How to Make an Alzheimer’s Diagnosis in Primary Care: A Podcast with Nathaniel Chin

Eric 00:00

Welcome to the GeriPal podcast. This is Eric Widera.

Alex 00:03

This is Alex Smith.

Eric 00:04

And Alex, we got a live in-person guest with us today.

Alex 00:06

Yes, a live in-person guest with us, Nate Chin, who is our visiting professor for grand rounds and has got a full day and is joining us for the podcast. To start things off, Nate’s a returning guest. He is associate professor at the University of Wisconsin and medical director of their Alzheimer’s Disease Research Center. Nate, welcome back to the GeriPal Podcast.

Nate 00:25

Thanks for having me. Great to be back.

Eric 00:27

So we’re going to be talking about making the diagnosis of Alzheimer’s disease in a primary care setting, not specialty care, but maybe we could talk a little bit about that. But before we do, we always start off with a song request. Nate, what is your song request for Alex?

Nate 00:42

Jungle Land, by Bruce Springsteen.

Eric 00:44

Why did you pick this song?

Nate 00:46

This is in honor of my father-in-law, Steve Hoppe, who passed away last fall. He was a die hard Bruce Springsteen fan and he went to, I think over 30 concerts. And my wife went to over, I want to say, 20 concerts.

Eric 00:58

Have you been to a concert?

Nate 00:59

I went one in Milwaukee, Wisconsin, and I’m so glad I did. I loved it and this was his favorite song and so I wanted to do it.

Alex 01:07

And Bruce Springsteen did a stage dive. We were talking about this before.

Nate 01:11

Very healthy man.

Alex 01:12

Very healthy man. I wonder how old he is now. And he’s stage diving and he’s incredible. All right, here’s a little bit.

Alex 01:25

(singing)

Alex 02:38

It just goes on and on and on, verse after verse. At first it’s a beautiful story and it just reminds me how much of a storyteller is.

Okay, Non Sequitur. I just saw that movie, a Complete Unknown, about Bob Dylan. Incredible movie. I loved it. Timothee Chalamet did a good job. A lot of the costars did a great job. And I would say that one thing I wish it did better was show how Bob Dylan told stories with his songs in much the same way that Bruce Springsteen does. And someday there’ll be a great documentary About Bruce Springsteen.

Eric 03:10

I think this is just a plug for future guests that Alex wants more Bob Dylan songs. Don’t let him fool you, future guests. [laughter]

All right, let’s jump into the topic. Things are changing real fast in Alzheimer’s world. So we now have blood tests that can reasonably approximate the degree of amyloid buildup in the brain. You got two new FDA approved meds that you can give to shrink that amyloid all the way. How much has this changed? How much should it change how we think about making a diagnosis of Alzheimer’s disease in primary care? What do you think?

Nate 03:55

I don’t think it changes anything about what we should be doing in primary care. And that’s because the syndrome of mild cognitive impairment and dementia doesn’t change. Right. So we need to know if a person’s having symptoms. We need to know if people are forgetful, if they’re losing their attention, if they’re struggling to solve problems like cook or clean or do any of those things. So knowing if it’s amyloid or if it’s tau or if it’s Lewy Body disease or vascular disease, that doesn’t really matter because we need to know what people are experiencing. And so I don’t think the biology is incredibly important, so don’t get me wrong, but what people are experiencing, which is fundamental and what we really care about, that hasn’t changed. And so in primary care, which they’re perfectly situated to address, that hasn’t changed.

Eric 04:48

That’s fascinating. So it sounds like what you’re saying is making a diagnosis of cognitive impairment is kind of paramount first over making the diagnosis of Alzheimer’s disease. Did I get that right?

Nate 05:01

Absolutely. Absolutely. Fundamentally, we need to be better, all of us, at addressing symptoms and getting to the diagnosis of MCI and dementia.

Eric 05:13

All right, I’m going to start off at the beginning, then. So let’s just say you have a healthy 55 year old or 65 year old in your clinic. Who do you think we should be screening and how should we be screening them for these symptoms?

Nate 05:29

Ooh. Well, so I guess it depends on what you say screening. Because if you’re the United States Preventive Task Force, they’re going to tell me, well, don’t screen any asymptomatic person. And what they’re really saying, which is fair, is don’t be giving a cognitive screen screening tool, a moca, a mini mental, to someone who’s healthy. And that’s fine if that’s what the evidence is bearing for now.

Eric 05:52

But really, because we got no Good randomized controlled trials. That screening influences kind of further treatment, actually, probably more importantly, patient outcomes.

Nate 06:04

Right. And it can cause harm because if you’re springing this test on someone, it actually could create a lot of anxiety. It can create mood changes. But the key part of that is asymptomatic person. Who should we be screening as far as. Are we worried about our thinking? Everyone. So whether it’s 50, 52, 55, 65, we should ask every person who comes into clinic at least once a year, how do you feel like your thinking is? Do you think your thinking has changed compared to last year, five years ago, 10 years ago? It’s a simple question. It normalizes the fact that there are other factors besides Alzheimer’s disease that can affect our thinking, like depression, like sleep apnea, like your medication side effects, like a thyroid. So every person should be asked, what’s your thinking like?

