The Peter Attia Drive - #164 - Amanda Smith, M.D.: Diagnosing, preventing, and treating Alzheimer’s disease, and what we can all learn from patients with dementia

Episode Date: June 7, 2021

Amanda Grant Smith is a geriatric psychiatrist with decades of experience treating patients with dementia and Alzheimer's disease. In this episode, Amanda shares how she developed a passion for geriatric psychiatry as a means to support dementia patients. She explains how to recognize, define, and diagnose dementia—a process that still remains somewhat elusive. They also talk about the significance of ApoE genotype and compare the various forms of dementia including differentiating between Alzheimer’s disease and Lewy body dementia. They discuss the current landscape of clinical trials, the drug pipeline, and talk about a very promising monoclonal antibody directed at amyloid beta that has the potential to be a disease-modifying drug. They conclude with a discussion about how to define “healthy aging” and reflect on how understanding dementia can shape one’s life philosophy.   We discuss: How Amanda developed a passion for geriatric psychiatry [3:15]; Defining and diagnosing dementia and Alzheimer’s disease [13:30]; Medical tests for dementia and their relationship to clinical symptoms [22:45]; The pathology of dementia, and the role of the tau and beta-amyloid protein in Alzheimer’s disease [33:15]; The significance of ApoE genotype, and differentiating Alzheimer’s disease from Lewy body dementia [43:15]; The evolution of Alzheimer’s disease prevention, care, and medications over the last 20 years [52:45]; Psychiatric support for dementia patients (and caregivers) with depression and anxiety [1:02:45]; Drug pipeline, clinical trials, and major challenges to overcome [1:13:45]; Redefining Alzheimer’s disease and designing effective trials [1:23:00]; The promise of monoclonal antibody treatments for Alzheimer’s disease [1:34:15]; How we should measure outcomes in dementia trials and define “healthy aging” [1:42:30]; How understanding dementia can reshape our life philosophy [1:53:45]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/AmandaSmith Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more

now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. My guess this week is Dr Amanda Smith. Amanda is the Director of Clinical Research at the University of South Florida Health Bird Alzheimer's Center and Research Institute. She is also a professor of psychiatry and behavioral neuroscience at the University of South Florida, and she specializes in the treatment of patients with Alzheimer's disease. She received her MD from Thomas Jefferson University and did her residency and fellowship at the University of South Florida.

She specializes in Alzheimer's disease clinical research, along with the diagnosis and treatment of patients with AD and other memory disorders. She's an active member in the memory disorder community, and I actually met her through our shared interest in a nonprofit that you may have heard of, hilarity for charity. In this episode, we talk about a number of things. Obviously, her background and what drew her into a field that many people don't necessarily think of, geriatric psychiatry, as a field pertaining to Alzheimer's disease. We talk a lot about the clinical diagnosis

of Alzheimer's disease, which actually is still somewhat elusive. And while it's easier to make the diagnosis today, then say 20 years ago, it's still far from a perfect diagnosis. And a number of other things need to be ruled out. We get into a pretty good discussion around the pharmacotherapy pipeline. There are at this time over 100 drugs in the regulatory pipeline for testing, and we get into a discussion of where they are in that phase and what they're targeting.

We discuss specifically a drug called adicana-mab, which is a monoclonal antibody directed at amyloid beta. And at the time of this podcast, it is very tenuously awaiting FDA approval, a decision that should be rendered on June 7th. This is a very important moment for the research community, because if approved, it would be the first drug approved, both as a monoclonal antibody and secondly, as a drug that is a disease-modifying drug as opposed to a symptom-based drug, which is currently all we have in the quiver. We conclude the discussion by talking about what it means to age in a healthy way.

And I think this is the part that probably has the broadest application, because even if you don't develop Alzheimer's disease, you will age. That is inevitable. The insights that Amanda provides here are going to be valuable for everyone. I certainly feel that way myself. Without further delay, please enjoy my conversation with Dr. Amanda Smith.

Amanda, thank you so much for making time to chat with me today. From the first time I heard you speak, I knew I wanted to have you on the podcast. You probably don't even remember when that was, do you? Well, I think it was that Zoom thing for HFC, right? That's right. It was hilarity for charity. And somehow, I was considered an expert. You clearly are an expert.

