for research is many things are pointing to the notion that the earlier in the disease process that we detect and treat the brain changes of Alzheimer’s, that in my mind, will ultimately lead to cognitive problems. Now, a person may live out their normal lifespan without that happening. So in those people, they lived out their entire normal lifespan with what I would call Alzheimer’s disease without symptoms. But that’s in a research context.

So I completely agree with you that in a clinic. But for me, it’s just a changing of the framework in which I think about the diagnosis. Because I think what we all know too, is the elephant in the room is that everything changes if a treatment becomes available that is found to be effective and safe for people without symptoms. But with certain biomarkers, and we’re not

Barak 13:08

there right now, the primary care perspective that I take is, like, thinking about this in a way, like diabetes. You know, like, we have, like, used this term, pre diabetes for so long with, like, kind of like a fuzzy concept of, like, what does that mean? And like, how do we treat pre diabetes? And does that mean that you are sort of destined to develop diabetes? And, you know, it’s like, no, it’s like, really complicated from a sort of a primary care perspective.

And so for me, you know, I really am sort of like, I encourage primary care doctors to sort of be humble in our understanding of, like, do we really understand the pathophysiology of Alzheimer’s disease? And so in some ways, I think the term like pre Alzheimer’s is like a better term than preclinical Alzheimer’s in a way, because I think that from a perspective of primary care, that makes more sense of, you know, lots of people live with pre diabetes for decades and decades and never develop diabetes. And you know, and so to me, I sort of come back on like, you know, there’s a lot about the pathophysiology of Alzheimer’s that we still don’t understand.

Eric 14:18

Okay, so I got a question. So it sounds like we are. You’re all in agreement that we shouldn’t be using biomarkers to screen individuals who are cognitively unimpaired. Is that, does that. I see everybody shaking.

Barak 14:31

Correct?

Heather 14:32

Yes. In fact, as a person who practices in a memory specialist clinic, please, please don’t screen them. Don’t, don’t, don’t order the biomarker.

Barak 14:42

Terrible idea, Terrible idea.

Heather 14:44

Don’t order it differently. Neighborhood specialists. Please don’t.

Barak 14:48

And the direct to consumer marketing for that is, is so harmful and not, not good.

Eric 14:55

Oh, yeah. Health fair is everywhere. Like people, it’s.

Alex 14:58

Yeah, it’s happening. It’s happening, it’s happening.

Barak 15:02

Yeah.

Eric 15:04

Are you guys getting it in your specialty clinics? Like people coming in with. Oh, yes, an amyloid test, but are cognitively normal.

Heather 15:12

Yes, yes. And extremely worried. And you know, we’re sort of, I mean, I was sort of making light of it a minute ago, but really, honestly, it’s. I feel so badly for people who, because they’re getting the test most often because they have a family history, so they’ve witnessed the toll of dementia and it’s their biggest fear.

And they’re cognitively unimpaired. Well, oftentimes very focused on health and trying to be helpful. Anyway, they get a test and my problem when they come in is there’s nothing that I would tell them to do differently, knowing this information, what we would be telling them without the information. But now I think positive or negative,

Eric 15:54

eat healthy, exercise control blood pressure,

Heather 15:59

risk reduction about sleep. Yep, all that stuff.

Halima 16:04

Yeah, I was going to say we’re not seeing it a ton, but I’ve had a couple of people where the child of a patient reached out to me because I actually sort of got their primary care provider to send a test. And guess what? It was in that indeterminate range of the, you know, FDA approved Luma pulse test or someone who was still uncertain because she had that. Again, thinking about the FDA approved test. P Tau181 was positive, but it’s got terrible positive predictive value. Negative PET scan, but still needed that additional reassurance that your amyloid PET was negative.

And so it was Hard to say. Like, you just, you should have never had that test in the first place. You are cognitively unimpaired. And now she had the amyloid pet, she had to come see a specialist and kind of go down that whole path.

