Eric: Welcome to the GeriPal Podcast. This is Eric Widera.
Alex: This is Alex Smith.
Eric: Alex, we had a little hiatus, but we’re back.
Alex: We are back. We’ve vacationed. Been to London. I’ve been to Kauai. Life’s good. Back in studio.
Eric: I have been eagerly awaiting this podcast. But before we go to the topic, who do we have with us today?
Alex: We have an all-star cast. We have Heather Whitson, who’s a Geriatrician and Professor of Medicine at Duke, and Director of the Duke Center for the Study of Aging and Human Development, and Co-Leader of the Duke UNC Alzheimer’s Disease Research Center. Heather, welcome to the GeriPal podcast.
Heather: Thank you for having me, and thanks for covering this topic.
Alex: We’re delighted to welcome back Jason Karlawish, who’s a Geriatrician and Professor of Medicine at Penn and Director of the Penn Memory Center. He’s been on several podcasts about this issue. Jason, welcome back to GeriPal.
Jason: It’s great to be back, Alex and Eric. Hi.
Alex: We have Lon Schneider, who is Professor of Psychiatry, Neurology and Gerontology at USC and Director of the California Alzheimer’s Disease Center. Welcome, Lon, to GeriPal.
Lon: Thank you.
Eric: So we’re going to be talking about redefining Alzheimer’s disease, but before we go into that topic, Heather, I think you have a song request.
Heather: I’m requesting the song Don’t You Forget About Me, which is one of the things that I think matters most to patients and families living with Alzheimer’s disease.
Jason: A bit of an irony there is that Simple Minds is the band. [laughter]
Heather: Good point.
Jason: Oh, well. Because it is ultimately about the mind.
Alex: That’s right.
Eric: So we’ve got a big topic. We’re going to be talking about redefining Alzheimer’s disease and a push to move from a clinical syndrome to a biological definition. There’s a lot been going on in the last six months with NIA and the AA putting out draft recommendations about this issue. But I wonder if even before we talk about how do we redefine Alzheimer’s disease, maybe we could just chat briefly about how is it currently defined? Just to let you know, I did look it up today. As a geriatrician, you’d imagine I’d know, but I decided I’m going to go to the CDC website. They say, “Alzheimer’s disease is the most common type of dementia. It’s a progressive disease beginning with mild memory loss and possible leading to loss of ability to carry on conversations,” blah, blah, blah. Alzheimer’s Association says, “Alzheimer’s is a type of dementia that affects memory, thinking and behavior.” I’m going to turn to you, Jason. How do we currently define…? Again, those are for lay public definitions.
Jason: Yeah, one word and only one word there is driving me nuts, and it’s “type.” I know everyone talks about Alzheimer’s as a “type of dementia.” I would say Alzheimer’s is a cause of dementia, just like Lewy body disease is a cause of dementia, just like progressive supranuclear palsy is a cause of dementia, syphilis in its tertiary state. I guess what I’m getting at is that there’s this disease that can cause dementia, and one of them is Alzheimer’s. I haven’t exactly answered your question, but the reason why I’m hanging up on that word type is it’s getting us back to 1980s, a la the music we just heard, 1980s nomenclature that to have Alzheimer’s, you had dementia. And the two were sort of intermeshed even to the point in the eighties, the thought was all dementia is Alzheimer’s or it’s some medical illness or combination of other stuff that’s not about it. I think we’ve moved far away from this idea that you have to have dementia to have Alzheimer’s and that it is a quote type of dementia.
Eric: What do you think, Heather?
Heather: I have thought a lot about this the more that I work with neurologists because I think there was some epiphany that I had about a decade ago when I realized that we didn’t mean the same thing when we were saying Alzheimer’s disease. This was a decade ago, and I realized that as a geriatrician when I was talking about Alzheimer’s disease, I was picturing in my mind people that have dementia and people that I treat with sometimes very advanced dementia. My neurology colleagues, what they were picturing in their mind was plaques and tangles and almost seeing the person there, but seeing as if they could see inside their brain to the slides and the plaques and the tangles. The truth is, I kind of think we were both right and it was a helpful epiphany to me to kind of knit those things together.
