LATE vs Alzheimer’s: Biomarkers, Mixed Dementia, and Clinical Realities with Nate Chin & Sterling Johnson

Eric 00:12

Welcome to the GeriPal Podcast. This is Eric Widera.

Alex 00:17

This is Alex Smith.

Eric 00:18

And Alex, we got a really interesting topic today. We’re going to be talking about something called LATE. Have you ever heard of that, LATE, before?

Alex 00:23

I have not heard of LATE. Am I late?

Eric 00:25

Yeah, you’re late to the LATE. Maybe you’re not too late. LATE and mixed dementias. How do we think about them when we’re thinking about cognitive impairment. And who are our guests for this episode?

Alex 00:34

We are delighted to welcome back third-time guest Nate Chin, who is a geriatrician and medical director of the Alzheimer’s Disease Research Center at the University of Wisconsin. Welcome back, Nate.

Nate 00:46

Thanks for having me.

Alex 00:47

He’s also author, we should say, of a book, When Memory Fades, recently out, right? Like last month. Yep. And we’ll have a link to that in our show notes. What’s that about, Nate?

Nate 00:58

It is the story of my own experience with my father’s early onset Alzheimer’s mixed in with what do you do when you worry about your own loved one who’s having thinking changes, and then bringing in the science and the research that we’ll be talking about today.

Alex 01:13

Terrific. Look forward to reading that. We hear there might be a mention of GeriPal in the book.

Eric 01:17

Oh, then all of our listeners, check that out.

Alex 01:20

Check it out. We’ll have a link to that in the show notes. We’re also delighted to welcome Sterling Johnson. who is a clinical neuropsychologist and dementia researcher at the University of Wisconsin, and also the principal investigator of the CLARiTI study of mixed dementias. Welcome, Sterling, to the GeriPal Podcast.

Sterling 01:39

Thank you, Alex. It’s great to be here.

Eric 01:41

And Sterling, I think you have the song request for Alex. Is that right?

Sterling 01:45

I do, Eric. I chose Blue Sky by the Allman Brothers.

Eric 01:50

Why did you choose this song?

Sterling 01:52

Well, it’s, it’s first of all, one of my favorite songs, always has been for most of my adult life as a guitar hobbyist. But also it has relevance to today, to what we’re talking about. Blue sky. Let’s see if we can make this stretch. That’s where we want to be in the diagnostic space. We want CLARiTI to our patients. What, what diseases do they have? How much of Alzheimer’s do they have? How much TDP-43 do they have? So we want that CLARiTI that a blue sky affords. So that’s why I chose that song. How did— how was that?

Eric 02:28

That’s great.

Alex 02:29

That’s great.

Eric 02:29

Let’s hear it, Alex.

Alex 02:36

(singing)

Eric 03:27

Great song. Well done, Alex.

Alex 03:29

Yeah, fun song.

Eric 03:29

That’s a tough one.

Alex 03:30

Oh, the guitar on that is amazing. People should listen to the original. It is incredible. And there’s some good covers on YouTube actually on acoustic guitars that do justice to the solos. Yeah, amazing choice. Thank you, Sterling, for that.

Sterling 03:46

Thank you. That was amazing.

Eric 03:48

So Certainly, you’re the PI for the CLARiTI study. What is the CLARiTI study?

Sterling 03:53

CLARiTI is spelled with an I at the end. It’s the consortium across the ADRCs to bring clarity to diagnostics in the neurodegenerative space. So, what we’re trying to do in CLARiTI is understand which of our patients have what proteinopathy in their brain. We know Alzheimer’s is, you can almost rely on that being present for our patients that come to us with memory complaints, but not always.

And sometimes the things that go wrong in their brain are related to TDP-43, which we’ll talk about today. Sometimes it’s alpha-synuclein proteinopathy, which is commonly the culprit in Lewy body disease and Parkinson’s disease. I know we’re already getting into the terminology weeds, but that’s the idea of CLARiTI, is to bring some clarity to the diagnostic picture for our patients and to provide the tools for that.

Eric 04:52

And let me ask you this. Why did you get interested in thinking about mixed dementias and CLARiTI AD? Seems like there’s a lot of focus on individual proteinopathies/diseases.

Eric 05:05

Where’d this come for you?

Sterling 05:07

I’ve been involved in the Wisconsin Registry for Alzheimer’s Prevention and also in our ADRC for a number of years and have been doing biomarker research in people who may be at risk for getting Alzheimer’s symptoms later in life. And what we see is that some people progress a lot faster than others. Some people reach symptoms within years, within a few years of their biomarker positivity. Some reach it after 20 or 30 years. Why all that heterogeneity?