Eric 16:48

What do you tell Heather? Like the patient who comes in positive, complete, like they are the asymptomatic, however you define it, like stage two or pre. Also, like, what do you tell them?

Heather 17:04

So, so what I tell them is I try to provide the reassurance that in some ways the very fact, if they had a family history, for example, was, was a risk factor. And so knowing this new information, we’re still in the, in the. If they’re cognitively unimpaired, this is a risk factor. It’s not a sentence that something is going to happen or a certainty that something’s going to happen.

And then I really try to point to the risk reduction opportunities and almost everyone, you know, if you take the Lancet figure of the, you know, 14 things, I really try to focus the discussion on what are things on this list that you feel like you have opportunities to improve, to lower your risk and really try to take the conversation that way.

Eric 17:52

We’ll have a link to the Lancet report on the risk reduction. So it’s a great thing to bring up. I wonder, okay, we’re not screening using biomarkers. Barak, how are you? Are you telling people to screen for cognitive impairment? Mci.

Barak 18:10

Yeah. So the work that we do with the cognition primary care program tries to be sort of open minded and agnostic about the question of screening. You know, in that I don’t think that screening is wrong. You know, I, it’s not necessarily something that I think like we, we have great evidence that it should be very strongly encouraged.

Eric 18:33

You’re like the usps. See, I always add letters to that. Uspstf.

Barak 18:38

Yeah. Not information. Yes. And when I experience a clinic that is doing screening, like I, I say, you know, good job. I think that you are probably doing good by doing that screening. But I really focus on the concept that, you know, the, the, the giant bottleneck that we face is not sort of whether we should be screening or not, but, you know, when a concern arises, whether it’s from an abnormal screening test or it’s somebody saying that they are sort of concerned about their cognition. You know, the real kind of important step to take is to help, to help primary care to do a cognitive evaluation that is like past the screening step.

So to me, I’m like, I think screening is good and it’s fine and places that are doing it are good. But I think that we’re wasting a lot of time sort of arguing about whether or not we should be screening because it’s like, it’s fine, but it’s also a little bit fraught and there is some uncertainty. And so to me, I think whether or not to screen isn’t the question. It’s how can we help people for which there is a concern.

Eric 19:52

Alima, you think you look like you’re thinking about that?

Halima 19:56

Yeah, no, I mean, I think I actually totally agree. I think I am usually more in favor of that kind of proactive case finding. Right. It’s like the semantics of screening versus case finding. So I’ve actually always sort of agreed with, I think some of what the expert task force have put together for like the annual wellness visit, which isn’t, oh, you should mini cog everybody. But it’s, you should ask and if there’s a concern, do a mini cog or if you can’t confirm it with someone else.

But I do think, I mean, I generally too, when I talk to primary care is just start asking about memory and start asking about brain health. The way we ask about all these other symptoms and conditions that we feel more comfortable about so that we can sort of more proactively detect or at least, you know, kind of give people permission to bring up a complaint that they may otherwise be nervous or anxious or unsure about whether they should bring

Barak 20:42

it up because screening is good and like there it is. Like, I think that screening is like important and a reasonable thing to do, but it, it’s just not sufficient. You know that there are plenty of people who have mild cognitive impairment who score fine on a mini cog. You know, there’s no such thing as a two minute screener that has such good sensitivity for MCI that you kind of like screen and you’re done.

Eric 21:07

So if somebody does have complaints, what do you, what are you training your primary care providers to do? What’s the assessment?

Barak 21:13

Yeah, so first ask more about what the concern is and making sure that it’s not just the kinds of things that freak people out, that are normal aging. But then if there is a real concern, then it really is bring somebody back for a dedicated visit to do a cognitive evaluation where you’re not going to talk about their knee pain and you’re not going to refill their diabetes medicines, but you’re just going to do a cognitive evaluation and you’re going to try really hard to get a family member or A close friend to come to that visit with them. And then you’re going to do three components for the evaluation, which is going to be a review for addressable causes, interview with the patient and the family member, and then some kind of a cognitive diagnostic aid test.