Alex 06:48

So is that. So that’s. And you’re not categorizing that as screening for Alzheimer’s disease or mild cognitive impairment. You’re calling that screening for thinking issues, which you’re saying is different.

Nate 07:01

Well, I mean, I guess I’m kind of walking that line because if that person says, well, you know what, Doc? I do feel like my thinking is different. Oh, well, because now I want to explore that, because now I’m going to characterize what is that thinking change. And that gives me one of the criteria potentially for mci. That’s that subjective complaint. And then that would actually lead me to using a screening tool like a mini mental or MOCA to look for an objective impairment.

Eric 07:27

Okay, I got a question then. Yeah, there’s this also idea is as we age, our body changes, organs change, our way, we think changes, sometimes for the negative, sometimes for the positive. Like, there are some things we do better with age, as we think there are some things that we do worse. How important is it that, like, compared to 10 years ago? I think I. I think differently than I did 10 years ago.

Nate 07:56

Yeah. And I. And I think that’s true now. I. You know, we’re all geriatricians here, so I do want to be careful that just getting older doesn’t mean everything’s declining. Right. So you did say some things get better, wisdom gets better, emotional maturity can get better.

Eric 08:12

I’m not sure that got better for me, but.

Nate 08:16

And there are some.

Alex 08:17

Ask your wife.

Nate 08:18

Yeah, I didn’t want to say it. You know him better than I do. And there are some lifespan studies, right, that at the age of 25, we reach our peak Cognitive performance, there’s gradual changes, so I recognize that. But I do think that we are really entering this age of are we really at our optimal? Like, if we truly address all those health factors, brain health, if we truly are addressing those, perhaps we could be better than what we were doing. And perhaps that means even now, maybe I’m not at my best, maybe you’re not at your best. I do think our culture, we have undervalued sleep so long only until the 1960s did exercise really become something.

And so are we truly addressing those lifestyle factors that could be leading to cognitive reserve? And with the Lancet Commission coming out with those 14 modifiable risk factors that could prevent dementia, could those actually lead to improvements in cognition? We have those studies that show cognitive ability can improve when we address some of these things. And so asking about that, I mean, perhaps people could actually feel better and then we’re just talking about well being. But if we catch someone who says, well, actually I do feel like my thinking is worse, well, then I think exploring that is worthwhile and could lead to people feeling better. It could also catch the very earliest change of mci and then we do go down that path.

Alex 09:46

Yeah. So maybe we wouldn’t call that a screening question. Maybe we’d call that more an assessment of people’s thinking and that, you know, a yes, no response isn’t sufficient for the clinician. You have to probe beyond that to see whether this is a concerning maladaptive change in the way somebody’s thinking or not. And also a plug for our listeners to check out our podcast with Christine Yaffe on prevention of dementia through changes in non pharmacological behavior and lifestyle factors.

Eric 10:18

I’ll put that in the show notes too. And I love this what you’re saying, Nate, because my sleep has not been good in the last couple weeks and I actually do think that’s affecting my thinking and I should probably do something about my sleep. That question opens the door for so many different avenues that you could potentially address, from mood to sleep to exercise. So I love that question. As far as the next step, when would you do an objective cognitive screening?

Nate 10:54

You know me, and so I’m. So we’re talking about primary care and so I’m a little bit biased here. So I’m in a specialty clinic, so I’m in this interdisciplinary memory assessment clinic. So I get all the referrals from my great colleagues in primary care. And I’m seeing people coming in with mini mentals of 10 out of 30 who we end up doing thoroughly testing and they’re perfectly healthy and they’re scoring well. And when I asked the patient, well, what happened, the test was sprung on them. It was administered by a well meaning person who doesn’t know what they’re doing when they administer the test. It was rushed. They said to them, you have dementia. And they never really conducted a functional history.

And so I’m seeing case after case of these really bad situations. And I know there’s plenty of good situations out there too, but what I’m seeing are scores that are meaningless. And so I really worry about cognitive screening not being done properly. And I do say this knowing that I don’t administer these cognitive screening tests in the right way. And I work with a lot of neuropsychologists and they will all tell you I don’t do it well. I’m holding on to the MOCA instructions and I’m reading it verbatim. I’m like a machine done, and I’m not doing it well, if you aren’t doing this regularly, if you aren’t confident in what you’re doing, if you don’t show compassion and yet stick to the rules, these instruments aren’t that helpful. And so I do worry about cognitive screening in primary care. And I know people don’t agree with me in this. I know lots of people don’t agree with me in this. And so it’s hard for me to imagine the beauty and complexity of the human brain broken down into a number that is done in a 10 minute test. And I know we want that. But these tests were never designed to diagnose.

Eric 12:40

10 minute test, 2 minute test. You got your mini cog right there.

Alex 12:43

Mini cog, yeah. And a shout out to our podcast with Sue Borson, creator of the mini cog, and Anna Chodos about assessment and screening. Similar to this podcast, though, I gotta.