And what we have consistently heard from the pathologists who look at these brains after a person is done using them is that there is more than one pathology, and that seems to be the norm for the pathologists. When they look at the brain under the microscope, they see this, these other proteinopathies, this TDP proteinopathy and the alpha-synuclein alpha-synuclein proteinopathy, vascular disease.

All these things can co-occur with the standard plaques and tangles that define Alzheimer’s disease. And so that’s what got me into it. It came from the avenue of doing a better job of diagnosing Alzheimer’s and also predicting when those symptoms might happen.

Eric 06:25

There seems to be a lot of push to diagnose a particular disease, like you have Alzheimer’s disease. I think Lately, because we have particular treatments for that disease. I want to hear from both of you. How much do you think that the focus on just, we are going to diagnose you with a disease and pretend it’s a singular disease, is moving us forward or potentially setting us back? Or should we be thinking about this more as you have this syndrome, which is MCI or dementia, and then you have these collection of underlying proteinopathies?

Alex 06:59

Yeah.

Eric 07:00

that may be resulting in that. I don’t know, Nate, what do you think?

Nate 07:04

So, I mean, your question was, are we moving forward or backward? And I think we’re moving forward, but I also think it’s because of what you just said at the second part of your question. And so, we haven’t lost track of the most important thing, which is the clinical presentation of our patients or our participants. We want to know their experience, which is, and then ultimately the syndromic diagnosis of MCI. Or dementia.

But the problem is we can’t really help people unless we understand what’s causing those symptoms and what’s leading to further progression. And this is where it then ties back into what’s underneath this, the surface of MCI and dementia. What are these proteinopathies, or just even below the neck, you know, what are these other comorbid health factors that are influencing your symptoms? And we have, so eventually we have to get to this idea.

Speaker 5 07:57

Yeah.

Nate 07:58

of what proteins are there. And we can’t get there until we know what we’re looking for and we have the tools to do that. And so CLARiTI is one way that I think we’re going to be effective at this. And so Sterling, Sterling’s very generous in saying he works, you know, at the ADRC and RAP. Sterling is our PI of RAP and has been an associate director of the ADRC. So he’s been leading this effort and trying to just characterize what does this mean when you have memory loss?

Alex 08:23

Yeah.

Nate 08:24

And we’re pretty good at doing that from a history. And I think that’s still gonna be fundamental and most important, but we need to get to that next level of, okay, and now that I’m starting to understand your experience, what’s, what’s the driving cause of this? Or what are the multiple causes of this? And this is where we need to put biomarkers to it.

Eric 08:42

So let me ask you about that, Sterling, is that, you know, there are some biomarkers in the last couple years, all of a sudden became very easy. To get, like in primary care, like you can check for P-tau, you know, other Alzheimer’s amyloid, other Alzheimer’s biomarkers. And there are some that are probably majority are very hard to get. So, you know, are you worried at all that when we think about like the underlying causes for somebody’s dementia, we’re going to be focused more on which proteinopathies are easy to diagnose versus which ones are not?

Sterling 09:18

Yeah, I think that is a, it is a worry. And that’s what’s happening now because the tool that we have now is p-Tau 217, which is remarkably accurate at detecting Alzheimer’s proteinopathy. It’s very good. But now we need a similar success story for alpha-synuclein and TDP-43. And what we know is that pure Alzheimer’s happens maybe at most 25% of the time. And that number is slightly higher for these, for younger onsets, but for someone who’s getting Alzheimer’s or being diagnosed with dementia in their late 70s or 80s, the chance of them having pure disease is less than 25% or less. So we need these biomarkers for the other proteinopathies. We don’t have them yet.

Eric 10:09

Yeah. So you keep on mentioning proteinopathies rather than like when we’re like when I think about mixed dementias, I think, oh, Alzheimer’s, vascular, Lewy body disease, learning about LATE, which we’ll get to. Is there a reason or is just like use them interchangeably?

Sterling 10:29

I think of those big 3, Alzheimer’s, Lewy body, which that’s an umbrella for both Parkinson’s and Lewy body dementia, and TDP-43, which is an umbrella for Frontotemporal disorder, ALS, and LATE. All those things are TDP disorders. So those are the proteinopathies. And of course, vascular disease that is always in play as a consideration and is going to impact cognitive decline.

Eric 11:00

Okay. So since we’ve talked about LATE, maybe we can, because probably—

Alex 11:06

I still don’t know what it is. I’m still waiting to hear. ‘Cause I’m LATE, LATE to the party.

Eric 11:12

What is LATE?