And you and me and Richard Isaacson were a part of a discussion in the days when we no longer do physical panel discussions. And I just thought, wow, I was really kind of blown away by a lot of your insights. Because they went beyond just the obvious topics we discussed, which are, you know, the research around what's the cause of Alzheimer's disease, how do you prevent it, what are the treatment, all those things are relevant and all those things are things that you speak to. But I think what impressed me was the attention you brought to the impact that Alzheimer's

disease has on the family just as much as it does the patient. And certainly that's something I want to talk about today. But before we get to that, tell us a little bit about your background. You specialize in geriatric psychiatry, which are not often things you think about, right? People think about psychiatry, they think about forensic psychiatry, they think about more of the DSM-5 type of psychiatry. How did you get interested in that? I grew up in Philadelphia and I had very active grandparents. They owned a nursing home. You know, a lot of people think grandparents in a nursing home. You know, a lot of people think grandparents in a nursing home, you know, my own and operated

in nursing home. And just from a young age being around them and their friends and, you know, seeing the vibrant lives they led even into their 70s and 80s, that to me was normal aging. I never thought of anything different until I was in medical school and I really saw the pathologic side of aging and the things that can go wrong as we get older, as well as I wanna say an attitude of ageism among a lot of the attending physicians

that we trained under. And there was this sort of epiphany I had one day, I remember I was in Brynmore Hospital in the emergency room. And the attending sent me in to talk to a woman who had come in from a nursing home with chest pain. That was all I knew. So I went in and I talked to her and I got the history. And I went and I presented the case to the attending in rounds and he just laughed at me and he was like, you went in the wrong room.

You know, he's like, the lady I'm talking about doesn't make any sense. And I was like, actually she does. She just doesn't have her dentures in because the EMTs forgot to bring them. But if you actually sat there and took the time to listen to her, she told a very normal coherent story about how she was eating lunch and she felt pain and went to her shoulders so she called the nurse. That for me was so enlightening because I realized how quick people are to brush off the elderly. And it kind of lit a fire in me, so to speak, so that that became my passion. So for the rest of medical school, I made sure that my elective rotations were geriatrics

and working with older people in different aspects of it. And one of my favorite experiences was on the geriatric psychiatry unit, where I got to work with dementia patients and psychotic patients. And I just found that personally I had more patients for them because of their life stories and the things that they've been through. And you know, it just sort of led me down this path to where I am now. And there are lots of ways as you experienced, I suppose, to interact with patients in a geriatric setting. Obviously, internal medicine,

you could go down that path through cardiology, you could certainly go down that path through other sub-specialties. When you were doing the psychiatric work, was it understood at the time that a part of dementia is behavioral changes and other things like that, or how much was it understood that Alzheimer's disease had a behavioral component that would be under the purview of psychiatric care? I think it was fairly well established. The part that was the bigger problem

was that there wasn't much that we could do about the cognitive side of things. And unfortunately, that's changed some in the time that I've been doing this. So I graduated from med school in 1997, which was actually the year that Danupazil or Ayrssept was first approved. So I've kind of witnessed the evolution of Alzheimer's treatments in that time.

But certainly from the behavioral standpoint, the behavior problems that can occur in people with dementia have always been treatable. Anxiety, depression, psychosis, Those have frequently been reasons for hospitalization and often were the reasons that we saw people on the Geriatric Psychiatry Unit because they were imagining things that weren't there or you know, acting out on delusions that they had that people were spying on them and they were taking apart

the stealing tiles and their apartment to find these wires that weren't really there and all that kind of thing. So we've always been able to treat that. And fortunately, there's also been improvement in some of the options there, not ideally, but to the point where we can control some of those behaviors so people can have a better quality of life

and so that caregivers can have a little more peace of mind as well. Is it common that a patient is known to have dementia and we'll get to how that's diagnosed in such in a moment, but a patient is known to have this diagnosis of dementia, either Alzheimer's dementia or some non-alcymer's form. And then they begin to exhibit some of the symptoms you've described, so that when they're coming in for evaluation, you're not going through a lengthy differential diagnosis to Rulat's schizophrenia or other forms of psychoses. Or is it sometimes the case that actually the presenting feature of the dementia can be some of these psychotic symptoms you describe where they feel,

hey, someone's talking to me or something like that. Yeah, in fact, the answer is both. Sometimes people will have a course of dementia that after a few years they'll start to develop some of these behavioral symptoms. Some people never get them and some people do actually present with them. Often with the latter, what will usually happen is they'll go be seen by a community psychiatrist or somebody else and get diagnosed with schizophrenia or bipolar illness or something that does not have an onset in the mid-70s. And so usually there'll be misdiagnosed for a couple of years until it becomes really apparent that that's not the primary problem, that there is an underlying neurodegenerative

process. I can't sort of imagine, because I haven't been close enough to it, what it's like for a patient in the early stages of dementia. I've seen patients in the later stages where at least on the outside, it seems that they're quite removed from what's happening. And paradoxically, they don't appear to be suffering very much. But is it safe to assume that it's quite unnerving in the early stages and that that might actually be what's driving some of this behavior? It's a legitimate and understandable fear of something is wrong, but I don't understand what it is. Yeah, I mean, sometimes. So, some people are always blissfully unaware