But it was also helpful to realize that, again, as a person whose mission now is to try to prevent and cure this disease, I think it’s really important to think about the plaques and the tangles. But I think what Jason said is also really important, that the plaques and the tangles are the disease that cause the dementia, which is the thing that people really care about. I understand the reason for defining it based on the biology and the pathology. I also think that there are whole swaths of people, not just physicians, but also lots of patients and families who for many, many years weren’t thinking plaques, entangles at all when you say the word Alzheimer’s disease. And we can’t just ignore that that link is not there in the minds of a lot of people who are important stakeholders in this field.
Lon: I was about to disagree with you, but then I got lost in what you were saying.
Heather: Lost in a bad way or a good way? Lost like it didn’t make sense? [laughter]
Lon: In a good way.
Alex: Like the Breakfast Club. We’re trying to reach across these differences in specialty and professions and background to understand these things. Go ahead, Lon.
Lon: If we stay on the idea of plaque and tangle pathology or plaque and tangle disease, using the term loosely, we’ve got the 1906 definition of Alzheimer’s disease, which is still the current diagnosis. We apply it to somebody who has pretty much a cortical dementia with memory impairment, who’s generally old and who on autopsy, or for that matter on a PET scan, has plaques and has tangles and loss of neurons. That’s a definition. The idea though is that you also need to have some symptomatology to make it a disease. You’ve got to have some cognitive impairment. Some impairment, that makes it a disease over the observations of pathology. That’s in my view as analogous as to any other illness. You can easily have fibrinoid necrosis of your kidneys and not have hypertension, but the pathology of hypertension is most commonly associated with fibrinoid necrosis.
Heather: What about cancer, Lon?
Jason: You could have hypertension and have no signs and symptoms. Indeed, wasn’t it the silent killer?
Lon: Well, there, the sign is the measurement of the high blood pressure.
Jason: [inaudible 00:08:45] which is the pathophysiologic measure, like a measure of, say, well…
Lon: Like a temperature and you may or may not have… That is the sign. That is the symptom.
Eric: Well, is the analogy here-
Heather: What about cancer?
Eric: Part of the question is, is it like cancer where you see some abnormality, you know that, most likely, that cancer will get worse over time. You can see it. Or is it more like, let’s say, hypertension where you have an abnormal value which may lead to another disease? Should we be calling this beta-amyloidosis which will lead to, once they have symptoms, Alzheimer’s disease?
Jason: I think that’s the conceptual issue that the field’s struggling with. I do. Which is, is amyloid a abnormality along a pathophysiologic continuum such that amyloid, like glycosylated hemoglobin, we all have a level of glycosylated hemoglobin. If we didn’t, we’d be dead. But there’s some level of glycosylated hemoglobin which very neatly correlates with abnormal glucose tolerance, which is diabetes, or is amyloid like mitotic figures spreading beyond the basement membrane? By definition, pathologic, that is cancer. I don’t get in these new criteria, where is amyloid? Is it a point along a continuum like hemoglobin A1C? That is to say there’s a level of amyloid which would be acceptable as part of just our physiology? Or is it mitotic figures, the mere presence is disease? I don’t know. I cannot tell from the new criteria.
Lon: From the new criteria, yeah, it could make you very dizzy. But from the standard criteria, it’s like you can’t have Alzheimer’s disease, dementia, Alzheimer’s disease, mild cognitive impairment unless you have plaques and tangles. Unless you have plaques. You need the plaques to have that illness. However, you can have plaques and tangles and not have dementia.
Eric: Can I take a step back real quick just for the audience? I’m going to let Heather go next. Just for the audience, we’re talking about, the NIA and the AA have been doing these frameworks since what, 2011? Mainly for research. There’s new drafts out there that’s pushing for changing to a biological definition where you don’t have to have symptoms to have a definition or be defined as having Alzheimer’s disease. Specifically their position is beta-amyloidosis. This is directly from their article draft, which we’ll have on our website: Beta-amyloidosis, having amyloid in your brain or in high levels in your plasma defines the initially detectable stage of Alzheimer’s disease. The disease exists within the earliest manifestation of AD pathophysiology can be detected, even though the onset of symptoms may be years in the future. I think that’s the underlying-
Lon: Pick up that implication. They twist it and they say, “Even though the onset will be in the future.” How-
Eric: The symptom onset.
Lon: … even though there won’t be onset because most people won’t develop symptoms.
Eric: Yes. We can talk about the natural history. Go ahead, Heather.