Nate 11:14

So LATE is an acronym, as we often do in medicine, limbic predominant age-related TDP-43 encephalopathy, which is, you can see now why we call it LATE.

Eric 11:27

Yeah, that’s a, that’s like, that’s a big one.

Nate 11:29

Right. And actually, I mean, it’s been studied for a while, but it really came into sort of its consensus and And criteria were starting to be built a little after 2019. Neuropathologists have been looking at this and came together and said, no, we believe we see this in brain tissue and we believe it’s separate from other current brain diseases. And then more recently, Dave Wolk from University of Pennsylvania, a great behavioral neurologist, and a team of people came together with clinical criteria, did the best that they can to sort of help clinicians get a sense of what this could look like.

They know, they recognize it’s far from perfect, but, you know, being able to identify this, there’s no specific treatment for it, but being able to potentially identify and talk to patients about it could be meaningful to them. And so now the field’s really moving forward and trying to develop a way of detecting it in a living person and not just after they die.

Sterling 12:26

It’s really important from a clinical syndrome side of things because The TDP part of LATE, that’s the T in LATE, is that it affects the hippocampus and amygdala. And so it’s the same areas of the brain involved in memory that are impacted in Alzheimer’s disease, and it can often mimic Alzheimer’s disease symptoms.

Eric 12:50

And TDP-43 is a normal protein in our brain, is that right?

Sterling 12:55

Yeah. TDP is a quality control protein, lives in the nucleus of our neurons. When it, when it diverts its way out to the, to the cytoplasm and mislocates, mislocalizes to the cytoplasm, its job as a quality control for DNA splicing, RNA splicing, it doesn’t do its job as well. And so then that, that’s when you get these TDP inclusions and, and clumps that build up in the neurons.

Nate 13:24

I’m glad you answered that, Sterling.

Alex 13:27

I remember we were talking with Jason Karlawish. I think it was Jason on one of our earlier podcasts about dementia and his book. And we were talking about how, you know, what is currently diagnosed as Alzheimer’s disease is probably some heterogeneous collection. And most dementias is heterogenous collection of dementias, some of which we haven’t yet figured out. And I want to just say that, okay, this is great because now we’re starting to figure out what some of these other unknowns are.

Sterling 13:57

Yeah.

Alex 13:58

Maybe, but I ran into Ken Kavinsky in the hallway and he said, well, here’s the skeptical view, right? Which is that we are just not comfortable as doctors saying, I don’t know what it is. So we gotta find some protein that accumulates that may or may not be actually related to the disease itself, and that we can identify a protein so that we can test for it, and then we can administer a medication to treat it that may or may not be successful.

Eric 14:25

That sounds like Ken.

Alex 14:27

Yeah. Right. Right. And maybe I’m, you know, amplifying what he said a little bit to make the point, but is there, is there room for skepticism about, is this actually, is it ready to be a disease, you know, or is this too early? Where are we on the spectrum here? And what are the forces that are driving this diagnosis?

Sterling 14:50

First of all, I think what you just described is like That’s science. We, you come up with a hypothesis, you put it forward, you develop some criteria, and we see if it works. And LATE is sort of in that stage where we’re iterating and developing as we go. And I think the clinical criteria that we have now, they’re going to evolve as we get more information and get more biomarkers.

But what the pathologists continue to tell us and what that literature is really evolving into is that this is something consistent. There’s all kinds of neuropathologic forms of this, and there’s ways that the pathologists can tell when it’s present. And then now it’s a matter of relating this to the various symptoms that we see.

Eric 15:40

And do you have a sense of like how deterministic is it to have these misfolded proteins in different places? Like the Is it like if you see it, you have cognitive impairment or you will develop it relatively shortly? Where does that fall as far as where we are with this disease?

Sterling 15:59

I think we’re still getting there. How much of a protein constitutes a symptom? You know, how much of, how much of a concentration? I don’t think we know that yet.

Eric 16:10

Yeah. I mean, I think we’re, we’re in kind of the same place as we continue to learn about all of these other biomarkers. how deterministic is it? I wonder if we can then just describe, A, what are the common symptoms that we see with LATE?

Alex 16:28

And then how are those different from Alzheimer’s?

Nate 16:30

Yeah. Well, I mean, that’s the key part is that it actually looks very similar. And so this is an individual who comes in saying, I’m specifically about short-term memory. I’m feeling very forgetful. I can’t recall Conversations. I can’t remember. I’m repeating myself. It, in all regards, it looks like someone with Alzheimer’s disease. And, but we, what we’re seeing, and now because of the advent of biomarker testing in living people, people can come in with those complaints and everything that’s available to us is negative. They do not have Alzheimer’s disease.

