AGS Alzheimer’s Disease: New Diagnostic Technologies and Treatments Podcast

Pathology and Diagnostic Frameworks for Alzheimer Disease

• American Geriatrics Society • Season 1 • Episode 1

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Join Dr. Michael Harper, Professor of Medicine at the University of California, San Francisco and Dr. Heather E. Whitson, Distinguished Professor of Neuroscience, Professor of Medicine (Geriatrics), Director of the Duke Aging Center and the Co-director of the Duke/UNC Alzheimer’s Disease Research Center, as they discuss Pathology and Diagnostic Frameworks for Alzheimer Disease.

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Michael Harper:

Hello and welcome. My name is Michael Harper. I'm a professor of medicine at the University of California, San Francisco, and I'm also a geriatrician, and I'm really pleased to be moderating today's podcast. This is all part of the American Geriatrics Society's new educational curriculum on Alzheimer's disease, new diagnostic technologies and treatments. And we designed this curriculum to support both experienced clinicians and our geriatrics fellows as they try to sort of figure their way through this rapidly evolving landscape of Alzheimer's disease, diagnosis, and treatment. So as these new technologies and therapies continue to emerge, it's more important than ever that we stay informed and prepared for the future of dementia care. And today I'm really pleased and I have the pleasure of speaking with Dr. Heather Whitson. She's a professor of medicine at the Duke University School of Medicine. And she also has appointments in the departments of neurology, ophthalmology, and head and neck surgery and communication sciences. She's also the Duke School of Medicine Distinguished Professor in Neuroscience and the director of the Duke Center for the Study of Aging and Human Development. I don't know how she does all this, but she also leads the Duke UNC Alzheimer's Disease Research Center. And she's here with me today because of her expertise both as an Alzheimer's disease scientist and clinician. And she's going to talk to us today. We're going to have a discussion about her module, which is titled Pathology and Diagnostic Frameworks for Alzheimer's Disease. So, Dr. Whitson, welcome.

Heather Whitson:

Thank you. Thanks so much for having me and I'm glad to get to talk with you about Alzheimer's disease.

Michael Harper:

Yeah, so you know, I guess we're really here because so much has changed in the last couple of years, both in the way we have in our abilities to potentially diagnose Alzheimer's disease and potentially treat it. Specifically, I guess I'm thinking about the sort of the new emergence of biomarker tools for diagnosis, FDA approval of two monoclonal antibodies, Lecanemab and Donanemab for the treatment of early dementia from Alzheimer's disease and MCI due to Alzheimer's disease. So I think for our listeners, though, really kind of better understand how this has all come about, we probably have to back to some basics and really talking about the pathology of Alzheimer's disease. And so for clinicians who may be thinking about ordering some of these new tests or even considering their patients for treatments, what are some things that we should know about the pathology that can lead to Alzheimer's disease and some of the other neurodegenerative conditions?

Heather Whitson:

Thanks so much for also just acknowledging the very rapid pace of changes in the field over the last few years and really an avalanche of new information, but also new practical tools to treat this disease that for decades went as a disease that was hard to diagnose and not really anything that you could do against the pathology. So, you know, we're kind of, I see us at like the tip of the wave, the first wave of sort of um major revolutions in the field. But I always tell people the last three to five years have been an amazing time to be an Alzheimer's disease researcher. It's been a really confusing and somewhat stressful time, I think, to be an Alzheimer's disease patient getting newly diagnosed or provider trying to keep up with this avalanche of changes. So, you know, I think you're exactly right that it's important to kind of back up. Probably the most common question that I get from patients is, and maybe from medical colleagues as well, is tell me what the difference is between Alzheimer's disease and dementia. Um, and so I think maybe one of the most key things is to remind people that Alzheimer's disease is one of many causes of dementia. Dementia is the clinical syndrome that we see and recognize as profound memory and thinking changes that are evident enough that they are recognizable. We can see the cognitive changes, and they're impacting people's day-to-day life and independence. That's dementia. Alzheimer's disease is the pathology biology diagnosis that is one of the many causes of dementia.

Michael Harper:

So obviously, I think we've all heard about amyloid for many, many years and this theory that amyloid is involved in the development of Alzheimer's disease. And now we actually have treatments that can remove amyloid from our brains. But that's not the only thing going on, right? So, what are the things we should know about what's going on in the brain as clinicians who are trying to figure this out? And again, really, you know, obviously you have lots and lots of depth of knowledge, but sort of what are some things that clinicians should know about this pathology?