Heather: That’s really what I want to stay with is I am very curious Lon and Jason’s thoughts on this. The asymptomatic person that has, and we could even get more specific than amyloid, but has, as Jason said, pathologic amyloid-42, A-beta-42 that is perivascular and certainly looks like it’s on the track to eventually being what we would all agree is Alzheimer’s disease and that that person likely is going to develop cognitive symptoms, but they haven’t now. The value versus the harm of labeling that person today with Alzheimer’s disease, the same way that I don’t have any symptoms, but if I had a colonoscopy in a couple of months and they determined that I had a pathological tumor, I would not reject the idea that I had cancer. I would say, “Yes, I have cancer even though I’m not having any symptoms. Pathology says I did.”
What do you think is the harm and the benefit of shifting our thinking so that we would find a person that had, and right now we might have imperfect biomarkers, but let’s say we had more perfect biomarkers that could say, “This does look like this is amyloidopathy that is consistent with what will eventually develop into Alzheimer’s dementia”? Would you still reject the idea of calling those people Alzheimer’s disease before they have symptoms?
Jason: If the actuarial data that described beta-amyloidosis in the brain was sufficiently compelling, of the likelihood of developing dementia, you could make the argument that I’ll call that the disease, period. Of course all the things that flow from that that you’re gesturing to, Heather, follow namely the burden of that label on someone’s sense of self-efficacy, how they’re treated by other people. In a word, the stigmas that surround the disease. I think I’m willing though to separate those very important social and cultural issues from what does the biology and the science tell us? I just don’t think that the biology and science that surrounds beta-amyloidosis alone is sufficient to rise to the level I’m going to call it a disease.
I think that the actuarial data are compelling, that elevated amyloid alone in some individuals can lead to downstream dementia. But I think defining a disease on actuarial bases alone is very difficult for reasons related to cohort, bias, et cetera. The strongest evidence, I think to help define a disease on the basis of, if you will, a factor only like lipids, for example, elevated lipids is the results of an experiment that if I reduce that, if I intervene, I can change the natural history of outcome. That’s what got hyperlipidemia turned into hyperlipidemia. So too systolic hypertension in elderly people, clinical trials. I haven’t yet seen those clinical trials with beta-amyloid in asymptomatic individuals to allow me to reach that conclusion. I’ll stop there.
Lon: Let me add to that with a bit of a disclosure, and that is we are NIA funded to develop amyloid vaccines, and I do that and I endorse that. I said, “Let’s give a try to amyloid vaccines that will essentially bust plaques in people who are asymptomatic, maybe even in people who don’t have plaques.”
Jason: That is a vision of a future.
Lon: And that is from the point of view that you can’t have dementia, you can’t have cognitive impairment, you can’t have this Alzheimer’s disease cognitive impairment if you don’t have plaques. Now having said that, back to exactly what Jason said. We are confronted with the idea that a bunch of people in their seventies without cognitive impairment, that 40 or 50% of them will have plaques, do have plaques, and that the vast majority of them do not go on to develop symptoms. A somewhat lesser proportion of those people could be said to have the equivalent of neurofibrillary tangles of tau tangles. They also don’t have symptoms. A few more of them will develop symptoms than the people who have amyloid alone. Yet still, most of them will not over the course of the rest of their lifetime.
The next part to this is that the research that’s actually done on this where we’d say things like, “Oh, well if you have this amount of amyloid, you are somewhat more likely to progress to Alzheimer’s disease than if you have a little less amyloid. If you have amyloid and tau together, you’re somewhat more likely than if you have a lot of amyloid alone. This is very serious because you will then decline more probably in terms of cognitive impairment.” But then when you look at those studies carefully, you see something else. That is that the studies are inherently flawed because the people who have a lot of amyloid score somewhat more cognitively worse than the people who have a little abnormal amyloid. The people who have amyloid and tau score a little bit more cognitively worse than the people who have a lot of amyloid. You can measure this. They’re not cognitively impaired, but you can measure this. What you see is that those are the people who then progress to develop Alzheimer’s disease. You’ve got to-
Jason: Develop dementia.
Lon: Dementia. Thank you, thank you. And further cognitive impairment. In my view, you can’t have this illness unless you start to show symptoms. If you don’t show symptoms now, it’s clearly a risk factor, but your likelihood is much, much lower. That conflation there is a real problem. I’ll just stop with one sentence. What the Alzheimer’s Association in this group is trying to do is reductionistically reduce Alzheimer’s disease to amyloid equals Alzheimer’s pathology. Amyloid plus tau biomarkers equals Alzheimer’s disease. That’s all you have to know. That’s the disease. It exists on a continuum and knock your socks off. I think that is inherently limiting, inherently reductionistic, and then doesn’t take into account all the other pathology that occurs in our brains that is related to aging and other illness.