They do not have amyloid and tau, but they’re continuing to progress. So something is clearly happening. And it’s at a greater trajectory than just perceived normal aging. And then they’ll go to autopsy and they’ll find these TDP-43 proteins. And so from a clinician standpoint, it doesn’t necessarily change how we’re managing things right now, but it does change conversation. And I’m sure we’ll get to that later in this podcast.

Alex 17:35

Yeah.

Nate 17:36

But in general, it’s an older person over the age of 80, but I certainly think I have patients in my 70s like this. And they’re going to have a very memory-specific complaint, really not that many other complaints, not language, not word finding, not executive dysfunction. And their decline is incredibly slow. And I think historically we would look at that person and say, ah, you must have some other genetics or you’re really resilient. Good for you. But your changes are so slow. I’m very happy for you. But we wouldn’t have an answer and we still don’t have an answer.

Eric 18:06

And probably before biomarkers, we would also just die. diagnose them with like a mild Alzheimer’s disease.

Alex 18:12

Right.

Nate 18:12

Right.

Alex 18:12

And now you’d, you’d, you’d first check to see if they have Alzheimer’s disease using some, what, what would you do?

Eric 18:19

A biomarker.

Alex 18:20

Biomarker, most likely. And you would find amyloid’s not elevated.

Nate 18:26

Right.

Sterling 18:26

And when amyloid is—

Alex 18:28

yeah, go ahead, Nathan.

Nate 18:29

Well, you can’t have both though, and that we wouldn’t know that clinically in a living person, but I mean, I have a handful of cases that I keep I keep in a separate file on my electronic record, medical record of people who have, are amyloid negative. They have cognitive, thorough cognitive testing that shows a memory-specific impairment. They’re declining slowly and I’ve ruled out everything else. And so I’ve told them, I believe this is late. And so I have these conversations in clinic.

Alex 18:58

Yeah, because you can’t, the diagnosis itself is made in pathology. On after the patient has died, right?

Eric 19:08

You can’t, there’s no biomarker that for—

Nate 19:11

There’s no biomarker for it.

Sterling 19:13

But yeah, there’s no smoking gun biomarker for it right now. But what does help, there’s, there’s some associated features that give us, that point us that way. Like Nate said, not just memory loss, but on MRI they’ll have hippocampal atrophy or somewhere else in the medial part of the temporal lobe. And their amyloid proteins will be kind of in the moderate range or less. If they have florid amyloid and tau signals in their brain, then that may be explaining their disease. And the conservative message there to the patient would be that Alzheimer’s is driving this.

Eric 19:51

Hypothetically, in the future, if you could test for TDP-43 or the misguided version of it. Is it very specific for LATE or do we see it with other diseases?

Sterling 20:03

That’s, that’s something that our field is grappling with right now. TDP is involved in 97% of ALS cases have TDP involvement and half of the frontotemporal dementias involve TDP-43. We just don’t know which half. So we really need these biomarkers. And we don’t know if it’s, if it’s going to be like the tau where we’re going to have a specific tau marker for one tauopathy. I’m talking about Alzheimer’s as a tauopathy now. You can do these, the PET scans are very specific to Alzheimer’s, but they don’t really light up when a person with a frontotemporal tauopathy is in the PET scanner. So we don’t know if, if the current biomarker strategy is going to work for all these TDP.

Alex 20:54

Yeah.

Sterling 20:55

variants, or if we will have to, we just don’t know what it’s going to look like, but we’re there. There’s some very good early leads on this.

Eric 21:03

And tauopathy means there’s tau buildup, abnormal tau buildup in the brain.

Sterling 21:08

Yeah. Yeah. And so that’s not TDP, that’ll be tau, like Alzheimer’s is a tauopathy. And the other half of the frontotemporal dementias that are not TDP, those are tauopathies, usually what we would call 4R tau or 3R tau. tau, just different isoforms of tau. And so our PET scans that we have for Alzheimer’s and our P-tau blood markers that we love so much in Alzheimer’s, those don’t work on the other tauopathies.

Eric 21:36

Yeah. And then who gets LATE? Like how common is it and what populations?

Nate 21:43

About 4 up to 20%, they say, of just older adults. And then it goes, it can get as high as 40% when you reach above a certain age, you know, we think of 80, but it could be, you know, in the 70s. So that based on those estimates, you know, it’s a good number of people will have the protein, the TDP-43 protein, but we need more, you know, that 150%.

Eric 22:08

Is that 40% in all comers or just those with amnestic symptoms like you were describing, the memory problems? Do you know?

Nate 22:16

Clarify, but I’m under the impression those are people presenting with symptoms that they’re doing autopsies on and looking at.