Eric 12:55

Keep on writing down all the podcasts. Alex’s plugin right now, so I don’t forget to put on this.

Nate 12:59

You guys have done some great interviews And I know Dr. Vorson and I mean, I think that’s incredible work. I just think when it, it’s hard, it’s hard to break down what the brain can do into something so simple. You know, it’s meant to filter, it’s right. It’s meant to screen who really is impaired or could be impaired and who’s not. But it’s so much more difficult than that. Whereas if you look at function, if someone comes in and tells me, I am struggling with remembering things that just happened to me?

Well, there’s my complaint. And then the family tells me they can’t keep an appointment, they can’t manage their finances. What is that screening test gonna do for me? I already know that the complaint is severe enough that it’s starting to impact their function. That is enough for me that I would want them to come to my clinic where I have a neuropsychologist that’s gonna conduct a 50 minute thorough cognitive assessment. And now I’m gonna get a real sense of what the brain is able to do. I just don’t know what the point of that screen is gonna do. It might actually scare the person. It might make them so frustrated they’re not willing.

Alex 14:02

Oh, this sounds so hard, Nate. Like it’s hard to do it. Well, even for somebody like you, who’s pretty familiar with the instruments, it might cause distress for the patient, maybe their family. There’s got to be an easier way. And I have to ask them about all these other things like seat belt use. And I gotta manage their blood pressure and their diabetes meds. I’m just gonna send them to lab and get the blood test.

Nate 14:25

Oh.

Eric 14:27

You mean a TSH Alex?

Nate 14:31

I appreciate that. Thank you. Because I would rather you look for reversible causes. Right. I’d rather you do something like that. No, I don’t want you to get the blood tests. And I don’t know if others in the specialty world would disagree with me, but I’m not in favor of these blood tests being in primary care.

Eric 14:48

And we’re saying the blood tests being facetious with the TSH, the PRS, you’re talking about amyloid biomarkers, your P. Taus, your amyloid ratios. Like those are the things we’re talking about right now.

Nate 15:02

That’s right. That’s right. And they are incredible tools. And for my grand rounds, I’m going to be talking about what they can do. And I think it’s amazing at a scientific level, even at a clinical level, for our listeners.

Alex 15:13

Could we give a preview? I’d love to hear more about that. I’m sure. Our listeners.

Eric 15:17

What do they do?

Alex 15:18

Yeah.

Nate 15:19

So what can they do? So they can reliably detect the presence of amyloid up to 10, 20 years before a person develops symptoms in certain groups. And this is all cohort based, meaning these are just in certain.

Eric 15:33

And when you say certain groups, you mean very white, wealthy folks?

Nate 15:38

Well, I mean in the rap population. Wisconsin Registry for Alzheimer’s Prevention, 22% of our population are African Americans. Hey. Or are things are changing groups. And so it is changing slowly. Yes, they’re predominantly white and urban and well to do, but that is slowly changing, and the numbers still are different. So you’re right. But that is a reason why we do need more people of color to come in so that we can understand it. And it still could be different. And I think there are reasons for that.

We need to understand that. But it doesn’t change the fact that when you do have amyloid in the brain, there is this very strong connection between amyloid chronicity, meaning how long you have amyloid in the brain, and the likelihood of developing tau, and that’s Alzheimer’s disease. Pathologically, the likelihood of having cognitive decline on testing and the likelihood of developing dementia. There’s a biological timeline that we are really starting to be able to describe, and it all starts with the first identifiable process, which is amyloid. And so when you start seeing this, it’s pretty convincing how important it is, at least from a scientific perspective. And then you’re going to ask the question of, well, you need.

Eric 16:47

Is it determinalistic? If you have amyloid, will you develop Alzheimer’s, dementia?

Alex 16:54

And just to be clear here, are we still talking about the blood tests for amyloid, or are we talking about, like, CSF or imaging studies? What are we talking about?

Nate 17:01

Well, no, the blood test. I mean, these days, a blood test looks just as good as the spinal fluid, and it looks almost as good as these PET scans. The PET scan has really been the. The gold standard biomarker tests. But it does look really good now. Now, frankly, at ucsf, the researchers here are phenomenal when it comes to these PET scans. I would say the researchers in Wisconsin are really good, too. And they are. I mean, they’re showing they’re comparable. I mean, there are certain advantages to the blood test. Obviously, it’s a lot easier to collect, more scalable. We can get more people, particularly people in, you know, where we’ve difficult. We’ve had difficulty in recruiting and engaging in those communities, and that’s on our end. It’s not on the community’s end. PET scans, though, the beauty of a tau PET scan is you can see where the tau protein is geographically in the brain, and I think there’s a lot of value to that.

But we’re getting into the weeds. I just think there’s a lot of power in these biomarkers. But to the person, I would say that when a person comes into a primary care clinic, you want to know, well, what exactly is happening to me? And. And first thing Is, well, let’s describe what’s happening to you and that’s what primary care is really good at. Let’s collect that history, let’s look at those reversible causes and then let’s start talking about the potential brain diseases. And that of course, if you feel comfortable in primary care, then great. If you want to see a specialist, that’s where I would potentially do that handoff to a specialist and they would be doing the blood test or. Well, I would actually do neuropsychological testing first and then do the blood test.