Alex: I’m probably the person who knows the least about this in this podcast because I know Eric’s been really interested. Of course, the three of you are directors of centers that study this issue are deeply involved. You know what Lon and Heather and Jason just said raises some issues for me that our listeners may be wondering about. One is, ought these social considerations, the stigma as Jason put it, play a role in determining how Alzheimer’s disease is defined, the very definition of Alzheimer’s disease?
Jason: What do you think, Heather, since you had raised it?
Heather: I think we have an obligation to do that. I think that it’s premature to push out a new revised framework. I say that as a person that probably, at least I think, I’m in a different part of the spectrum than Lon. I’m not quite sure yet where Jason is, but I’m more accepting of the idea that if we had a perfect biomarker for the kind of amyloidopathy that normally leads to Alzheimer’s disease, I would be okay calling that Alzheimer’s disease from a scientific standpoint in people who don’t yet have symptoms. I could see benefits to doing that for being able to target therapies if we had therapies and developed therapies that would be better.
The problem is I think we have an obligation to the living humans today to recognize that that’s a sea change from how most of the world thinks of the word Alzheimer’s disease. By rushing this into clinical practice and suddenly saying people that have positive amyloid based on an imperfect biomarker, especially now they have Alzheimer’s disease, I think we’re opening massive potential for harm and distress and predatory practices upon these people. That’s where I sort of just want to pump the brakes on taking what I see as a very helpful research framework rushed into clinical care-
Jason: I would say if I put my cards on the table, someone with cognitive impairment, whether it’s causing inefficiencies or disabilities in daily living as otherwise known as MCI or dementia, I think the role of biomarkers is very clear to help sort out what’s causing that problem. If it had elevated amyloid and meet other criteria, there’s even the treatments now available. That’s that. I think though, once we push into the space of someone who pounded with cognitive testing and monitoring is doing fine, I think considerations of saying, “Well, you’ve got Alzheimer’s elevated amyloid.” I think that the matters of cultural and social stigmas should be thought about, but if someone showed me that an intervention in those individuals could change the natural history of decline, I’d say, “Look, we’re just going to have to work through those stigmas because I’ve got some way to alter that natural history.”
And indeed, as we saw with HIV, there’s certainly still a stigma that surrounds HIV, but the ability to treat HIV very much transformed the nature of what it’s like to have that disease. We can go through any number of diseases where that’s the case, mental illnesses, et cetera. I’m not saying they’re stigma free. I’m not. But these will be ongoing cultural conversations. I guess I’m just sticking to the position that I would like someday to be able to diagnose Alzheimer’s as well as Lewy body disease, et cetera before someone has disabling impairments. I would, absolutely, but I don’t think that right now the science says that elevated amyloid alone is the label Alzheimer’s, which engenders the notion that it’s a valid construct. I don’t think the construct has been validated. I want to see results of studies like the AHEAD Study, Trailblazer-3. These are studies testing drugs in individuals who are cognitively unimpaired and yet have markers of elevated amyloid and or also tau. Those results will be very compelling to have me change my view.
Heather: You’re talking about intervention studies, and there’s a whole set of studies that I also want to see, which is just population studies of these biomarkers in observational populations of young people to understand how many of them have these biomarkers.
Jason: I’m with you on the observational data, but I think observational data alone to define a disease are very slender read. Having said that, clinical trials have their faults as well, but they’re very compelling experiments to validate causation. That’s what I find very compelling.
Lon: Back to the licensing of PET scans and amyloid PET scans, and the Alzheimer’s Association and definition. Everything is tied to the PET scan, to the amyloid PET scan, in terms of this kind of diagnosis. The amyloid PET scan itself was definitionally validated, if that’s a term, against pathologic specimens. It was imperfectly correlated with pathologic specimens. You take these people who are near death and you get a PET scan and you wait six months, eight months until they die, then you try to correlate this. And there’s a really, really, really great correlation, but it’s still only about 0.9 or 0.95. This is not good enough. Then you start going backwards. That is with one particular ligand. The other ligands are different and they will have different correlations.