Eric 21:58

Like a biomarker?

Barak 22:00

No, like a, like something like a MOCA or equivalent.

Eric 22:06

How do you feel about the Heather?

Heather 22:07

So I love the term case finding. So I am a big proponent of proactive case finding. And I think I was hearing Barak say the same thing that you’re almost more worried about. Somebody would just screen and then decide, oh, this person’s fine because they scored well on the six item screener. And we all know that we’ll miss a lot of cases. So I also worry that we miss a lot of cases that are out there. And the reason that I do think that proactive case finding and cognitive assessment is now important, this will probably pivot us into the treatment fair. But we have treatments now that are available for people with cognitive symptoms.

And if we have people with cognitive symptoms, I’m of the opinion that they deserve the discussion and the consideration of whether they want to go forward with these treatments. And I say that knowing that more people that I talk to about these treatments choose not to take them than choose to take them. But we have treatments now for people with cognitive deficits who are then found to be amyloid positive. And I feel like it’s increasingly important that we don’t miss somebody who might be a person that, that would benefit.

Eric 23:25

So the treatments you’re talking about is the amyloid antibodies. So lecanemab and donanemab. How do you talk to patients about the. What we know or what we don’t know about the effectiveness and risks about them?

Heather 23:39

Yeah. So I think, I mean, and it differs. And I will say in my practice, I work in a, in an interdisciplinary memory clinic. We have psychiatrists, neurologists and geriatricians and nurse practitioners and PAs that all sit together in the same workroom. We all follow the same. We don’t prescribe the drugs unless it’s in accordance with the use recommendations. So we don’t kind of go completely into cowboy land with them. But even within that, I mean, like all things in medicine, you can be prescribing within the use recommendations and still real differences.

And so I will say again, because I think it’s important that we show our cards on the table. If you line up like all eight of us, there’s a spectrum of how many, how. You know, I always Say that I always kind of think of the scales with risk on one side and. And benefit on the other. For me, in average people, the average population, the risk benefit of these drugs sits pretty close to one. And then sometimes particular patient factors or priorities and goals shift it a little bit, you know, from more towards risk or more towards benefit. I am a person that, for me, if it were me thinking about taking them for myself, I’m not gonna take a medication unless the benefit, the risk benefit ratio favors benefit pretty significantly. So probably especially a medication that you

Eric 25:05

have to go in every other week or once a month. You get MRIs, you get the whole.

Heather 25:10

For me, all that’s on the risk side, like on the. On the. On the risk, sacrifice, burden, cost. Everything bad is on one side and everything potentially good’s on the other side. I know that of my colleagues who know the literature well, and I trust. And if they were thinking, if they were making the same decision for themselves, knowing everything that I know, they’d be more likely to take the drug in the same scenario as me being less likely to take it.

And that just, I think, emphasizes how much personal priorities and goals and preferences weigh on both sides of those scales, too. So I would say that these are the hardest conversations that I’ve ever had in my time as a geriatrician. And we all know that we have a lot of hard conversations.

Eric 25:55

Do you think these conversations should be discussed in primary care, like, brought up?

Barak 26:00

Yeah. So, I mean, it’s the number one question that, you know, we get when we do our training for primary care is, you know, what about the drugs? And I think that it’s really important for primary care to be aware of the drugs, to be aware of how to talk about them. And I will say that, you know, there are drugs that are, you know, have been shown to be, you know, better than placebo and that, you know, they’re not a lot, lot better than placebo, but they’re better than placebo. And the potential for somebody to be eligible for them is like an important thing for primary care to be aware of and to be feel comfortable in talking about.