Sterling 22:23

Yeah. And it goes even higher when you look under the microscope and they have Alzheimer’s proteinopathy, Alzheimer’s neuropathologic change, 40 to 60%, depending on the study, it gets to be pretty high. 40 to 60% have this co-occurring TDP disease in addition to their Alzheimer’s.

Alex 22:44

Uh-oh. This is really, we do need studies of mixed. Wow. Yes, we do. Yes.

Eric 22:51

Do they have those other pathologies too that you were mentioning, like vascular?

Sterling 22:55

Yeah.

Alex 22:56

Lewy body?

Nate 22:57

Yeah.

Sterling 22:57

There’s, uh, you could have all 4 or some mixture of those.

Alex 23:02

And then there’s probably a flip side too, where if you look at autopsies of brains of people who are cognitively quite functional, normal, you probably see some of these pathologies as well, right?

Sterling 23:17

We do. We see some of these pathologies and, and, and it’s really an important question. We don’t know how fast these diseases progress. We know this for Alzheimer’s disease. We can, we know how many seniloid units per year that an average person would, would progress by. But we have no idea For these other ones, we do know that the brain is a remarkably resilient organ and it takes a hit before— it takes quite a lot of this pathology to happen before symptoms occur.

Eric 23:52

Okay. So I can imagine, I’m just thinking my brain, I got a couple of buckets going on in my brain. You have these older than age of 80, they have cognitive symptoms, That’s mainly memory, amyloid negative, and then you’re thinking late. Is that right? Am I getting that bucket right? That’s pushing us to— is there anything that we should do in that group where we’re thinking this is probable late? Like, is there any drug treatment or is there any— do any of the amyloid antibodies work or, you know, the Aricepts of the world, the cholinesterase inhibitors?

Nate 24:30

Well, I mean, Eric, you’re a geriatrician, so we don’t just jump to drugs here, but—

Eric 24:34

Oh, good answer.

Alex 24:36

He didn’t fall into his trap.

Nate 24:38

You wouldn’t, and you wouldn’t think of anti-amyloid therapies because there’s no amyloid there, right?

Eric 24:43

There’s nothing to get rid of.

Alex 24:44

Right.

Nate 24:45

There’s nothing to get rid of. I think it’s more of this counseling conversation with the patient who already has, in this situation, they would have MCI or dementia anyways. They’re going to be focusing on the symptoms. They don’t care about the terminology per se. They want, what can you do to help me? And that’s where we talk about our lifestyle. That’s where we talk about routines and structure and support and all the things that we know are meaningful and helpful for both the patient and their family.

However, the family might be very interested to know if this is truly LATE and not some form of Alzheimer’s, because there’s, you know, when people have Alzheimer’s disease, they think of their own inheritance and what that looks like. And so, but I also think it’s counseling on if it truly is LATE, This is probably going to be slow. We don’t hear about rapidly progressive late, at least not now. And so I think people can feel a sense of reassurance, at least some of my patients have, in not only validating—

Eric 25:40

Like how slow does it eventually turn into like more advanced dementia or is it just like a very slow…

Alex 25:48

Oh no.

Nate 25:49

I mean, it progresses.

Eric 25:50

Yeah.

Alex 25:51

It progresses.

Nate 25:51

And frankly, other things could happen too. So you could have a stroke. They develop Alzheimer’s during the interim, but the people that I think I’m treating that have LATE, it truly is incredibly slow and people are just really appreciative. And I think people like knowing, oh, okay, it might be this new thing that we’re thinking about. And that would explain why we’re not seeing, quote, the typical case of decline.

Sterling 26:15

Yeah.

Nate 26:16

And I think in that regard, there’s personal utility to families and patients hearing this. And to Ken’s point, it’s okay to say, I don’t know. I know it’s not Alzheimer’s based on this, but it could be this. And my patients have been very content hearing the, I don’t know, but it could be.

Eric 26:34

Do you ever use— I’m going to go back to the pharm part. Like, do we ever use memantine or Aricept in this population?

Nate 26:44

Yes, because I think of those drugs as nonspecific. and, and palliative. And I will make that case over and over again.

Alex 26:51

Yeah.

Nate 26:51

That if it’s really just about quality of life and symptoms, and these medications were to reduce the frequency or severity of symptoms, then yes, I think that that could be meaningful to some for a short period of time. But it takes time to have that shared decision-making conversation. But yes.

Eric 27:08

And I guess, Sterling, if we actually thought about this from an evidence-based standpoint, from the original cholinesterase inhibitors, memantine trials, we actually don’t have biomarkers from there. So it probably was a mixed bag of patients with Alzheimer’s-type dementia that they were studying. Is that right?