The way to read the PET scan also vary. The way to administer the ligand, the tracer, also varies. The way to read it also varies and has error. Now that has become the gold standard. That has become the standard against which you then develop other biomarkers. You see the problem, each biomarker is in itself going to be imperfect against that gold standard. Not only that, it’s going to be even misleading depending on the population you use. If you use an older population with a high prevalence of amyloid, it’ll sound better than if you use the biomarker in 50 year olds. This is just mathematics.
Alex: Let’s be honest, probably 99% of these studies are mostly in white populations. Is that right?
Lon: I think before you get to that, they’re mostly in populations that are made to the extreme comparisons. Let’s get some people who are dementia from our research clinics, who have-
Lon: … and then let’s get controls. Where are we going to get controls?
Lon: Get alumni. We’ll get retired professors. Now you have this great, extreme comparison. Then there are variations on that theme.
Jason: All those issues that Lon has raised, I think the AB 45 and related amyloid scans and the tau scan, the one that is commercially available, I think the data support their use in individuals who have clinical disease with all the caveats around the potential. I think what you’re getting at Lon though is there’s still enough noise in the system to say it is a bold reach to use those results in individuals of younger ages who are asymptomatic and call that a disease. I think that’s where I think we’re struggling.
Lon: Even in older people, the standards become, in living people, it’s some sort of an amyloid PET scan. But this was validated against people who had basically a certain set of agreed upon pathologic criteria after they died for Alzheimer’s disease. Severely impaired people, because those are the ones who die. Let’s say the names of the criteria are variously rigging criteria or NIA criteria for the pathology of Alzheimer’s disease. Those two are inherently imperfect because the pathologist has made a diagnosis based on plaque tangles, loss of neurons, but also includes people who have vascular disease, who have other proteinopathy. If you look hard enough, you kind of find that this kind of pure Alzheimer’s pathology that was conceptualized more than a hundred years ago is really uncommon. It doesn’t really stand alone, so that some pathologists, Julie Schneider for instance at Rush University, likes to say that Alzheimer’s disease is the least common cause of Alzheimer’s disease, and she speaks at it from a pathologic point of view.
Alex: I’m going to set Eric up with a softball thrown over the middle of the plate here.
Eric: I need softballs on this one. [laughter]
Alex: As a lay listener who isn’t deeply invested in tangles and plaques, et cetera, I’m interested in hearing what’s the push behind this shift? What is the driving force here? Some deep suspicion and concern that money is the driving factor.
Eric: I think when I think about this, and would love your all thoughts, is that I do think there is a strong push, and this is just an example, I think it’s an exemplar of this push generally from industry to relabel or rethink thresholds for disease so more and more people have that disease. It is not just Alzheimer’s disease. Low T is a great example. Low testosterone. Now every older man has low T and new diagnosis. Diabetes, you see the same thing. You have pre-diabetes now.
The threshold is not just to define the disease but to change that threshold to more and more people have it, more and more drugs could be used. Then the question is, who gets to define these diseases? And if you look, who gets to define this, it’s pretty well documented. The who in the room who defines it is heavily industry biased. The NIA guidelines being drafted out, a third of the people in the work group are directly employed by industry, another third have significant conflict of interests, and the other third don’t.
Lon: Actually, it’s more than half when you include the 4 advisors and the 10 reviewers added to those 22 on the committee. Then you have to actually look at the document and ask, did any one of these 36 people read the document from cover to cover? Because it doesn’t read well.
Eric: They actually had to change the word guidelines in it because they can’t call it guidelines because this is not how you create a guideline. You’re supposed to have really good… There are now guidelines on how to make guidelines and you have to address conflicts of interest and minimize them. This is not how you do it with a third of the people coming from industry and making these guidelines. And this is, again, just an example. I wish it was just this, but we see this with a lot of these changes in thresholds of how we define disease.
Jason: Welcome to the world that we live in. Welcome to the world that we live in. It is a fact though that, and I think Jeremy Greene nicely documents this in his book Prescribing by Numbers, that a variety of diseases, particularly diseases that exist along pathophysiological pathological dimensionality, are in part defined by drugs. Because those experiments show that the actor being targeted, lipids for example, is part of the causal pathway to an undesired event. Now that’s just criteria and validation-
Eric: Can I ask real quick about that?
Eric: Does amyloid fit that? Because when you look at aducanumab, donanemab, it slows down the progression, but people still progress.