Eric 18:39

Yeah, I do worry a little bit because I recently had a primary care appointment. Well, not recently, like six months, a year ago. I forget when after not having had one and even before I saw the person. I just had lab tests done. I didn’t know which lab test got my lab tests looked on there. All of a sudden, as a 49 year old, I see I have a PSA on my lab test. There was no shared decision making about the psa. It just happened.

Alex 19:08

This is the reality. Same thing happened to me.

Eric 19:10

Yeah, right.

Alex 19:10

Yeah, I got a psa. Yeah.

Eric 19:12

I also had like these, like my lipids were broken down into every possible category. So I worry that this is going to be like Alex said, it’s the shortcut. Like you could spend a half an hour with a patient getting a great history, functional history, doing an exam, doing some basic workup first and then getting those amyloid biomarkers potentially, or just sending them to specialty clinic. Or press the easy button, get that amyloid blood biomarker and call it a day.

Nate 19:49

Yeah. Well, first of all, let me say I feel sorry for the two of you because that is a horrible experience. I mean, I don’t want to speak to your healthcare system and what’s happened, but that to me seems inappropriate. I Recently, I turned 41. So when I turned 40, I went in to get my checkup. I hadn’t been to the doctor in five years and I’m the one who said, please, can I have an A1C? Can I have a lipid panel? I want to be checked for these things. I had to ask for that. There was no labs ahead of time and that’s how I think things should be. And so maybe it’s a little bit different in the Midwest, I don’t know. But I don’t think it’s appropriate to order these things in advance. I agree with you. Shared decision making is critical.

I do think there is something different about Alzheimer’s than there is about high cholesterol. And even a prostate cancer. Cancer, I know is still a scary word, but I do think someone has to own the result in the counseling of that result. So for primary care providers, you order that blood test, you own that. And I think that’s a common part of our culture. You should be scared. You order that amyloid test and you don’t have shared decision making. You should be fearful of having that, that conversation when your patient comes in. I think that fear is enough that you’re not going to order it, fearful.

Alex 21:03

Of it coming back positive and you hadn’t had the conversation. And then. And then what?

Eric 21:09

And this, what does it mean?

Nate 21:10

Right?

Alex 21:10

Yeah. And then how are you going to explain this to the patient that, well.

Eric 21:14

What does it mean to, let’s say an asymptomatic 50 year old?

Nate 21:18

Oh my gosh. Right. And that’s the. Because that’s even being debated in the field of experts.

Eric 21:24

We don’t know what it means yet.

Alex 21:25

Right, but didn’t you just say a little while ago that there’s a clear correlation between these biomarker tests and development of Alzheimer’s disease?

Nate 21:36

I don’t like how close you listen to me. Well, so there is a debate in the field as to the definition of Alzheimer’s disease. Right. So the new criteria came out. Amyloid alone is enough of a definition of Alzheimer’s. So in someone who’s cognitively healthy, having the presence of amyloid would be enough for the definition of Alzheimer’s disease.

Alex 21:55

Is that a done deal?

Eric 21:56

That is per the Alzheimer’s association.

Nate 21:58

That’s only per one set of criteria. Right.

Alex 22:00

Per the Alzheimer’s association. That is a done deal to the Alzheimer’s association.

Eric 22:04

Done deal to Alzheimer’s association. There is a different work group.

Nate 22:07

There’s a different. There’s an international work group and then there’s clinicians in general who are facing patients who are asking these questions too. And so I think there’s just a dispute discussion in the whole field about, well, what are we talking about? And certainly the criteria said we shouldn’t be testing people who are cognitively healthy.

Eric 22:24

Of note, that is on box four, page 14, nowhere else, one sentence. You shouldn’t do this. You shouldn’t test asymptomatic people. No suggestion of what you should do with subjective cognitive complaints. Like, is that okay to test people? Like, if somebody comes in, they watch an advertisement during the super bowl, they say, hey, if you forgot your keys, you should talk to your doctor about checking your amyloid levels in your brain. Eli Lilly. They’re not asymptomatic anymore. They have subjective cognitive complaints. Hey, let’s press that easy button, and let’s get those Alzheimer’s biomarkers done.

Nate 23:05

I think they were saying that if you weren’t impaired, though, I mean, because they’re breaking into asymptomatic MCI and dementia. So I think they were grouping everyone into that one.

Eric 23:13

I just think it should. If they don’t want it done, it should be on page one. Don’t do it.

Alex 23:18

Wait, they meaning the Alzheimer’s Association?

Eric 23:20

Yeah, in the work group.

Alex 23:21

In the work group. And these are the proposed guidelines.

Eric 23:25

I’ll get off my bandwagon.

Alex 23:27

We want to hear this.

Eric 23:29

One of the proposed guidelines on how to diagnose Alzheimer’s disease.

Alex 23:34

Okay. And it’s proposed.