throughout the entire course of their illness. I can't tell you how many times I see a patient and they sit down in my office and I'm like, so what brings you in today? And they're like, my wife, there's nothing wrong with me. I'm fine. They have no idea whether they're there, even in the very mild stages, whereas some people

are so acutely aware that something's not right, and sometimes they know for two or three years before we can even find any discernible changes on their testing. You know, they're like, I know something's wrong with me, and a lot of times they're right. Sometimes they're just anxious because a family member had it or they're worried, but a lot of times they're very in tune to what's happening. And I think you're right. Usually those are the people that suffer the most because they know what's happening to them

and they don't like it and they know what they're facing. Some patients are extremely insightful and really are aware of what's happening, aware that they're losing things that they used to be able to do or that things aren't coming as quickly. Even yesterday, weirdly, I had two patients with Louis Voddy dementia, which is a type of dementia that has parts of Alzheimer's

parts of Parkinson's and some very prominent visual hallucinations. And whereas often times when people have hallucinations or false beliefs to them, they're real and they don't know that they're not real, both of these patients were like, I see things that aren't there and it drives me crazy. Like they knew this one woman has people all over her living room and she can't find a piece of furniture to sit down on because these people are sitting there and she knows they're not real. But yet she feels like she has to ask them to move

in order to sit on her own furniture. But she was insightful enough to be able to say, I know they're not there, and I know my family members don't see them. So it's really variable. Let's talk a little bit about how one makes the clinical diagnosis first of dementia, and then how one starts to separate out Alzheimer's from Louis body, from presumably an unspecified form of dementia. So starting with the former, what is the clinical definition in the diagnosis of dementia?

Dementia is an umbrella term that just sort of describes changes in memory and other areas of cognition, and it represents a change from how you used to be so you weren't born with it, and it interferes with your day-to-day function. So there are many causes of dementia, Alzheimer's, far and away, the most common, although there have been advancements in many of our tests and more sophisticated imaging techniques and blood

biomarkers that are coming along. The real crux of diagnosis is a good clinical interview with a patient and with an observer. So usually it's a spouse or an adult child or a loved one who has observed changes over time. And in interviewing them separately, that's key separately because otherwise the most important information is left out, you know, because they don't want to hurt the loved ones' feelings or whatever. So getting a good clinical interview from the patient, informant, doing some cognitive testing to look for patterns

that support one diagnosis over another, and then doing some brain imaging to look for certain things like strokes or shrinking in certain parts of the brain, as well as some lab tests to rule out reversible causes of memory loss, thyroid disturbance, vitamin deficiencies, things like that, syphilis, although frankly, I've stopped really testing for that because it's just tertiary syphilis is so uncommon these days.

And once we do all that, generally speaking, we have a pretty accurate diagnostic chance of getting the right label for them. Sometimes we need formal neuropsych testing with a neuropsychologist. Sometimes we do need pet scanning to look at certain patterns. For example, frontotemporal dementia is one where people often present with relatively preserved memory, but significant changes in language or behavior. And usually within a minute, I can diagnose them because the loved one will say, well, his memory's not so bad, but,

and it's either, you know, he can't really talk anymore, which can also happen in Alzheimer's, fairly early in some people. Or I'm embarrassed to take him to church because he'll get up and take the microphone from the pastor. And you almost know, okay, this is FTD. Those are often the people that erroneously get diagnosed with bipolar illness because of these sudden and really profound behavior changes. Problems with judgment where they get labeled as being manic because they're spending lots

of money or they're responding to every publisher's clearinghouse thing that comes in the mail. So there's these typical sort of stories and behaviors that we see that kind of support one diagnosis over another. So, I mean, there's a lot in there and I kind of want to go over that in a bit more detail. So, to make sure I'm understanding this and obviously the listener as well. The first thing I heard you really say there was the absolute importance of the clinical story. So, unlike cancer, where the diagnosis is made typically off imaging and then ultimately through a tissue sample, right?

The gold standard is a histological diagnosis. That's not the case in Alzheimer's disease. We don't do biopsies of the brain. I also didn't hear you talk about CSF sampling, sampling this re-brosbino fluid to look for emaloid beta or tau. Anything you want to say about that before we continue down this rabbit hole? Yeah, I mean there are a few things I can say about that. First of all, certainly it is extremely helpful in the diagnostic process to have formal tests like

CSF or amaloid pet in terms of confirming a diagnosis. Although we certainly don't do brain biopsies, unlike when I graduated, when you literally could only see amyloid at autopsy under microscope, we now do have the ability to image amyloid and living patients, which has, and I know we're gonna to talk about research later, allowed us to really go much earlier in the process

and design some prevention trials based on targeting people who have brain amyloid but don't yet have memory symptoms. So it's been a really amazing revolution as far as that goes. However, from a cost standpoint, although it's a test I can order, it's not covered by any insurance and would cost a patient about $4,000 out of pocket. So other than doing it in the context of a clinical trial, it's really not realistic for many of the patients. As far as CSF goes, there is a good correlation between the PET and CSF findings. Because I am a geriatric psychiatrist and not a neurologist, I'm not typically doing lumbar punctures as part of my practice.