Lon: These drugs are perfectly designed. These are the best antibodies that you can ever imagine, several of them. What they do is that they kill fibrils, they kill plaques. That’s how they were designed and that’s how they work. These medicinal immunologists are just great. This is a success. Period. Now go on with that.
Jason: My point is, but the social political reality is of course that drugs are patented, inventions that are owned, the diagnostic tests similarly. All of a sudden you have this very interesting phenomena that occurred in late 20th century and into 21st century America, is that the definition of diseases is wrapped up in the business of developing drugs and diagnostics. That’s just the fact. I think that is a bit disturbing because the individuals who own inventions, O-W-N, have been part of the process by which we say that defines that disease. I do think that creates a little bit of disquiet where the borders between the expert physicians will decide what is a disease, freed of all conflicts, simply is a historical event. I do think that efforts to define diseases where they require tests that people own, the results of drug studies, drugs that people own, I think we have to pay attention to the fact that matters of ownership now are wrapped up in the definition of diseases. That is something I think we need to think about.
Heather: Can I make one more point on this topic?
Alex: No, please, Heather.
Heather: I completely applaud skepticism and paying attention to where the money’s coming from and who’s getting the money and what people’s conflicts are. Completely applaud it. A little bit in defense of the field though, I want to also say that I think that some of it is motivated by genuine belief out there that our best chance to help people is to detect them earlier and earlier in the disease process-
Jason: Yes. Absolutely.
Heather: … and before they have symptoms. Again, with cautions to pooled analysis and sub-analysis and comparing across different trials, but if you take all of the signs, they all point in the same way, which is that the earlier in the disease process and before, as early in symptomatology as possible, is the time that you get the best benefit from any of the antibody drugs-
Jason: From a public health perspective, that’s what you’d want as well. Why wait until you’re disabled to treat a disease? That’s a values perspective too. I agree. I would like the day where Alzheimer’s and Lewy body disease and FTLD are diagnosed before people have to surrender a certain degree of liberty and suffer impairments in their mind. I share that vision. It’s just that we’re doing it in the context of the social and political structure, which sometimes is not aligned with the interest of patients.
Lon: I agree with that, and maybe we can transcend back to drug companies and NIH and the Alzheimer’s Association.
Eric: And the lab companies. Quest just came out with a direct to consumer test kit for amyloid.
Lon: Look, we measure every biomarker we can. We invent biomarkers to measure as well. We’re all for that. That’s a research issue. If the Alzheimer’s associations should say something like, “Plasma A beta biomarkers are good,” and enough experts agree, then why shouldn’t a company that’s good at measuring stuff try to market it? That’s all Quest is doing, is trying to market an assay for a protein. Then the pushback is from some of the stakeholders, “Oh, well you can’t do that. You can’t just give that value to a patient. He wouldn’t know what to do with it. You need a specialist, a sub-subspecialist to be able to evaluate that.” You can’t even let attritions take a look at this measurement, and it costs $250 and all this other stuff that gets in the way of the ordinary business of medicine. I think that is really a side issue.
I think the main real issue here is that we allowed a definition in order to help develop drugs. We’ve allowed a definition of Alzheimer’s disease and a surrogate marker to take the place of a clinical syndrome and a clinical outcome in drug development. You have the idea Alzheimer’s disease equals amyloid. If you get rid of amyloid, you must no longer have Alzheimer’s disease, and so these several antibodies do get rid of amyloid and that’s good enough.
Heather: But what we’re all waiting for is show me Trailblazer-3, show me AHEAD, show me these other studies that would show that. We don’t have that. I don’t think that donanemab and lecanemab are compelling data to make that conclusion in people who lack evidence of elevated tau, who lack evidence of cognitive impairment. They’re-
Lon: The entire field changes if there are clearly positive studies-
Jason: Obviously. Obviously.
Eric: Jason, can I ask you a question? Because you brought up atherosclerotic heart disease. I would imagine if I have a drug that targets plaques, atherosclerotic plaques, it makes those plaques go away. I no longer have atherosclerotic heart disease after I’ve taken out-
Jason: No, you had it. You still have it. But because of treatment-
Eric: Well, I don’t have it anymore. They’re gone.
Jason: Well, no, you have the disease because you required treatment.