Eric 23:35

Yeah. Define Alzheimer’s disease.

Alex 23:38

Okay. Not accepted dogma throughout the field yet. Maybe. Although Nate sort of talked about it just a moment ago like it was maybe.

Nate 23:45

Well, so. So what I’m saying to you is that when you start looking more and more at these cohort studies, meaning individuals who have volunteered for decades, and you start looking at the science of what happens when people are followed and they have amyloid in their brains, and you see that many of them, most of them, are developing Taurus, and if you follow them long enough, are they developing symptoms, and we need to follow them longer. And I can speak to the RAP study, the Wisconsin Registry for Alzheimer’s Prevention study, and that’s been around for 24 years. And we are seeing people with amyloid, and nearly all of them that develop amyloid, that live long enough, that have amyloid for more than 22 years, are developing tau.

Eric 24:24

So we just gotta follow them for 100, 200 years, and then all of them will develop Alzheimer’s.

Alex 24:31

And I thought you were gonna end that with. And many of them are developed tau. I thought you were going to end with many of them develop Alzheimer’s disease. Developing tau is not a disease.

Nate 24:42

Well, no. So if you have amyloid and you have tau biologically. So now, again. So prior to the new criteria that were proposed in 2018, the criteria were the presence of amyloid in tau was the definition of Alzheimer’s disease. And that is the neuropathic definition of Alzheimer’s disease. And so now you’re getting into the nuance of. Are you accepting of an asymptomatic phase.

Eric 25:05

Of Alzheimer’s disease or subjective cognitive plans without any objective, like asymptomatic assumes that there’s. Where does the subjective cognitive complaint. I forgot my keys. I’M forgetting some groceries. Commercial says this is more than normal aging. But when Nate sends me to the neuropsychologists, they do this testing, they find nothing. But somebody checked an amyloid test on me and it’s positive. Do I have Alzheimer’s disease?

Nate 25:37

Yeah.

Eric 25:38

I think that is the big controversy right now. What should we label those people? Not just asymptomatic, but subjective cognitive complaints. If somebody does this test, and per the Alzheimer’s disease work group, it is, you have Alzheimer’s disease, could they be you shouldn’t have done it, but you got it.

Nate 25:54

Yeah.

Alex 25:55

And why does this matter? Whether you. What we call it. Is this just semantics? Whether we call the person, we say the person has Alzheimer’s disease or doesn’t like. From the perspective of advancement of research and development of interventions, maybe we do want to call it Alzheimer’s disease. Whereas maybe from the perspective of a patient who has got some subjective mild memory complaints and a positive amyloid blood test, they don’t want to be called, you know, labeled as having Alzheimer’s disease. They’re still working, like, what’s their employer going to do?

Nate 26:31

Right, right. Yeah.

Eric 26:32

They’re an airline pilot.

Alex 26:33

Yeah.

Eric 26:33

Can they fly anymore? Because they have Alzheimer’s disease.

Nate 26:36

Right. So it matters a lot to the person, to their family, to the community. Right. So that’s a powerful term.

Eric 26:42

Yeah.

Nate 26:42

And so if we’re going to be using that term in a new way, there’s a lot that has to go into the education and reframing of that.

Eric 26:50

Yeah. And diagnosing a disease drives treatment, so there will be an inherent push to start. These amyloid antibodies in people who don’t fit the categories that were included in the studies, MCI and mild dementia. You have somebody with subjective cognitive complaints, no objective issues, but they got a positive amyloid. That’s pretty scary.

Alex 27:15

What about these amyloid drugs like lecanemab, Donanemab? Those drugs?

Nate 27:20

Yeah. But now there are already those studies, though. So Trailblazer Alz 3 and then the head study, these are good studies that will likely result ahead, will probably result in the next couple of years. Trailblazer ULS 3 could potentially result this year or next year. And those were people who do not have mci, who have amyloid in their brain, were given these monoclonal therapies, and they are looking at those similar outcomes.

Eric 27:45

Yeah.

Nate 27:46

So. So that would potentially tell us what is the meaning of. Of these interventions in those individuals.

Alex 27:51

So this is what Eric was talking about. This is the patient. Eric’s talking about subjective Memory complaints, but doesn’t even have mc, doesn’t even meet the criteria for mci. And we’re starting them really early.

Nate 28:02

Right.

Alex 28:03

And my recollection from the early drug tests for anti dementia medications was you got to start earlier, probably because those studies were negative. So maybe there is a scientific rationale that if we’re going to intervene, it’s better to intervene early than later, right?

Nate 28:21

Could be, yes, could be. That does make sense. And then Donanemab’s phase three study, Trailblazer LS2, they split people into those who had low medium tau and those that had high tau. And those that had low medium tau did respond better to Donanemab than those with high tau, suggesting that those who are earlier in the disease do respond better to therapy than those later in the disease.

Alex 28:43

So what’s the harm here? I think we should be. Shouldn’t we? Don’t we want to know early? I mean, I would want. Does the public. If you ask the public, if you ask older adults, don’t you want to know early on the chance that you might be able to intervene early? Think about the number of people who sign up for clinical trials, et cetera, on the basis of, you know, they think it might help them, though, you know, it’s not. It’s. These trials are designed to help future patients. Most of the public wants to have access to treatments and interventions that might help them forestall a devastating illness.