Sterling 27:29

Oh yeah. We were so hobbled back in those early days. We did, we had no idea. I think that really explains the lack of treatments over the those, those 20 years before lecanemab and donanemab got approved, yeah, we were flying blind in a lot of cases.

Eric 27:47

Do you think if there was a drug that cleared TDP-43 like it clears amyloid that it would work, or we just absolutely just don’t know?

Sterling 27:57

That’s the million-dollar question. We need to get to that place. We need to identify targets, these drug targets, and Try these things out. But before we do, we need to know who’s got it. And that’s the catch-22 that we’re in.

Eric 28:14

Yeah.

Sterling 28:15

Yeah. We don’t have a biomarker to tell us who’s got it.

Alex 28:18

So on average, I’m hearing that LATE progresses more slowly than Alzheimer’s disease progresses. That while Alzheimer’s disease can progress slowly, on average, Alzheimer’s disease progresses faster than LATE.

Sterling 28:35

That’s right.

Nate 28:36

Yeah.

Alex 28:36

And that patients may have much, a much longer life expectancy with LATE than they do with Alzheimer’s disease, to put it another way.

Sterling 28:47

That seems like a fair statement.

Eric 28:48

Yeah.

Alex 28:49

Maybe more likely to die with LATE than of LATE, potentially, maybe, given that it, you know, it’s so common in advanced ages and people have other conditions in advanced ages.

Eric 29:01

So that feels like the easy bucket for me, these people who are amyloid negative. But if they’re amyloid positive, if it really is that common just in people who are amyloid negative, I’m assuming it’s just as common in people who are amyloid positive. So that probably means that a lot of people who were also saying have quote unquote Alzheimer’s disease, maybe we should put those in parentheses from now on, have all of these underlying other proteinopathies. Is that fair?

Sterling 29:33

I think so. And when those are present, then we don’t have, you know, LATE is typically thought of as this indolent, slow progressor, but if it’s co-occurring with Lewy body or co-occurring with Alzheimer’s, then that progression rate’s going to be a lot faster. Is it fast? But it seems to be a lot faster.

Eric 29:54

Is it faster than just LATE itself, or is it faster than just having Alzheimer’s by itself?

Sterling 29:59

It’s faster than having Alzheimer’s by itself.

Eric 30:02

Oh, so the combination now — do we see that with other mixed dementias like vascular and Alzheimer’s disease? So the combination of these multiple insults increasing the speed of the disease progression.

Sterling 30:16

That’s right. When you have Alzheimer’s plus vascular, your progression’s going to be faster. If you have Alzheimer’s plus alpha-synuclein, your progression’s going to be faster. Okay.

Eric 30:30

So we have this bucket now where they’re amyloid positive, but we can’t rule out LATE. So do we know anything about like how, let’s say that amyloid antibodies work in this population, or we, that’s, we also don’t know.

Nate 30:47

I mean, we don’t know that either for Lewy body disease, you know, and vascular disease to some degree.

Eric 30:57

It was a more pure population enrolled in these studies, right?

Nate 31:01

Well, I just think it speaks to this fact that when we tell someone, okay, you have mild cognitive impairment, Alzheimer’s disease is the most likely cause. There has to be this space of, but there could be other things too that we have yet to be able to detect that we don’t know even exist. Because the brain is still sort of this, you know, it’s this last frontier of our true understanding.

And so if we leave that door open to, there are lots of things that could be happening. We believe in this LATE, this alpha-synuclein, we believe in these other proteins, we just can’t detect them. They could be present, may not be, but we’re leaving that possibility.

Eric 31:40

Yeah.

Sterling 31:41

A lot of what we know about the longitudinal nature of LATE and its amplifying effect on Alzheimer’s, if they happen to have both, A lot of this has come from the knowledge that we’ve gotten from the Alzheimer’s centers where you’ve got a group of very generous patients who donate their brain. We look at their brain, but they also have had maybe 10, 15 years of observations when they were alive and participating in the center program, and they would get their cognition measured every year. So we can take the information from the actual brain, from the microscope, the late diagnosis, the Alzheimer’s diagnosis, and then work backward. And a lot of this has come from that kind of experimental design. It’s not ideal, but it’s not a biomarker. That’s what we’ve gotten so far.

Eric 32:34

Can I ask you from a generalizability standpoint? So historically, a lot of these memory centers were wealthy and white and well-educated. I guess that’s 3 W’s. Is that changing? And how generalizable are these studies even around late to a more diverse audience or more diverse population?