Eric: Well, if I had lung cancer and I got the lung cancer cured, I don’t still have lung cancer. I’m still not in… I guess the question is where we’re comparing this to other, we’re compare it to cancer, we’re comparing to diabetes, we’re compared to all these other things, but how much of is it really comparing versus, should we just separate? You have beta-amyloidosis, you have high levels of beta-amyloid, which may result in Alzheimer’s disease, which is a clinical syndrome, or are we saying this is like hypercholesterolemia? Is that it’s always going to be a cutoff. You’re always going to have some level of cholesterol which may result in some bad thing happening in the future, like cardiovascular disease, and you’re always going to have this-
Jason: Heather, you may have, please weigh in. I think this is what the field still needs to figure out.
Eric: Yeah. Heather, you have strong opinions on this.
Heather: Yeah, I’ve heard that. I’ve heard this debated actually of if they’re going to have to add a new classification for people who had Alzheimer’s disease, but now they don’t because their drugs removed their pathological features of it. It is a thing that has occurred to people, that if we end up with people who were biomarker positive people and now they’re not because they’ve been treated, would we say they used to have Alzheimer’s disease?
Lon: That’s right. I go to my group, I’m Lon Schneider, I am an Alzheimer’s survivor for five years, every day at a time.
Eric: I just imagine if Lon’s treatment comes true, you get your vaccine for Alzheimer’s disease, you get rid of all your amyloid. You don’t still have…
Jason: There’s another angle on this…
Eric: You still don’t have flu. If you’ve had flu two years ago, you don’t still… I guess you can call yourself a flu survivor.
Jason: I think we’re walking into an area that I think we haven’t talked about, which we ought to, which is the public health implications of a redefinition of disease on counting the disease and claiming what the burden of it is. I do think that that needs some discussion. To date, the way we, say, count Alzheimer’s is still the figures that are put forward by NIA and the Alzheimer’s Association is reliant on individuals having some evidence of cognitive impairment. The Alzheimer’s-
Eric: From 6 million US adults, somewhere around.
Jason: That number relies on having at least MCI based on the data they use in the Chicago study. If you define the disease on the basis of amyloid alone and you want to count Alzheimer’s disease, you obviously would start, I don’t know, go to the HRS dataset and look at pooled bloods from that and test them for amyloid. You could come up with an estimate of the prevalence of Alzheimer’s. It’ll be a dramatically larger number, which I guarantee will make headlines. But it’s a very different Alzheimer’s than the Alzheimer’s. That state has preoccupied America’s attention, has preoccupied policymaker’s attention. The word I have is just that, the misinterpretation of that number and almost a creation of constituencies in the plural with Alzheimer’s. Well, yeah, you’ve got the beta-amyloid Alzheimer’s and otherwise are fine.
I’ve got the Alzheimer’s that has me needing someone to manage my checkbook. I don’t drive anymore and I rely on someone else to handle my meals. Those are two very different ways of living with the disease. I think we have to think a bit about the policy implications there that would flow from that new way of counting the disease. But again, if we could validate that some biomarker measure does quantify Alzheimer’s disease independent of symptoms, and we may get there, that would be the way we would count the disease. But then we’re going to have to also count the disease based on clinical severity to not lose sight of the fact that dementia matters, and that’s why we care about this disease. If you didn’t get dementia, it wouldn’t be a problem.
Eric: I heard about 1 out of 10 50 year olds will have amyloid positivity as far as-
Heather: Yeah, I’ll tell you in our study where we do very young people with family histories, we’re finding people in their twenties that cross the threshold for abnormal amyloid on lumbar punctures.
Eric: Which would then be defined as Alzheimer’s disease.
Eric: 20-year-old with Alzheimer’s disease.
Heather: So people in their twenties but strong family history. Then the scary thing is many of these people, who knows what the population prevalence is. We don’t normally do lumbar punctures on healthy people in their twenties.
Eric: And for 80 year olds, what’s the prevalence of having positive amyloid biomarkers?
Lon: 50% at least on a PET scan, if not a majority for 80 year olds.
Heather: But is that people who have presented because of some cognitive or memory concern?