Nate 29:18

Well, we’re waiting. I mean, but I think we’ve kind of gone off on a different path here. But we went from primary care to this.

Eric 29:24

Welcome to the Jerry Pop Podcast. It’s not as formulated as Dementia Matters, your own podcast.

Alex 29:30

But I. Dear listeners, I’m trying to be provocative. Let’s see if I can get a rise out of it.

Nate 29:34

And I think, though, that, I mean, this. This is the point of scientific investigation in clinical trials. And Eric is bringing up some really interesting and important questions which are being addressed with these clinical trials. And so for our listeners, we should come back to this episode, because when these trials result, Eric might be sitting here and saying, see, I told you these trials are going to tell you.

Eric 29:57

Don’T do this, or, hey, it worked, let’s change this definition.

Nate 30:03

Or Eric is going to have me fly out so I can sit here and be like, well, now what are we going to. Because these trials resulted and there’s benefit. And I know what he’s going to say. Well, it’s a clinically meaningful.

Eric 30:13

Yeah, we all know if it’s beneficial, it’s going to be some.

Nate 30:17

Well, and we can have that conversation. But, you know, there is a. There is rationale. Earlier is better. But we do need to prove that in a trial, in a structured, you know, scientifically sound trial. Yeah. And so that is for a different population than the person coming into clinic that has a diagnosis of MCI or dementia.

Eric 30:36

Well, I gotta ask another question about trials, because there is this discussion online about maybe not even online fda. What about just forgetting these patient outcomes and just look at these surrogates, like amyloid, as our results for the trial. Should we just say, for these new studies, all that really matters is, does it reduce amyloid? That is a great surrogate marker. Because as you said, said, Nate, if you follow people long enough and if they live long enough, they’re gonna develop Alzheimer’s disease. Maybe. Mostly. Well, let’s just use that as our surrogate.

Nate 31:16

Well, no, I don’t. I mean, ultimately, we’re in this to help people, so that’s a dangerous path to walk down. I do think, you know, if earlier is better and you want to talk about prevention.

Eric 31:27

Yeah.

Nate 31:28

And it takes 30 years, 20 years of developing amyloid and tau and 10 years of developing symptoms and then dementia. We can’t wait long for a prevention study to then see if it works or not. So you do need a surrogate in a prevention study. And I mean prevention of developing the amyloid that you would have to have already established leads to the development of dementia. So you already have to do steps before you get to that. And that’s what these longitudinal studies are so important for. So, I mean, the interesting thing to me is that I hear a lot about, well, these clinical trials are really. Are they going to put longitudinal studies out of business? Like, do we need longitudinal studies? I think it’s the complete opposite.

I think these clinical trials are emphasizing the importance and gratefulness that we have for participants who have been in studies for 30 years, because we need them to continue to be in studies. Because ultimately we need to know the questions that we’re getting at. Does amyloid always lead to dementia? And we need people to be in the study for 40 years, 50 years to know that. Because if we do know, if we can show in multiple different cohorts, meaning Wisconsin and Adni and Baltimore and Mayo and down in Texas, if we can show that, if you develop elevated amyloid and that will lead to dementia, if you live long enough, well, then that’s your conclusion. Then removing amyloid or preventing the buildup of amyloid means you prevent that type of Dementia. We still haven’t talked about vascular and Lewy Body. They’re equally important. But I mean, at least that string of dementia could be prevented.

Eric 33:05

So can I ask you then, going back to the biomarkers, you know, I’ve heard that the most common type of dementia is mixed. There’s a lot of going on in the brain from vascular issues. And when we think about prevention, like, there’s more more to it, even like depressive symptoms of sleep and everything else. When you get a positive biomarker, how do you interpret it, knowing that there’s probably a lot of other things going on in the brain?

Nate 33:33

Absolutely. It’s just one piece of data. And that’s why a biomarker can’t give you everything you need. You need a clinician to put everything together. I mean, I feel like you’re just giving my grand rounds for me. I mean, honestly, I was going to practice before 4 o’clock today and I don’t feel like I need to. I feel like this is done. I mean, I talk about, can we.

Eric 33:54

Just show this video during the grand round and you’re done?

Nate 33:57

I could just sit back and just bring my guitar. I can have some fish tacos with you guys and just sit around. No, I agree with you. And I think what is super fascinating to me, I don’t want to go too much in the weeds, but what I find really interesting is the timing aspect. And this is why I think the biological process and timing of these biomarkers is so important. Let’s say someone comes in and they have dementia. We’ve diagnosed them, we’ve done this proper workup, they have dementia, mild stage dementia, and we get a PET scan and it’s amyloid elevated. Well, traditionally we would say, okay, well, you have dementia and it’s due to Alzheimer’s disease. But if we knew that they had just become elevated in amyloid, that two years ago they were not elevated and they just became elevated, I would say to you, no, that’s not Alzheimer’s disease. Dementia, something else has been going on for years that caused that dementia and it just became, yes, Alzheimer’s. This process is probably there and it’s.