Heather Whitson:

Yeah, I think one of the important things that clinicians should know is that amyloid is without a doubt implicated in some way in Alzheimer's disease. There is a lot of controversy around how directly it plays a role and whether it's the only sort of causative agent, if you will, of Alzheimer's disease dementia. But what we know now from following people with tests like pet images and cerebrospinal fluid for for many years over time, people that that were at risk of developing dementia but didn't have it yet, is that amyloid accumulates first, um, and then tau is the second aberrant protein, mis-phosphorylated tau and tangled tau are the next protein that that develops. So even understanding that sequencing in the cascade that, you know, amyloid seems to come first, then tau, it's the tau actually, and not the amyloid that is most closely linked to the cognitive changes. And in fact, we know that there are a lot of people out there that can tolerate high levels of amyloid in their brain and don't exhibit cognitive changes. And that I think has also created, you know, some of the tension and stress around diagnosing this disease because we now have the ability to tell a person before death, you have amyloid in your brain. And nobody wants to hear that they have amyloid in their brain because having amyloid in your brain, if you are not already cognitively impaired, puts you at much higher risk of being cognitively impaired at some point before you die. But it's not a given. And that's that's I think something that's important for clinicians to understand too.

Michael Harper:

We could develop these abnormal proteins in our brain, but does that mean we're going to develop the clinical signs or symptoms of dementia?

Heather Whitson:

That is the key question. To me, that's the million-dollar question. And the answer may be that if you live long enough, you will. But in our population, as geriatricians, what we know is that if we're talking about a disease that is everybody agrees, is measured in years, not in months or weeks. It may be that if you live long enough, amyloid will eventually lead to the other tau and then neuron loss and synapse loss, and eventually you will develop cognitive problems. But you may live out a normal lifespan before that happens. And I so I think the million-dollar question is when can we get to a point where we can tell somebody, we see this change in your brain, and we can guarantee that on a short time horizon, it will impact your daily life. That's what we wish we had and what we kind of don't have right now.

Michael Harper:

Yeah, and I think this one as clinicians are struggling with now is what do we call Alzheimer's disease? I think in the past, we if we said Alzheimer's disease, it was assumed or understood that you also had dementia, that may no longer be the case.

Heather Whitson:

Yes, that is also really one of the sort of rubs right now because as an Alzheimer's disease researcher, it is important and helpful for me to be able to identify the pathology, the biology that I consider what I want to intervene on, you know, the molecular and cellular changes that ultimately lead to the symptoms, are really important to be able to recognize. It's going to be fundamental to our ability to be able to prevent or treat the disease. And so for me, it's not a problem at all to call that Alzheimer's disease and to recognize that it's very similar in some ways of, you know, if I underwent a colonoscopy, even though I don't have any symptoms, but if I did a colonoscopy and the they came back and they said the pathology says you have you have cancer, I wouldn't reject the diagnosis of cancer. I would say, okay, I believe it. I have cancer, it's it's asymptomatic, and thank goodness we caught it now before it caused problems. But I wouldn't say, no, I don't have cancer because I have no symptoms. For many researchers for a long time, I'd say we've kind of been there with Alzheimer's disease that we'll call it Alzheimer's disease based on the classic pathology of Alzheimer's disease, whether or not it has symptoms. But I think because the the field for so long has used Alzheimer's disease almost synonymously with symptoms of memory and cognitive problems and dementia, by changing that label out there in the world, we risk number one, just stress and stigma for patients, but but really potentially real consequences if like insurers don't understand the difference, if employers don't understand the difference, if the DMV doesn't understand the difference. You know, if we start labeling people with Alzheimer's disease, which by pathology is a condition that, as I just said, a person could live out their normal life, always harboring that in their brain and never have cognitive symptoms. We've got some educating and cubing, you know, aligning to do before we we can make that change for the whole public and not risk potentially negative consequences.

Michael Harper:

Yeah, and I think that's a good reason why we one of the reasons we wanted to do with this this series was to sort of begin to get people to sort of understand these distinctions. Because as clinicians, we're gonna have to be the ones that are educating our patients about about this and hopefully, you know, being mindful of policy that could be impacting them as well. I wanted to shift a little bit more back to the sort of the development of dementia or um and so we know about the accumulation of these sort of abnormal proteins, but are there other contributors that can sort of that we need to be aware of that maybe playing a role?