But I think it’s not necessarily the top priority, like, the very top priority after a diagnosis of mild cognitive impairment is made is to really, you know, work through the easily addressable factors that can be sort of like, you know, it’s what primary care doctors do all the time. And so I think that is, you know, that is the focus and the key. But just like Heather said, there’s going to be Some people who are like, you know, I want to talk to a specialist right away about one of these drugs. And I think that it is a disservice for primary care to kind of get, you know, get in the way or use what my own personal sort of preference would be if I was in that situation, to in any way kind of shift somebody away from getting that, that possible validation.

Eric 27:24

Yeah, I think about that a lot. Would I take these drugs if I had MCI or mild dementia and I fit the, the guidance and it’s, it’s a struggle. I, I probably wouldn’t just, it would be just on the amount of medical stuff. Like, I don’t even like taking like a blood pressure pill every day. So that probably would influence how I think about it.

Halima 27:47

Eric. Oh, one thing I was going to say that’s interesting there is I have had a, I’ve had a few patients who, like, they miss going to the infusion center now that they have completed treatment. Like, they actually enjoy the social interaction. The nurses. Yeah. So, you know, while a lot of us look at infusion as a burden, and I think the other hard part, right. Is for me right now, like, oh, I have so much going on. But hey, if I’m 70, I’m retired. Like, there’s a lot of people like, oh, that’s no trouble. I had a patient recently, they were deciding which infusion center based on. Yeah, are there better cafes and restaurants near that site?

So, you know, some of that burden, I think we, or, you know, we think, oh, the MRIs are hard and people are like, that’s no problem. But these are long conversations, like, even in memory clinic, sometimes, like, I don’t have enough time. I need to do a separate video visit first to discuss risks and benefits, talk it through, do it justice. Where, you know, I don’t expect primary care to have that time. And to be honest, I don’t know that even community neurologists who have 15, 20 minute visits can actually do justice to that conversation.

To really make sure patients understand risks, benefits, that it’s not a cure. But there’s definitely cases. I mean, I will say now I might lean towards, if I didn’t have risk factors to. Now that we’re seeing that in clinical practice, we’re not seeing sort of increased adverse events from the clinical trials that, you know, in the right setting, in the right space, I would be open to it. But it’s still, I mean, I have a lot of patients where I sort of say, I would love to be able to give You a recommendation, but I don’t have a strong one one way or the other. You know, there are some people where you can go strongly, you know, against, but I think for other folks, it’s. It’s trickier.

Barak 29:26

And for me, it’s like. It’s like. It’s. It’s kind of like one of the superpowers of primary care. You know, like, you. You. The relationship that you develop with somebody over years have experience of how they have faced sort of like, complex decisions where they’re like, you know, oh, geez, you know, I don’t want to take a statin. Like, why are you recommending a statin versus the person who’s like, you know, can you check my, you know, you know, lipoprotein little a. Because I really want to, like, know what my risk is. You know, like, you.

You kind of, like, you understand and develop rapport with your patient over time, and that really can help in a situation like this where you develop, where you diagnose somebody with MCI and you sort of, like, have a sense of, like, how to kind of, like, frame the conversation with them. And you have, like, a hunch going into the conversation, like, oh, this is somebody who is definitely going to want to see a specialist right away, versus this is somebody who is, like, never going to want, like, testing that you’re not absolutely certain is going to have, like, big giant.

Eric 30:24

I have heard, and this gets us into biomarkers, that some neurologists want the primary care doctor to order the biomarker first to determine if they should see the patient.

Alex 30:36

Yes, we’ve heard that maybe on this show as well.

Eric 30:40

Barak, do you ever order biomarkers or do you ever teach primary care providers to order biomarkers?

Barak 30:45

Yeah, so, I mean, and so this is, you know, so the number one question I got get is like, what about these new drugs? And then the number two question that I get is, you know, what about these biomarker tests? And for me, it’s so important to see, like, the big giant picture. Like, what does this biomarker tell you? And, you know, so, like, the number one is like, you know, never primary care should you be ordering a biomarker unless somebody, you have already diagnosed somebody with MCI or dementia. You know, like, I think that it is a big giant sort of like, sort of trap to fall into is if you sort of, like, include it with your, like, initial workup of like, TSH B12. And biomarker is like, you know, like, a terrible way to work somebody up for cognitive impairment because you, they, you might very well end up sort of like with the great news that somebody does not have cognitive impairment. And. But then you’re sort of left with this biomarker result.