Eric 34:52

Building because every decade you get older, the chances of you having amyloid in your brain increasing is increasing.

Nate 34:58

But I would say something else is there. So I actually think there’s a lot more nuance to just the biomarkers. So there’s other things that are happening that are probably contributing. But even just the nuance to the biomarker and the timing which is why I worry about primary care having to go through this process and explain it. Because when I think about it, and I think about these things every single day, it takes me 30, 45 minutes to talk to my research participants about these biomarkers. And a primary care provider has 18 minutes. And Alex said they got to talk about other health conditions, equally important, high blood pressure and cholesterol. And how can I expect a primary care provider to do that?

Eric 35:35

So I do want to acknowledge. So that’s something about Alzheimer’s association. They actually published a really good article in December on what’s the role, how should we diagnose Alzheimer’s disease in primary care? Beautiful flowcharts. And it kind of mimics exactly what you’re saying. The role of the biomarker comes very late in that diagnostic pathway, generally at the specialist and in primary care, it’s what you’re saying. You do the history, you do a physical exam, you’re doing non specific, you know, blood tests and potentially imaging, and only after that do we even consider the role of biomarkers. Does that sound right?

Nate 36:17

It does.

Alex 36:17

And when you say non specific blood tests, you’re talking about like the TSH, the RPR, that sort of stuff.

Eric 36:23

Okay, yeah. You know, basic CBC, like those types of things, right?

Alex 36:27

B12.

Eric 36:28

Yeah, but you’re, you’re. The most important thing, like Nate is saying is that the history, like, is that. Are they depressed? How’s their sleep have been different? Have they been drinking every night? Like, what’s going on in their life? What’s their functional status? And we’ll have a link to those Alzheimer’s diagnostic kind of guidelines, which I think are fabulous. Great flowcharts for anybody who wants it. And importantly, those biomarkers are really reserved mostly for specialty care.

Nate 36:54

Yeah, I think they nicely described that.

Alex 36:56

Eric just gave kudos to the Alzheimer’s disease.

Eric 36:58

I give kudos about. Yeah, it was great. Importantly, there are no pharma or diagnostic companies involved in that work group. So kudos on that too, like starting to think about conflicts of interest. So big kudos. I’m going to get off my rant.

Nate 37:17

To the next one.

Eric 37:19

Yeah, to the next one. I’d love to hear your thoughts. So let’s say you do this diagnostic workup you have diagnosed with MCI or mild dementia. You send them to the specialist, confirmed, they do blood tests, they may do a PET scan. What do you think the role of the amyloid antibodies are in this case? How do you talk to your patients about the benefits and the potential Risks. I’m not going to ask you for the 40 minute spiel. I’m going to ask you for the 30 second spiel.

Nate 37:52

Yeah, well, this is where I think shared decision making is so important. And I do. In our program, we do offer monoclonal therapy, lecanemab and tynanemab. And I talk to all of my patients that fit eligibility criteria. And most of my patients are coming into a specialty clinic with that in mind. And so every single person, pretty much with that diagnosis of MCI or mild stage dementia will hear me talk about monoclonal therapy. And usually for those that aren’t eligible, I’ll say, you’re not eligible because you have moderate stage dementia. You’re not eligible because you’re on a blood thinner. You’re not eligible for A, B and C.

So they’ll hear that because I want them to know that. And then for those that are eligible, I’ll say, okay, so you’re potentially eligible. There’s a separate evaluation process for determining if you really could be on this therapy. But let’s talk about if you really want to go through with that and what that means to be on the therapy. So I actually start with logistics. Are you willing to go into an infusion center every other week? It may not be in your area. You might have to drive an hour or two to do that. Are you willing to get an MRI scan four or five times over the next 18 months? Do you have someone who can take you there? If you are on this medication and you have a stroke or a heart attack, you wouldn’t be able to get certain medications because you could have this bleed. And then let’s talk about the bleeding and the swelling that could go on in your brain. So I go over Aria, and I think that’s really important for people to hear. And I pretty much present it as.

I start by saying, these are the risks of this. And then I’ll say, what it can do is pretty incredible. It removes this protein, this starting protein, and they all know what I do. So, I mean, all of my patients that see me know them mostly in research. It’s pretty incredible. It removes this protein, but what does that mean for you? It slows your decline. You are still declining. And I say it the same way. You are still declining, but it slows it. And they’ll usually say, well, isn’t that what your donepezil is doing for me? Well, and I’ll have to say, no, donepezole doesn’t actually slow it. It helps with your Symptoms, you’re still progressing. This is actually addressing your biology. It’s slowing it. What does that mean? Potentially three to six months, you know.

Alex 40:02

Oh, three to six months of prolonging.

Nate 40:05

Where you currently are versus not being on the therapy. That’s sort of the way they framed it. And I just think that’s a statistician that sort of framed it that way. And then I’ll go over it. If this is your life goal, what are you hoping for?