Generally speaking between the other markers such as MRI imaging and PET, FDG PET, which measures how well the brain is using glucose as its fuel and has different patterns, supporting one diagnosis over another. And that is usually covered by some insurance. We're able to make a diagnosis without the additional marker, such as CSF, But there are times when it is helpful and when we do refer people to neurology specifically for that.

So this clinical diagnosis is so important in a way that it's not really as important in the other major chronic diseases, right? When a patient comes in and they're being diagnosed with diabetes or naffled, nobody's really taking a great clinical history, you're sort of assuming you know how they got there. But here you're having that discussion as you described both with the patient and with someone who can give some of these details you're looking for. So I kind of want to identify some of these patterns. Now, I guess the textbook cases are first thing is a loss of short-term memory I'm assuming, is that the textbook version of Alzheimer's dementia?

Yes. I mean, an Alzheimer's disease usually people start to complain of forgetfulness repeating. So a loved one might say, well, he asked me what time this appointment was four times since yesterday kind of thing. But he can remember all the names of his high school football teammates. That's very classic. So the preservation of long-term memory with difficulty with short-term memory. Now Amanda, how do you differentiate distraction from the path to dementia? Because if there's one thing I've heard so often from patients, I just got introduced to this person

and I can't remember their name and it used to be so easy for me to remember names or my wife told me to do this thing and I just completely spaced on it. And in my practice, most of those patients when they're saying that tend to be distracted. There tends to be something else going on. It's really not the pro-dram to sort of dementia. But obviously in your practice, specifically, that's one can't assume that. Do you have a way that you try to differentiate that? Well, I think it has to be taken in context with all of the other information.

I mean, quite frankly, it happens to me, too. Literally, yesterday, I thought it was Friday. Because I knew I was normally on Friday. I wear sweatpants and a USF thing, and I knew I wanted to not wear that for this podcast today. And so I was in my Friday outfit yesterday. And so at one point, I literally was like, oh, it's Friday. And then I was like, oh, no, it's not Friday.

But I'm not worried that I have dementia. I was distracted. I'm busy. I have a lot of things going on. And so those kinds of things happen to all of us. So it has to be looked at in the context of A a the fact that some of this does happen with normal aging. The fact that stress, a bad night's sleep, all that kind of stuff can affect it. And the other part of it is the frequency and intensity of it. If it's the exception rather than the rule, it's probably not dementia. But when that becomes sort of how you are and what happens every day, then it's more concerning.

I think you alluded to MRI, and although you didn't state it explicitly, were you talking about hippocampal volume or other brain matter loss? Was that kind of what you were getting at? Yeah, the typical things that we look for in an MRI when evaluating for dementia, A is ruling out vascular disease or quantifying the amount of it. So we all get with aging some amount of tiny little strokes. And I know that sounds scary, but as we get older, for various reasons, high blood pressure, high cholesterol, smoking, diabetes, and even just normal

aging, there can be blocking of blood vessels, changes in circulation that cause us to have these tiny little infarcts. These are not anything you would notice. You would never have symptoms. You wouldn't go to the hospital, but there can be an accumulation of them. And there's a certain amount that's sort of normal, and it's extremely mild or scattered. But then when they start to coalesce or they start to extend into cortical areas, parts of the brain that sort of matter more in terms of critical thinking, then they can be symptomatic. So that's one of the things that we look at is how much vascular disease. Another thing that we look at is how much shrinking there is both globally. And then as you mentioned in the hippocampus, which is where short-term memories are kind of formed and before they go off elsewhere. And so it is known that that shrinking in the hippocampus, particularly disproportionately to shrinking elsewhere, can be a biomarker of Alzheimer's disease.

Now there are sometimes people who have hippocampal atrophy and turn out to be amyloid negative. So there are these other pathologies that could be considered. They call it hippocampal sclerosis. Some people have that from a stroke. Some people have it potentially from chronic traumatic encephalopathy and other build-up of other abnormal proteins beside amyloid in the brain that kind of fact memory as well. I want to come back to the amyloid negative case in a second.