Eric 31:41

Heather Alema, I see you nodding yes, you’re, you’re in agreement.

Barak 31:45

So, you know, wait, wait till, in primary care for sure, wait till after a diagnosis of MCI or dementia has been made. And then the question of sort of what role does a blood based biomarker have in the primary care setting? And to me, like, because you have to sort of step back and say, what’s that biomarker gonna tell you? It’s gonna tell you that, that cognitive impairment is due to Alzheimer’s disease. And then you have to ask the question, like, what impact is that diagnosis of MCI due to Alzheimer’s disease gonna have on that patient’s career?

And if somebody is the kind of person who like, yes, I would absolutely want a monoclonal antibody treatment and you feel confident that you’re going to be able to get them to see a specialist within, you know, two to four weeks to get that treatment started, then I could see that being a situation where primary care would order a blood based biomarker as a way of kind of fast tracking somebody into monoclonal antibody treatment. But in a setting, which is what most primary care providers are in, where even if I get that blood based biomarker, it’s still gonna take months to get in to see the specialist. And in those months it’s gonna be up to me to interpret what this result means for the patient. Then I don’t wanna be in that position as a primary care doctor and

Heather 33:05

for the patient, I think, you know, for me it’s will make my life easier as the receiving specialist if I already have that result at the time that they come in. But I like to think that I’d want the patient experience to come before my convenience there. And I do worry about patients that will say it took five, six, seven months to get in to this clinic. And I’ve been sitting on pins and needles because I was told I had this positive, that someone did appropriately diagnose me with mild cognitive impairment. Then they told me that this test was positive. Sometimes it’s an amyloid pet, sometimes it’s a blood test. And now I have to wait six months to see someone.

And everything I’m reading because I’m obsessively reading on the Internet and everything I’m reading is Saying that earlier, I get treated. You know, there’s a, there’s a window of, of benefit opportunity. And I feel like that is a real challenge that we’re just dealing with in the field right now.

Eric 34:00

I’m also a little like the idea that if somebody has, let’s say MCI or mild dementia and their amyloid is negative, does that mean that they don’t need to see a multidisciplinary memory? Like it’s almost more like, oh, wait, we don’t know why this person is having memory problems. Almost increases in my mind the need to see someone like Halim or other Halima. What do you think about that?

Halima 34:24

Yeah, no, I agree. I think I generally have been again, when I talk to primary care audiences now, saying I would probably rather order the test myself, choose what I’m ordering, be able to have a discussion about the quality of these tests and what they tell us, what we’re going to do with the results before getting them. Otherwise. I have occasionally said to a primary care provider, right, if someone’s really excited, if, you know, they have an appointment, order the test like two weeks before, have them get it three weeks before. So they’re not sitting on it for six months, but then they’re coming straight in.

But I do think that’s important, right, because they still have cognitive impairment and sometimes that’s when. Now I’m thinking about do we need more neuropsych testing, do we need an FDG PET scan? Are we thinking about other types of dementias? What do we need to do for monitoring? But there then I think what we’re running into is the bottleneck of just there’s not enough dementia specialists now to handle this influx. I was actually curious, Barak, to premiere perspective is we also have some patients who just want to know they’re not a candidate for treatment for some reason. And I know I order biomarkers in that case, right? Someone’s, oh, they’re deciding if they’re going to move or something. I was just curious your thoughts on that, like if that might come up, start to come up on the primary care side.