Sterling 32:54

I would just maybe just offer our experience with CLARiTI with an I at the end. When we approached the Alzheimer’s centers and we said, is this something you want to do? And what do you think is going to be important? All the directors almost to a T would say, We want this study to be diverse. We want it to be generalizable. And in CLARiTI, we’ve, we’re about to enroll our 1,000th participant this month. 50% of our participants are from a diverse group.

Alex 33:24

Wow.

Sterling 33:25

36% are from these race and ethnicity defined subgroups. And then we’ve got a, we’re looking at education levels as well as how rural their zip code is. And we’re looking at all those things, but 50% are…

Eric 33:41

Broad view of diversity too.

Alex 33:43

Yeah.

Sterling 33:44

Yeah.

Nate 33:45

I think what Sterling’s pointing to is really important. You know, every center’s going to have their own limitation based on the population that surrounds them. I think a lot of centers still struggle with this idea of rural versus urban or just geographically. Yeah. But there are 35, 36 centers across the country, each focused on something different. And so whereas Wisconsin might be, you know, we have great participation, we’re having increasing participation with rural, African American, Native American, but others might be focused on Latino in California.

They might be focused on East Asian. So when you look at all of them together and NACC, which is the National Alzheimer’s Coordinating Center, which really collects all of the data from these centers, there’s over 10,000 human beings who are, you know, collectively representing more of a diverse sample. So when you analyze that as a whole, then you start getting better representation. It’s still not perfect. I don’t think anyone thinks it is, but it’s improving. And so I think they’re starting to have, when we say these things of like, this is what we’re seeing, it is starting to feel more generalizable than one single center or one single study.

Eric 34:54

So, uh, I’m gonna ask you another, Increasingly controversial question. So let’s say you look at the donanemab study published in JAMA, I think excluded people older than age of 85. Leucanemab excluded people over age of 90, but there were few people who were a lot older in that study. Given that LATE is very common in those who are older than 80, how generalizable do you think those studies are given that, that there’s an increased Mixed picture as you get older for cognitive impairment, dementia.

Nate 35:30

I mean, I think that’s a limitation of these trials. Whenever you have a cutoff or you just don’t have enough—

Eric 35:36

Do you bring it up with patients?

Nate 35:38

What’s that?

Eric 35:38

Do you bring it up with patients? Like, we don’t know.

Nate 35:42

Yeah, I bring it, I bring it up with my, my patients of color as well, that this is what the study showed, but there weren’t many people that looked exactly like you. They didn’t look exactly like me. does that really deter their willingness if they’re already interested? In most cases, no. I think it really does motivate people to join research to get that representation.

Eric 36:03

Yeah.

Nate 36:04

But I think, and you guys see this too in your clinics, you know, when you have for years not had anything to offer people that would modify the biology and the course of disease, and then you do have these trials that were done as they were supposed to be done and show even a modest benefit, I think people are willing to say, okay, this is imperfect science.

Sterling 36:25

Yeah.

Nate 36:25

We need to do better in, in better representation. But based on what I’m seeing, okay, I’m gonna make this decision one way or the other.

Eric 36:34

Do most agree to take the drug in your experience or?

Nate 36:37

No, no, not in my clinic. I, I, and certainly I have, you know, a lot of older patients as a geriatrician. And many of them will say to me, I feel like I’m doing pretty well and I’m not wanting to address the hassle factor of going to the infusion center. Yeah. Or address the risks that you talk about, but let’s, let’s keep me posted on what’s happening in the field. And, and so, no, the majority of mine are not. There’s still a good percentage in our program that do. And I think they feel good about these decisions, you know, probably because we spend so much time going over this discussion.

Eric 37:12

And Sterling, I’m going to ask you the same question, especially coming from a mixed dementia standpoint. How pure Alzheimer’s do you think that sample was that they studied in lecanemab and donanemab versus there’s still probably a lot of mixed dementias going on? And that probably maybe is contributing to the fact that it didn’t work as well as—

Alex 37:36

It removed a lot of amyloid.

Eric 37:38

But people still continued to progress. Like, where do you think it falls in that spectrum?

Sterling 37:43

Oh yeah, it, it did hobble the clinical outcome. There was a 26% reduction in lecanemab and 35% in donanemab. And if those had been pure cases, I bet those, the percent reduction rate of change on the Clinical Dementia Rating scale would’ve been more pronounced. Well, we just saw last week in London, there was a new tau phase 2 that Biogen presented, and they did take the time to measure copathology. They, they, they took spinal fluid and they did the, um, seed amplification test for alpha-synuclein.