Is hippocampal volume a reliable marker to check progress? So for example, if you had a patient that was high risk theoretically, so I don't know if you're seeing people who are high risk but don't have symptoms yet, but if you had a patient who is high risk, you did an MRI, you got a baseline, so to speak, you had their hippocampal volume, would tracking that over time for changes, reductions, presumably, would that provide any meaningful insight? Sometimes, but not always. So other things can affect hippocampal volume, for example, people who are chronically exposed to

elevated levels of cortisol or stress hormone, you know, who people have post-traumatic stress disorder. We know they have smaller hippocampi than people who don't have that. And so there are times when we can track hippocampal volume over the course of progression of Alzheimer's and the shrinking sort of correlates with the amount of cognitive impairment, but sometimes not. You know, sometimes we have people who are very impaired and their brain doesn't really look that bad. And sometimes we have people who look like they shouldn't be able to, you know, put on their own pants based on what the brain looks like, but they seem fine.

So it's, again, one of those things that really has to be taken in context with all of the other information. And part of the reason why the clinical evaluation and interview and the intangible stuff is so important. And just to be clear, the diagnosis, it requires the clinical story with or without amyloid. And so when you look at the Venn diagram of people with amyloid and people with clinical symptoms suggestive of dementia and you line them up, there's an overlap, but it's not a perfect union. And what that tells us is that amyloid is neither necessary nor sufficient for Alzheimer's disease, correct?

Well, amyloid is necessary for Alzheimer's disease. It's not necessary for dementia, but if you look at the definition pathologically of what Alzheimer's is, it is the amyloid plaques and the tau tangles in the brain. So that was what's required pathologically to make a diagnosis of Alzheimer's disease. But that diagnosis will only be made post-mortem, technically? Technically, yeah. But that's why the advent of amyloid imaging has been so helpful in terms of making that formal diagnosis in living people,

which is obviously more helpful for them. You know, the correlation, I believe in one of the studies with Ami Vid, Florida peer, which was one of the first family imaging ligands that came out. The correlation between the PET and their, these were people who were kind enough to donate their brains after they passed to compare to what their PET scan looked like. And it was a correlation was about 97%. Meaning when they were alive, they had an amyloid PET scan. And an amyloid PET scan, unlike FDG PET, where you're putting radio labeled glucose,

here you're putting an antibody to amyloid as their tracer, correct? Yes. And so they had this scan while they were alive, and you then had a distribution of people that had this much amyloid, that much amyloid, et cetera. But all of them to be clear had a diagnosis of Alzheimer's disease based clinically, correct? Right. They had a suspected diagnosis of Alzheimer's, and then they underwent the PET and then they

donated their brains and then the correlation. And then on exam, yeah. So what we're missing there, of course, is the control of people who had amyloid in their brains that would go on to have amyloid on autopsy but didn't have Alzheimer's disease. Do we have a rough sense of how big a population that is? I've had a hard time finding this, by the way. What percentage of people on autopsy have amyloid in their brain, but did not have dementia during their life?

I don't know, honestly, but I think more than you would expect, because what we know about amyloid and one of the reasons that amyloid imaging has been so helpful is because it's helped us understand that amyloid starts to build up 10 15 20 years before you start to have symptoms of forgetfulness and other cognitive symptoms and so you know it's this process where

it's occurring and then it reaches a critical mass. And there's a lot of debate scientifically about what that critical mass is or what the downstream effects of amyloid build up. There's some people who think that you can have as much amyloid as you want, and it's not until you start to have tau. Whereas amyloid is sort of widespread kind of from the beginning and builds up all these years beforehand.

So the tracking amyloid doesn't correlate to symptoms. Tau, on the other hand, is very different and has a very specific pattern in which it spreads. That does indeed correlate with symptoms. So some people feel like it's really the towel that kind of stages where things are, whether you're going to be symptomatic or not. So to answer your question, I think there are a lot of people who start to build up amyloid maybe in their 70s or whatever and then die of something else.

So a way to think about it is it's sort of like saying, and this is a bad example, but I think it's the best one I can think of on the spot. It's like coronary calcification where if somebody dies of cancer and you see calcification in their coronary arteries, you knew they have atherosclerosis, but it may have never clinically manifested itself.