Barak 35:40

And I see that as like, you know what, where we might be with blood based biomarkers in five years or so. I mean, I think that what I think to me, like the number one clear use case for blood based biomarkers is establishing eligibility for monoclonal antibody therapy. And so, you know, like, no question you’ve got a neurologist who can fast track them in and get them in right away. You Know, if, if they have an abnormal biomarker, like, yes, I will definitely order that test in primary care to kind of like ease the way to help the patient. But if somebody is like, you know, what is the other use case for these biomarkers?

Which is like, you know, just to know, you know, I think that’s sort of like tantalizing and interesting and sort of like down the road, because, I mean, I will say that as a primary care clinician, to make a diagnosis of MCI is often like, you know, a weird kind of like gray place to be, because you’re not really sure exactly what to say to somebody about their prognosis. You know, where, you know it. We see dementia as this, you know, generally progressive disease. You know, there’s a lot more uncertainty about what does MCI mean and, you know, what is somebody’s prognosis who is diagnosed with MCI. And whether a blood based biomarker could be part of a helpful sort of prognostic sort of piece of information to know is interesting. But I think that will probably be part of a package of, you know, a blood based biomarker for Alzheimer’s disease and a biomarker for Lewy body disease and a biomarker for frontotemporal disease, where you’re going to really be able to say, you know, gee, you know, you have MCI.

But we have done a really pretty thorough biomarker look for the pathophysiologic causes of neurocognitive degeneration, and we haven’t found them. That’s like, you know, you’re in a, you’re in a low risk, better place. And so I could see us being in a place like that five years from now, but I don’t know that we’re there now.

Heather 37:44

Can I bring up a question around that? That, that is about the sort of getting there with the evidence and that is comorbidities. Um, so I don’t know, I’m curious for, for Barak, sort of, when you’re teaching people about how to potentially use and interpret the, the biomarkers, the presence of comorbidities obviously affects the accuracy, particularly of the blood based biomarker. Disease, cardiovascular disease, obesity, certain medications can affect amyloid levels.

You know, things depending on what biomarker is, is being ordered different, different comorbidities. And then there’s the specter of comorbid pathologies in the brain. So if, if I might get this result and it says amyloid’s present or it’s not, but it Is just as you’re saying, it doesn’t also tell me what other things might be in the brain. And we know from autopsy that oftentimes these things co occur, we think it probably affects the prognostic utility of knowing about amyloid. If somebody also has heavy vascular burden or also has Lewy body disease, what are thoughts right now about how to sort of manage all that in a heterogeneous real world primary care population?

Barak 38:54

So I tell primary care, don’t do it. You know, it’s just so complicated and confusing and you know, and it, it really.

Eric 39:03

That’s why you say five years from now.

Barak 39:05

That’s right. It’s out. It is currently outside the scope of primary care. Like, you know, I think the best analogy that I sort of use that really kind of resonates with a lot of primary care providers is, you know, if I diagnose somebody with, you know, what looks like a mineral persuasive disorder, you know, where, you know, their cbc, their death is abnormal, and I’m sort of really worried that they have like some kind of lymphoma, but I don’t know exactly what kind. I’m going to get them to in to see, you know, a hematologist oncologist within two to three weeks and that hematologist oncologist is going to say, oh, you know, in preparation for their visit, could you get flow cytometry for me?

Because then if, if I see them for the first time and I have that data in front of me, it’s really going to sort of like speed along my ability to sort of like, you know, diagnose and get them into treatment. And I’m like, sure, because I know that they’re going to be able to be seen in two to three weeks and I’m not going to be on the hook for interpreting and counseling them about that result. And so to me, that’s like the great analogy for blood based biomarkers where if I feel, and I think this is what we should be sort of like skating towards as sort of a best practice, like every health system, every, you know, cognitive neurology clinic should have some kind of a fast track path where if a patient has a blood based biomarker that indicates high eligibility for anti amyloid therapy, that that patient should get seen like quickly and get started on therapy.

Eric 40:39

So hypothetically, in that fast track, like Heather, like in your mind again, patient experience versus your own, like, wouldn’t it be nice if it was. Wouldn’t be nice. You got options for biomarkers you got amyloid beta ratios, you got P Tau217, P Tau181 neurofilament light chains. Like what are you asking people to order? What do you order?