Heather Whitson:

Yeah, absolutely. So there's a lot that goes on in an aging brain and some of it we think is maybe just normal aging, and others is not normal aging. There are certainly other proteins that we know can become, can accumulate abnormally or become abnormally folded or have post-translational modifications that make them behave abnormally. Amyloid and Tau are not the only ones. There's also um this protein TDP43, which is associated with late um dementia. That's a really important one for geriatricians to know about because it clinically looks just like Alzheimer's disease in the way it presents with profound short-term memory loss, but tends to be later in life. So people in their 80s and 90s sometimes will, everybody thought they had Alzheimer's disease, and then when they die, they go to autopsy and the pathologist looks. Actually, they didn't have much amyloid in tau at all. What they had was this protein called TDP43. And that was part of this avalanche of new knowledge that we've discovered in just the last five years or so. So other proteins that that can exist, Alpha-synuclein, of course, is associated with bluey body dementia, Parkinson's disease dementia. And oftentimes these are comorbid. So these other proteins, you know, I always say the brain didn't read the textbooks about how we like to really neatly classify these different kinds of dementias. Um, and so sometimes the brain just has a lot of abnormal proteins, and maybe one is more prominent than the other, but it's kind of comorbid. The other thing that's happening in the brain is these changes that we think contribute to the dementia syndrome and maybe even drive some of the pathology of these abnormal proteins, and that's things like changes in your brain's immune system, changes in your brain's vascular permeability and um vascular features. Um, there are certainly things that also contribute to all this, like injury. Um, so traumatic injury or ischemic injury um can create sort of local um alterations in brain metabolism, brain immunity. And those things seem to be important contributors to all this as well.

Michael Harper:

And it seems to me that um, you know, one of the things you talked about now is this on the research field, we can sort of detect some of these changes much, much earlier than when as you know, as a scientist, when are you when can we start to begin to even see some of these changes in the brain? How how much sooner before potentially clinical symptoms are?

Heather Whitson:

Yeah, so that's the that is the the um other thing that has really emerged is that it looks that some changes in the brain in some people are evident in their late 40s, 50s, in many times decades, years to in some cases decades before they exhibit cognitive symptoms. And that part is highly variable by different people. So the time between how long, how much amyloid you accumulate before you start to develop tau or before you start to exhibit symptoms is highly variable between different people. Um, and so you know, I think though, recognizing that those changes are happening in people's often mid-40s and up. Um, you know, and in the study that we're doing, we're already seeing that the rates of amyloid accumulation are greater in the people who are APOE4 carriers. Um, and that begins in the mid-40s. And they're all cognitively normal, and most of them will remain so for decades. But we can already see those differences in their brain.

Michael Harper:

Yeah, and so and so the fact that we we can detect these earlier obviously is great from a research point of view. I think it's probably led to some tension around where the sort of intersection of research and clinical care come into play. And you discuss in your module some of these sort of frameworks for how to think about this. I wonder if you could sort of share your thoughts about these evolving frameworks and how to think about applying them in sort of these different contexts.

Heather Whitson:

Yeah, I think you said it exactly. It's that there's this tension between how helpful it is to sort of be at the at the leading edge of understanding these changes that we can detect very early moving forward treatment. And yet, right now, how stressful that can be in a clinical setting to have these tools to potentially detect changes that we don't really know what to make of them, especially in a person who's not having cognitive impairment yet. It really speaks to the fact that even the field of experts in this disease are not fully aligned on this yet, not fully aligned on what is the most helpful framework right now to understand this disease. So, you know, there's one framework that has been developed as an as an evolution by the Alzheimer's Association. It's not the first framework that they've put out, it's an update of frameworks that have been coming out for almost 15 years. Um, but it really advocated to move from research world to clinical world, this understanding of Alzheimer's disease as biopathology aside from symptomatology. So um amyloid and tau, the diagnostic biomarkers of Alzheimer's disease, we would call them having stage one Alzheimer's disease, even if they don't have symptoms, and we don't know at that point we give them that diagnosis if they ever will live to have symptoms. And the recommendation was to move that on into clinical care. At the same time, the same year, um, an international work group, also made up of neurologists, geriatricians, memory disorder specialists, neuropsychologists, said, hold on, we don't want to go there. You know, we would rather label those people as at risk and acknowledge that having amyloid in your brain means you are at elevated risk, but we don't want to call it Alzheimer's disease until there's also evidence symptomatology. Um, and that was, you know, another framework published at the same time. And what I would say is there's sort of just not agreement on which one is is the best framework for us as clinicians um to be using. Um, you know, rapid, rapidly changing times.

Michael Harper:

And yeah. One of the things I think at least we're as geriatricians, we're we're pretty good at dealing with uncertainty. It's one of our uh I think one of the things are our our trademarks. Uh so I I've I would love to just sort of I appreciate that. I mean, and that and again, it's it's really acknowledging this is I think that tension that exists. What do you sort of see, I guess maybe at least in the short term, for the kind of the implications for some of these both the revised Alzheimer's Association criteria and the international working group. Like again, I'm maybe asking you to predict the future a little bit, but what do you sort of see? How do how is this maybe going to move forward?