And if they had not died of cancer, they may have died of an MI 10 years later. That's exactly right. And that's, frankly, the analogy we most often like to use. So before 2011, the definition of Alzheimer's was dementia. So there was no place in research for these pro-dromal patients or, you know, testing these interventions in people before they had full-blown dementia. And that was very much like waiting till someone had a heart attack to say that they had coronary artery disease. One of them, it's like, no, you knew that

because they have eye cholesterol and they were building up and you could see on an angioplasty or whatever, you know, that this was happening. And so in 2011, with the advent of amyloid imaging, Pittsburgh compound was the first thing that came out that allowed us to see that, although its half-life is so terribly short that it really is not clinically useful,

because it has to be made and used within minutes. But that really allowed us to redefine what Alzheimer's is, so that we could see this amyloid building up in patients before they started to have symptoms. And it allowed some redefinition, and there were white papers that came out kind of dividing. And I know on a previous podcast, Richard Isaacson, did go into this in some detail. But the preclinical phase of Alzheimer's

then mild cognitive impairment, and then dementia. So it really has allowed us to then kind of take a step back and see if we can intervene. Well, four people have these symptoms that we may not be able to reverse. Yeah, to me, Amanda, that is probably the most exciting part of this field, which is effectively taking from the playbook of the chronic disease we understand most. I talk about this with patients, which is like there's basically these three main chronic diseases, which is Alzheimer's disease cancer, even though of course that's not one disease and the atherosclerotic diseases, both cerebrovascular and cardiovascular. And those three legs

stand on a platform, which is metabolic disease, which is then basically the distribution from hyperinslinemia to insulin resistance naffledi and type 2 diabetes. So that becomes the table and you have these legs that stand on it. Of these, I think we have the best understanding of atherosclerosis, where lesion by lesion we can stage them. We understand what a fatty streak is, we understand what a foam cell is, we understand what leads to calcification, how we go from soft plaque to vulnerable plaque

to a ruptured plaque to an MI. And we clearly understand, as your point is made, to sit there and wait until someone has a major adverse cardiac event to say, oh, this guy's got heart disease is nonsensical. I would go one step further and say, waiting until a person's 10-year risk exceeds 5% to intervene is equally nonsensical, yet that is still largely the standard. Because we know from autopsy studies of teenagers, the process begins then. I mean, it probably begins even younger,

but we don't have too many autopsies of people below the teen years, but certainly autopsies of people in their late teens and early 20s who have died for other reasons already show foam cells, fatty streaks in some cases. So, if I'm understanding you correctly, by definition now, based on everything we understand, anyone who clinically classifies as having dementia with amyloid has Alzheimer's disease

is tau necessarily preceded by amyloid or are there scenarios in which tau arrives with minimal to no amyloid beta? So the answer to that question is yes, but I want to kind of go back for a second. So anyone that has dementia and has amyloid does have Alzheimer's, but they may also have other pathology too. So you could have a mixed dementia where you have Alzheimer's and vascular disease, or you could have a mixed Louis body in Alzheimer's. And we know from the autopsy studies, certainly that are done by dentists, Dixon, up in Mayo and Jacksonville, most pathologies actually mixed. I don't have the numbers and I don't remember them quite frankly, offhand, but I know that the number of pure Alzheimer's is actually lower than the number of mixed cases.

So most people have something else too. Is vascular the most common additional diagnosis? Yes. And so what does that mean? Let's think about that for a second. You may recall, I interviewed Francisco Gonzales Lima, probably two or three years ago. He's here actually in UT Austin, works with Jack Delatore, and they really have a strong point of view that says, look, it's this microvascular disease that is really a big driver here.

And there's a very compelling rationale for that. You mentioned it earlier. It's very hard to make it into your seventh, eighth, ninth decade without unbelievable amounts of microvascular damage. And to your point, if a critical mass of that is reached, it's quite likely that that's going to result in the cognitive impairment, and ultimately, even higher levels of impairment

beyond memory, such as executive function. And if, as you said, amyloid is sort of accumulating along the way, it makes sense that you could have this mixed picture where you have the clinical side. So you meet the criteria for dementia, you have amyloid beta, and you have a heavy enough, so you meet the criteria for dementia, you have amyloid beta, and you have a heavy enough burden of vascular disease. I guess it

begs the question, if you had a time machine and you could go back in time for that particular patient and you correct the vascular insult. So let's just say in one patient, you aggressively manage their hypertension and another patient, you kick the smoking cessation in 20 years sooner and another patient, you manage the dyslipidemia. You're going to impact the vascular stuff. Do you think that has an impact on the amyloid side of the equation? And more importantly, does it impact clinically their development of dimension? I think definitely, yes. I mean mean I know when you had your conversation with Richard Isaacson, you know, he stressed the importance of those cardiovascular risk factors

and the development of Alzheimer's. The other thing that we know is, and again it's not exactly the same protein, but it's so closely related, Amalid is a component of blood vessel loss. So I think there's still room for more understanding in that and what the exact relationship is between normal amyloid and pathologic amyloid. So it's important to say in Alzheimer's, the build up of amyloid is this abnormal length amyloid that's not the usual thing that we find in our bodies.