Lon: No, that’s a straight out screen. That’s 40% or so of people in their seventies who have no cognitive impairments as screened will have a positive amyloid PET scan. Another factoid is the recent Mayo Clinic Longitudinal study report from, I forget the author’s first name, Podik, I think, is that 8% of people with a positive amyloid scan, only 8% of people would be eligible to receive lecanemab. That kind of puts disease or symptomatology in one relationship to just having a positive amyloid PET scan. You can go with that as you will. One thing I want to come back to what Heather said about finding quote unquote Alzheimer’s profiles of amyloid and tau in younger people’s CNSF. Essentially, we have no standards. Essentially, you don’t really know how abnormal that is or what is going on in those 20 year olds because all the work or the vast majority of the work was done in older folk or-
Jason: I hope that 5, 10, I don’t know how many years from now, this conversation will be viewed as very historical because it was all about amyloid. 5 to 10 years from now, we will have developed ways of measuring the brain that allow you to say whose brain is beginning to show, showing signs of neuron dysfunction, neuron death. I think that’s the exciting field that is unfolding. Measures like neurofilament light, GFAP, measures of neuroinflammation, nerve generation, some of which are agnostic to disease. They just indicate whether neurons are dysfunctional or dying. I would say to my colleagues listening and watching, the few, don’t be cynical about biomarkers. I think the one takeaway I wouldn’t want people to have is, these biomarkers are just the latest flag poll sitting.
This is the beginning of a new way of measuring and defining the brain in health and disease. I think amyloid gets a lot of attention because it was one of the first markers to be developed and the work they did was beautiful and elegant. Tau is very compelling. But again, measures like neurofilament light, GFAP, et cetera, are very exciting measures that could allow you to say, “Yeah, you’ve got amyloid, but you’ve got no neurofilament, no GFAP. Things look really quiet, versus you’ve got amyloid and you’ve got evidence that there’s active neurodegeneration going on.” I see this as our future and we need to get ready for it.
Lon: What you’re addressing though is, what is it that you’re measuring and what does that thing that you’re measuring actually mean? So when you’re measuring amyloid fibrils, you’re measuring this extracellular clump of stuff that’s a reaction to injury and probably has nothing to do with the cellular pathology of what’s going on. When you’re looking at something like GFAP, you’re looking at something particular about glial cells and their state of activation, which may have very little to do with amyloid.
Jason: But may have a lot to do with brains not working well.
Eric: I want to be mindful of the time. We’re getting close to the hour. I like Jason’s point, it was like, what’s the take home for our listeners, the people here? I’m hearing from Jason, don’t give up on biomarkers here.
Jason: Absolutely. Do not give up on biomarkers.
Eric: Heather, what’s your take home?
Heather: All right, so you can tell that I’m a fan of your show because I prepared my magic wand answer. [laughter]
Eric: Oh yeah? Good.
Heather: If I had a magic wand, and I think Jason would want to use my magic wand too, which is that we would understand the mechanisms of this disease, meaning the disease that leads to dementia and the symptoms people care about. We would understand the mechanism well enough to have the perfect biomarker that detected that. Then I agree, we’d be all about developing treatments against that and detecting the biomarker as soon as we could and treating it.
Alex: How about for you, Lon?
Lon: We don’t understand the pathology and pathophysiology of this thing we call Alzheimer’s disease. We do understand how to diagnose it microscopically, essentially by pathology. We do see and expect, as with all illness, to be able to develop diagnostic tests for this illness. But this is a work in progress, so we’re not going to be able to talk about individual diagnostic tests today or tomorrow. We can see what’s coming up. We can be pretty optimistic. We can also be optimistic that we’ll understand the cellular pathology of neurodegeneration, which would include Alzheimer’s disease processes and other things.
But having said that, we do have at least one clinically useful set of biomarkers, and those are amyloid biomarkers and probably very, very soon phos-fatal biomarkers in blood that are clinically useful in the sense that if a person does have cognitive impairment and cognitive impairment is largely memory impairment, cortical slow, progressive impairment and doesn’t have another obvious reason for having cognitive impairment, and you do get a positive amyloid biomarkers such as a amyloid PET scan or a CSF profile with phos-fatal and tau, that is really, really reinforcing that you can give this person a diagnosis of Alzheimer’s disease and Alzheimer’s disease pathology. They do have plaque entangled disease and they do have neurodegeneration.
Jason: Two cheers for MRI, Lon. Don’t forget the value of MRI.
Eric: And hopefully better interventions in the future so they won’t forget about you…[laughter]
Eric: Heather, Jason, Lon, thanks for joining us for the GeriPal Podcast.
Jason: Thanks a lot, Eric. Thanks a lot, Alex.
Heather: Thank you.
Lon: Thank you.
Eric: That was a blast. Thank you to all of our listeners for your support.