The only reasonably good marker for Lewy body, uh, proteinopathy that we have is CSF. But they did that in their study and they found that 30% of people had synuclein in their, in their supposedly very clean study of Alzheimer’s disease. And so it’s, it’s going to be present. We just have to figure, we got to be clever enough with our experimental designs to just know that it’s going to be there. And just the pharma companies are starting to do that now.

Eric 38:53

So my probably last controversial question.

Alex 38:56

And then I got one that’s less controversial.

Eric 38:59

Given that we are not like, we are like, I don’t know. I just did a PubMed search for LATE. The first time it came up, it was 2019, as far as the full title for LATE, which I’m not going to repeat because I won’t remember. Like we are in a phase, we were learning so much and we’re learning so much that there may be these underlying proteinopathies that it may be more confusing than just the single one. How important is it that we, like, there’s 2 camps, it seems like right now.

One camp you have, like, saying that we are going to diagnose Alzheimer’s just based on tau and amyloid proteinopathy. And then you have Alzheimer’s disease if you’re positive versus another camp is no, you know, the science isn’t quite there yet. We’re still going to call this a clinical pathological construct and maybe just call it a proteinopathy instead. Like they have this. amyloidopathy that may be resulting in their cognitive impairment. Where, where do you fall in those camps, Nate? All right, Sterling.

Sterling 40:01

Yeah, I’ll, I’ll start. Nate’s the sage one here. He’s got better, more circumspect advice than me, but I am very much of the camp where we have to get more precise as in our constructs. And so I would be in favor of splitting these into into the various proteinopathies that are there. That’s how we’re going to treat these things.

Eric 40:22

Yeah.

Sterling 40:23

What do you think, Nate?

Nate 40:24

I mean, we’re from the same institution and we conduct research together, but Eric knows my answer because he and I talk about this frequently and via emails.

Eric 40:35

I’m going to be on Nate’s podcast. We’re recording tomorrow, Dementia Matters. Go check it out.

Nate 40:41

That’s right. And we’re going to talk about the importance of assessing you know, clinical symptoms and function, but I still believe biology is biology. And we define Alzheimer’s disease as the presence of elevated amyloid and tau neuropathologically. We can identify that in living people. Just because they don’t have symptoms does not mean that biology is not there. I think from— we have to separate the science from the human experience. And of course, we care the most about the human experience.

Speaker 5 41:11

Yeah.

Nate 41:11

But by understanding the science and intervening with the science, we can improve that human experience. So I’m very comfortable with this concept of preclinical or asymptomatic or presymptomatic. And I say that to my patients too. I, I, I just think that we, we have to disentangle that part of it.

Eric 41:31

Yeah.

Nate 41:31

And I don’t just, I, I completely understand the people who are wanting to combine it because I love the fact that they care the most about the person. But I do think we help the person the most, especially the future, when we start looking just at the biology too, separate from symptoms.

Eric 41:47

Yeah. Why not both? Tune into Dementia Matters hosted by Nate Chin.

Alex 41:53

Read When Memory Fades, also by Nate Chin, and look for the results of the CLARiTI with an Eye study. Last question from me before we go. What is your blue sky here? Like, if you cast your mind into the future, I’m sure if you cast your mind like 200 years into the future, to be sure, we’ll have cured all these things. We’ll have figured it out, but let’s talk something more in immediate future, like 5, 10 years. What’s the blue sky of where we are at that time point in terms of like the dementia diagnosis and treatment landscape?

Nate 42:30

I’m going to go with 10 years to be a little bit safer. And I’m going to say my blue sky is being able to identify the multiple different things that we believe are happening in the brain so early that we can then have multimodal therapies to intervene there and therefore prevent the onset of symptoms and/or just delay progression of symptoms so that people die of something else besides a neurodegenerative disease. I would love for people to not have to go through that end stage of dementia and instead have something else like other Americans where it’s Cardiovascular or cancer or something else.

Sterling 43:10

Well said. I agree completely with Nate.

Nate 43:12

Great.

Eric 43:13

How about we get a little bit more blue sky then?

Alex 43:21

(singing)

Eric 44:11

That was great. It’s a good song.

Alex 44:14

Yeah, yeah, it’s a jam. I wish I could do all the little licks. Sterling can probably do the licks.

Eric 44:20

Next time, Sterling will play the song.

Alex 44:21

Sterling, can you do the licks?

Sterling 44:22

Well, I used to be able to do it, but yeah.

Alex 44:24

Yeah.

Sterling 44:25

That was great.

Eric 44:26

Sterling, Nate, thanks for joining us.

Sterling 44:28

Yeah, happy to do it. Hopefully there’s something in there that’s, that’s useful.

Eric 44:32

Oh, that was fabulous. And thank you to listeners for your continued support.

This episode is not CME eligible.

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