Eric 40:19

Do you talk about uncertainty, like what happens after a year and a half, like that unknown that we have with these drugs?

Nate 40:27

We don’t know the long term consequences of this. I will say to you, people will say, oh, that’s kind of interesting. And then I’ll say to them, you know, we don’t know the long term consequences of Ozempic and everybody wants to be on that drug. We don’t know the long term consequences of lots of drugs. And yet nobody seems to question that. And so everyone seems to question the long term consequences.

Eric 40:51

I’m going to push back. There’s a little difference between this and a statin though, right?

Nate 40:55

No, well, Ozempic, everybody wants to be on a zempic. And we do know about 20 years. Somebody recently pushed back and said, well, it’s been around for 20 years.

Alex 41:04

It has been. Yeah.

Nate 41:05

But you know, there’s a lot of drugs that, that come out that people don’t seem to mind. But for some reason with Alzheimer’s, maybe.

Alex 41:15

It’S the brain bleeds, maybe it’s the.

Nate 41:18

Brain bleeds, maybe it’s the couple deaths, you know, and. But in a great. Yes, people. But people have died in other clinical trials too. I mean, I do feel like everything is heightened in this field that I.

Eric 41:31

Also worry that like part of this is the, the taint that educated me put over everything.

Nate 41:38

It was the worst way that we could start. And well, when we wrote this, I feel like I’m just doing everything in my presentation.

Alex 41:45

Oh, this is great.

Nate 41:46

I mean, we had this great editorial in jama. This is my first editorial in jama, thanks to Eric. And we were very fair about this. This was a horrible way to start these therapies was with disapproval.

Eric 41:59

That was our first paragraph, I think.

Nate 42:01

Yeah. And it just.

Eric 42:02

I want to ask, because I’m going to bring to your last article that I was just reading last night again, which I thought was fabulous. It was in New England Journal last year. Like you were in New England Journal three times, two videos last year. But you wrote an article about what primary care Needs. If you had this magic wand that you can change how primary care thinks about diagnosis, screening screens for Alzheimer’s disease, what does primary care need? And we’ll have a link to your New England journal article so listeners want to know more. They can read it.

Nate 42:33

Yeah.

Eric 42:33

What does primary care need around Alzheimer’s disease?

Nate 42:37

Oh, gosh. Well, I think based on talking to my colleagues, I think primary care needs more time with their patients without the pressure to go through, like, they need more than 18 minutes. They need more people working with them. They need social workers like I have. They need more nurses. They need more of that support, support. And then I feel like they. I mean, they know so much about Alzheimer’s and cognitive impairment, but I think they want more training in the ability to counsel people on these conditions, particularly geriatricians. I think really want to be experts in this field. And so I think of it as the three T’s, time, training and team. And so I think the system needs to be supporting the clinics. And so it’s a structural resource change.

Eric 43:26

And I just want to also acknowledge, because you said geriatricians and specialists in the field, I just want to acknowledge that individuals like you, Nate, Sharon Bragman, Heather Whitson, we have so many amazing people as geriatricians who are leading the way as specialists, not just as geriatricians, but as dementia specialists. And I think that is a sign that geriatrics has a really important role in the future of dementia care.

Alex 43:59

Oh, this brings me to my last question. That’s a great shout out. And there’s been all this stuff. There’s an article in the New York Times about the decline and fall of geriatrics as a specialty. Last week, we had a podcast about this. We talked with Jerry Gerwitz and Mike Harper on is this a field where geriatrics can make a claim, establish expertise, and potentially lead to increased revenue through giving these antibodies in infusion centers?

Nate 44:29

Oh, well, that’s a different angle that we’ve never really thought about. We are cost saving. We save healthcare.

Eric 44:37

Geriatricians.

Nate 44:38

Geriatricians do. By taking care of complex patients. But I’ve never heard of it.

Alex 44:42

Yeah, because these are infusion centers. Right? You’re infusing.

Nate 44:46

Yeah.

Eric 44:47

Well, in five years, are we still going to be infusing these or just going to give subq shots? Everybody agree with? So things are. Things are changing. Well, I’m going to skip over that last question because we’re out of time. Alex, wait.

Alex 45:02

A little bit more time.

Eric 45:03

A little bit more time. You’re the one who has to go.

Alex 45:05

Yeah, I have to go do rounds with patients. Ok, we’re done.

Eric 45:12

We’re done. All right, we’re done. Geriatricians, it’s a little bit of a jungle. You have your shout out, dementia care. You are the experts. And with that, Alex, a little bit of the song…

Alex 45:34

(singing)

Alex 46:48

It’s like the GeriPal theme song. It’s like Jungle Land in here. [laughing]

Nate 46:51

Thank you.

Eric 46:53

Thank you, Nate. Thanks for joining us on this podcast and also a big shout out. If you guys haven’t listened to Nate’s podcast, Dementia Matters, go to it. One of my favorite podcasts out there. Thank you for doing that too, Nate.

Nate 47:05

Thank you, guys. It’s been great.

Eric 47:07

And thank you to all of our listeners for your continued support.

This episode is not CME eligible.