Heather 41:01

Yeah, so, so when I start with a blood based biomarker and I wouldn’t treat somebody without at this time without confirmation for a positive result with a pet or lumbar puncture, but I start with P Tau217 ratio with a beta 42. So that’s the ratio that I use. And the issue is, is that it gives you this intermediate values in the middle. So about 10 to 20% of the people that we order that in have to then go on to the, you

Eric 41:32

know, why are we using ratios of two different cow and amyloid?

Heather 41:38

Yeah, so it does a couple of things. One thing is it just appears to be a better performance characteristics for how well it predicts the presence of brain amyloid by gold standard tests. So by PET or, or you know, the, the area under the curve, if you will, is better with that ratio. So it’s just performance characteristics are better. It also in my mind it appears to guard against some of those comorbidity issues that we run into. So the ratio for example, looks less sensitive to kidney impairment. And so, so that’s why I choose the ratio.

I serve on a panel that is, is putting, has, is doing systematic reviews and then clinical practice guidelines based on them for how to use the blood based biomarkers and we’ll continue to update them. But P Tau 2, 17 and particularly the P Tau 217 ratios, either percent of P Tau 217 out of all the phosphorylated tau or with the ratio of a beta 42 are some of the top performers so far.

Eric 42:41

I also love the altsdiagnostichub.org website like it has. I didn’t realize how many biomarkers out there.

Heather 42:49

Yeah, that’s, you know, and that’s actually

Eric 42:50

an interesting sensitivity and specificity differences.

Heather 42:53

So huge difference. And I would say that’s the biggest myth of when, when, when other providers come to me, they’ll say, wow, I heard that there’s a new blood test for Alzheimer’s. And it’s like, dude, there are lots of blood tests for Alzheimer’s. There’s not one blood test for Alzheimer’s. So and, and they vary a lot. So it is really important for people to know what they’.

Eric 43:13

Halima, what do you order?

Halima 43:14

I was gonna say, what I was gonna add to that conversation is what can I order? In my emr, right? So, like, people are like, oh, this is FDA approved. I was like, well, I can’t order it yet, like, for my patients. But in general, we end up doing actually sort of similar P Tau217 and then a beta 42 to 40 ratio. But because it’s what we can order, ours is linked to LabCorp. So there’s like, the ATN profile, which the way it gets interpreted when it says that someone’s amyloid negative is actually incorrect because they might be positive.

That one’s got P Tau181. But then we end up kind of pulling the P Tau217 separately, pulling in the a beta 42 to 40 ratio. The neurofilament light chain, I feel like for our Alzheimer’s patients, unless they’re advanced, is almost never positive. And so I’ve only really seen that positive if someone, again, has more advanced Alzheimer’s, or sometimes that drives me down that ftd or thinking about other causes, pathogens.

Eric 44:10

Okay, lightning round question. I know we’re out of running out of time, but the question came up earlier from Heather is, what would life. What would things look different if some of these primary prevention studies. So studies of amyloid antibodies in people with normal cognition showed a benefit? So I think there’s gonna be a report out in July or something on lecanemab’s primary prevention. There’s a Donanemab study going on. Interestingly, they’re not looking at, like, conversion to mild MCI or mild dementia.

Alex 44:44

Right.

Eric 44:44

Because the time from amyloid positivity to symptoms could be 10 or 20 years. They’re looking at very small changes in very. Correct me if I’m wrong, Heather, very sensitive cognitive tests to see, are we seeing any change in that? Does that sound right, Heather, as far as the outcomes from these trials?

Heather 45:05

Yes, yes. Yeah, there. There are lots of things in the pipeline.