Heather Whitson:

Yeah, I you know, it is hard for me to to predict exactly how it's gonna move forward. I do think that we're gonna get more information that will help. Because I what for me, what is the the most challenging thing is I wish that we had more data that had come from people in those years before symptoms. So we have a little, we have, we have a little bit of information from people who are in their, say, 30s, 40s, 50s with really detailed brain information. But to get that really detailed brain information requires things like pet images or cerebrospinal fluid. So you can imagine that there haven't been just loads of data collected on asymptomatic young people followed for a long time with pet images and cerebrospinal fluid. Because it's only recently that we realized that, wow, even though these people don't have any memory or cognitive symptoms, we're already picking up changes in their brain. We we need to know more about that. So I think as more information fills that sort of gap of how how you know, how common is it that people develop amyloid and maybe never go on to develop tau? How common is it that people develop amyloid and how long until they develop symptoms? I think those are critical things. And then also really importantly, the evidence base right now is really skewed towards people who are highly educated, tend to have high socioeconomic resources, and tend to be majority European ancestry. So I think we really need to fill in those gaps as well to understand how these brain changes evolve and shift across midlife in a much more representative population.

Michael Harper:

And is it safe to say that we're also on the early side of emerging treatments? And that maybe as better or clearly more clinically beneficial treatments come on, it'll help us to sort of think through whether making these early diagnoses really have clinical benefits.

Heather Whitson:

Yeah, very important point. So right now, an important thing for clinicians to understand is that the new tools to diagnose Alzheimer's disease with blood and the currently FDA-approved treatment are both the blood tests and the treatments are only recommended in people who have cognitive symptoms. So that's today. Now there are studies going on to see if some, if there are treatments, both the anti-amyloid antibodies and other treatments that are wrapped, you know, right now in the treatment pipeline, it's estimated that less than 20% are anti-amyloid. So treatments that are coming along on, you know, on the next wave of treatments are targeting all sorts of things, not just amyloid. And so many of those treatments people really are looking at. Is this helpful to be giving in people with evident brain changes but without symptoms? And if some of those clinical trials come out with positive findings, that yes, we can help people by treating them with something before they have symptoms, then suddenly it becomes much more pressing to potentially find people that have the brain changes because we have, you know, if you could imagine a future where we have a proven effective and safe treatment to give them, then, you know, who wouldn't want that? Who wouldn't want to say, gosh, if I have brain changes, I mean, that's like then then then we're going back to the this is why we do colon cancer screening. You know, we want to detect it before it causes symptoms. But the problem is right now we don't have the treatments um that are proven and safe for people who don't have symptoms.

Michael Harper:

So I want to give you the last word, but I think I'm gonna go back to something you said at the beginning, which is despite all of our uncertainty, this does feel like kind of an exciting time because for as you said, for decades we were kind of stuck, but it seems like the field is moving forward, which is I think a good thing. So I want to say, like, can you give us a bit of optimism to sort of leave us with?

Heather Whitson:

Oh yes, I'm overflowing with optimism. I mean, I have to say that I really truly feel that the last five years have been an amazing, you know, we'll we will look back on the last five years as just a renaissance of of uh Alzheimer's treatment with the kind of rapid pace and momentum of new information coming to bear and and truly new tools to diagnose and treat. And I suspect that in my lifetime, before I retire and stop practicing medicine, we're gonna have much better um tests and and tools to treat. Uh, and then it really does convert this from, you know, when I went into medicine, my grandmother had Alzheimer's. I wanted to take care of people who had Alzheimer's disease and kind of ease the burden on them and their families. Uh to dream that there might be something I could do besides comfort, ease the burden, uh, help make choices about how to take away the car keys and get somebody in a safe position. And, you know, to dream that you might actually be able to prevent my children from having the disease is amazing. It feels like we're we're planting seeds and my children might be the ones who sit under the shade. And that is really, you know, just more than I dreamed of for my career.

Michael Harper:

Uh, that's a great way to sort of summarize and and end the podcast. I want to thank you not only for being here today, to sharing all of your wisdom and expertise, but also for being on the front lines and trying to work through this for all of us and figure this stuff out because uh it's so important. And it's really nice to know that people like you who also know how to care for folks living with dementia are also thinking about how to ease the burden, both for the patients and our families. So once again, thanks for being here. It's been great to talk with you.

Heather Whitson:

Well, thank you. I really appreciate it. And we as geriatricians, we are on the front lines, we know everything that's at stake.