So it's changed a little bit. But there is normally amyloid that's part of our being. And so because it is part and parcel of blood vessel walls, it's only natural to assume. There must be this interplay between the vasculature and the Alzheimer's side of things. I would be lying if I said I knew what that was. I think that still needs to be elucidated. That's why we have floors of people smarter than me upstairs doing experiments.

And I'm down here in the clinic. Does Amaloid beta exist outside of the blood brain barrier? Does it exist on the other side of the blood brain barrier? Honestly, I don't know. That's interesting. I never actually thought of, you know, until you said what you said about the relationship to the endothelia, might never thought about that. I'm guessing somebody has looked into that. And the answer is probably not enough to matter, or else we would simply be doing a blood test to look for enough amyloid, right?

Right. Well, that's coming, though. So, you know, there are some really exciting, I don't wanna forget about your tau question. So I have like that over here. There are some really exciting developments in terms of looking at blood biomarkers, including plasma amyloid, in terms of potentially having a blood-based test for Alzheimer's.

So there has been progress there, and I think that as time goes on, we're going to be able to do these less invasive tests and really have a better sense of both risk for people who aren't maybe symptomatic yet, as well as diagnosis. So you had asked about whether you could have other things like tau without amyloid, and the answer is definitely yes. So front of temporal dementia, some of them are characterized by abnormal tau build up in the absence of amyloid. There are some familial genetic front of temporal brain diseases that are characterized by

tau burden, chronic traumatic encephalopathy that we see in football and other boxing and things also have abnormal towel often in the absence of amyloid. So yes, that definitely has a role in the development of dementia in other types of dementia too. We sort of glossed over it, but maybe it is worth explaining what it is that amyloid beta is doing to neurons and what it is that tau is doing to neurons to actually injure

them. You want to spend just a second kind of outlining those things? To the extent that my blonde self can, I will. To a first-order approximation. No, but I mean, I focus on the patient part of things. I let the neuroscientists do their part. But, you know, it is this sort of cascade of damage. There is activation of glial cells which help protect our brain against intruders and they can release toxins. They can, it's called auto phage, you know, eating up our own tissue. So there's damage both inside

the neurons and then outside, plaques and tangles and it creates a cascade that eventually leads to cell death. Is it more the death of the neuron itself or would the injury to the glial cells alone be sufficient to lead to these symptoms? Because the glial cells, of course, when I was in medical school, which was not that long after you, I don't remember that we talked that much about glial cells in our neuroscience classes. I feel like we talked more about the neurons, but I know that in more recent discussions I've had with neuroscientists, they really place almost an equal emphasis on the glial cells.

So I'm curious as to whether or not injuring the glial cells in this particular pathology is equally responsible or at least to a first-order approximation, equally responsible for the damage. I think they're more responsible for the damage. They're part of the cascade that leads to the death of the neurons because they're trying to protect the neurons and in doing so, injure them. I want to go back to a biomarker question. We're going to talk about the ApoE genotype at some point, but of course one can actually

measure ApoE in the plasma. You can actually, just like you can measure Apo-Lipoprotein B, which we use, obviously extensively in cardiovascular risk stratification. To my knowledge, there's not a commercial assay for measuring ApoE, though it can be done. Are you aware of any utility to that? Would looking at ApoE levels, I read a paper seven or eight years ago, I think suggesting that the lower the level of ApoE,

the higher the risk, but I could entirely have that backwards and I could entirely be wrong. But is that something you're aware of at all? Not really. I mean, it's really more about the genotyping than the quantification of it. And again, you've talked about it on prior podcasts, the risk that E4 genotyped carries

compared to the others. And the fact that E4, homozygates have higher risk and also different responses to cardiovascular meds, different risks for other diseases besides dementia. It is typically not something that we check for in the routine day-to-day clinical care. For a couple of reasons, one is it's not diagnostic, right? So you can have E4, E4 and not have Alzheimer's or you can have E2, E3, which might be protective

and still have Alzheimer's. So it really just makes people worry. It does have a lot more utility in the research setting in terms of looking at how carriers versus non-carriers respond to certain treatments and helping us understand that carriers may respond differently to different lifestyle interventions, may have an earlier onset compared to people who don't have it, but ultimately end up with the same disease. Yeah, so when people come to see you in clinic, there's not a lot of utility added by looking at it. I mean, my view is ApoE4 is great to help people identify risk early on, but at the same time,

nobody gets off the hook. And you use a great example. The two-three shows up a lot. And I tell my patients with the two-three, you're not off the hook. You've got about a 10% risk reduction relative to the three-three, but the three-three is clearly not at risk. And on the flip side, the three-four patients, or even the four-four patients, I say, look, it's certainly not a fate of complete, but I would take this a lot more seriously than maybe you otherwise would in terms of preventative measures. Let's go back to Louis Body dementia. Most people have heard of this. There have been some notable examples in the public sphere about folks that have died

from this. Is it still the case that that's a diagnosis that can be made only post mortem? Again, yes, but there's this sort of classic clinical picture that is so compelling that it can be made fairly accurately in the clinic without diagnostic testing. And so the clinical distinction between, I hate to use this term, the clinical distinction between classic Alzheimer's dementia and classic Louis body. So let's exclude the mixed variants of that.