Eric 45:10

I wonder. Heather, I’m gonna go to you. Cause you said, you know, my risk benefit if I had MCI or mild dementia. I guess my question to you. Let’s say it’s a positive study, that there is this, you know, signal. It’s probably gonna be the same as. Honestly, like, lecanemab. You’re gonna see a small change, and we’re just gonna be arguing about clinical importance of it, because that’s always how it’s been with Alzheimer’s drugs. Like, how would you think about whether or not to take these drugs or how to talk to patients about these if the same thing happens here? Again, statistically significant clinically we’re arguing what does X amount difference on this subscale mean?

Heather 45:50

Yeah. So I will say that the drug that I’m really waiting for would be a decade away because we would need that long of time to know for sure is this a drug that is eventually going to make me not get MCI and dementia if we had that. So I don’t know that I would change my own personal choice that I would make based on wishy washy clinical outcomes or clinical outcomes that I’m not sure I’m getting benefit.

Because here I would have a different calculation if I were a person without symptoms and was pretty convinced that taking this drug for 18 months, even if there was some, some high risk to me during that 18 months and it was a bit disruptive, if I thought that 15, 20 years from now it would make me have more older years without dementia, I would be much more likely to do it. Actually for me, more likely to do it than doing it when I already have cognitive impairment. Because a little bit for me the calculation is if I have to accept something like lecanemab now and I already have cognitive impairment, in a way I’m making what could be some of my best time yet really difficult with having to take infusions.

And for me the anxiety, like I would be anxious about all the ARIA and all that kind of stuff. So personally for me, the trade off of that 18 months when I’m already cognitively impaired and that means things are moving and that could be some of my best time left. I’d actually rather take my 18 month risky hit earlier in my life maybe when I feel like I have more of a Runway left of really good.

Eric 47:25

That’s really well said. I haven’t thought about that. That is really well said. Halima, what do you think?

Halima 47:30

Yeah, well, that comment I appreciated because I was going to say I’m hopeful that I’m young enough that I’ll have that like 10 year data to see what it looks like, the long term data. But I think it would depend. But I think I could be convinced if. Right. Especially I think for folks who know, for example, they have a family history, that there’s something about them that sort of feels higher risk that that amyloid positivity will mean something. And then I think the other big piece too is we know that like the subcutaneous lecanemab is coming where the risks might be the same, but the administration might be easier. But I agree with you. I think it’s going to be very similar to now where it’s cloudy, there’s not a right or wrong answer, and everybody sort of makes the decision.

Eric 48:15

Barak answer here.

Barak 48:18

Yeah. So I mean, to me, it, it’s, it’s like, it’s also hypothetical because I think to me, I would really want to see like, you know, what was the benefit and what was the risk, you know, and so to just say that it’s like a positive trial, like, leaves a lot unsaid about like, how positive, you know, I mean, I think you said it exactly right, that it’s more than statistical significance. We really are going to want to look carefully at clinical significance and how does that sort of balance against potential harm? So to me, I have trouble sort of giving you a hypothetical answer without sort of.

Eric 48:52

I’m going to be fascinating what the hypothesis is. I think we’re going to need all three of you back on because I think we struggle with these drugs with MCI and mild dementia. If there is a positive signal with these trials, I think the struggle is just going to be so much more magnified and the questions about clinical significance is just going to be so huge. Um, so. But that’s for a different time. Maybe Alex, you can take us off with. What’s the song title again?

Barak 49:18

Heather?

Heather 49:19

Oh, Harmony Hall.

Eric 49:21

Harmony Hall.

Alex 49:22

Before I sing Harmony hall, quick plug from my co host who published a paper on the importance of function in Alzheimer’s disease management and diagnosis in Jam Internal Medicine this month. We’ll have a link to that in the show notes. Here’s a little bit of the chorus.

Alex 49:44

(singing)

Eric 51:11

Heather, Halima, Barak, thanks for joining us on this podcast.

Barak 51:15

Thank you.

Eric 51:17

And thank you everybody for your continued support.

This episode is not CME eligible.

For more info on the CME credit, go to https://geripal.org/cme/