How would you differentiate those patients? Classic Alzheimer's would begin with short-term memory loss and slowly but surely over time progress to having difficulty, you know, paying bills and then eventually needing supervision, needing assistance with activities of daily living, cooking, bathing, the classic sort of decline. May or may not have behavior issues, may or may not have some changes in walking. Louis-Body disease on the other hand

presents with a fairly classic triad of symptoms that occur within two years at one another. One is an Alzheimer's-like cognitive impairment that can notably fluctuate so that some days people seem really good and some days they seem really, really bad. There is a Parkinsonism component where they will often be stiff,

have trouble rising from a chair, shuffle. They may decrease arm swing when they walk so that they walk, you know, normally when we walk our arms move, but their arms don't move. They may have less expression on their face. They don't necessarily have a tremor. So true Parkinson's disease proper often begins with a tremor, a slow, writhing kind of tremor at rest on one side. And often we don't see that in Louis-Body disease,

but they have these other elements of Parkinsonism. And so we've got the cognitive impairment, the Parkinsonism, and very often prominent visual hallucinations. Seeing things that aren't there, fairly elaborate, often delusions that go along with it. There's this family living in my house. There's people in bears living in the trees. People will close their blinds because they don't want these people seeing them

and all that kind of stuff. So that classic triad of symptoms with some additional supportive features, including restless leg syndrome, even many years leading up to it, as well as REM sleep behavior disturbances. So people who often act out in their dreams or a spouse who says, I have to sleep in the other room because he punches me. That's sort of a classic, Lewy body picture. And furthermore, they fluctuate. Both the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of the blood flow of blood flow of the blood flow of the blood flow of the either in hospice or incapacitated or dead is typically how long. Is that a quicker disease?

Sometimes. I mean, it's usually about eight years, but for some, you know, my experience, I've had a lot of Louis body patients who have sort of this precipitous decline, and then kind of hit a plateau for a while and then really drop off. This is anecdotal. This is not based on any data, but it's just my experience with them and having seen enough of them to see that that's frequently kind of how it goes. But it's usually about an eight to 10 year process. And it's less often as protracted as Alzheimer's can be.

Even though the average for Alzheimer's is still also 8 to 10 years, it can be significantly longer. How hereditary is Lewybody dementia, either with respect to Lewybody itself, or being predictive of the next generation's risk for Alzheimer's disease, or Parkinson's for that matter. I honestly don't know. I don't think it's terribly genetic.

You know, we don't have well-established, as with early onset Alzheimer's, which does have some specific mutations that cause it. I don't know that we know of specific mutations for Lewybody disease, but I may be just not informed. I mean, that makes in some ways, Lewy body a bit more of a mystery

because as you said, for Alzheimer's disease on the very early onset side, we have the PSEN1 to APP mutations, which are about as close to deterministic as you get. And then you have the APOE4 gene, which is not deterministic, but is highly suggestive for the more typical variant. And we also have known risk factors, diabetes, microvascular disease, dyslipidemia.

I mean, these things are absolutely known risk factors. We seem to have none of that on the side of Louis body, correct? As far as I know, yeah. What's the relative incidence of Alzheimer's versus Louis body dementia? Is it like eight, 10 to one, or how much more prominent is Alzheimer's? Well, it depends, I guess, if you're looking at

the autopsy confirmed versus sort of what we see in the clinic. I honestly don't have the numbers specifically for you, but I do know that it's diagnosed less, but found more on autopsy that people do have looibodies that we may not have expected. I got it. And just in your experience in your clinic,

what's the approximate distribution of those? It's about, I would say, 50 to 60 plus percent Alzheimer's, about 20 percent true vascular, about 20 percent Lewy body, and then the rest is FTD, and some of these Parkinson's plus syndromes, progressive super nuclear palsy, and some of these other less common things

that we only see once in a while. Back to kind of the way your practice works. Presumably, people are coming to you at the referral of a neurologist, correct? Not necessarily no. We get people referred from their primary doctors, we get people that are self-referred, we get people that are referred by neurology. It varies widely. That in and of itself is actually quite interesting, right?

If you think about the different paths that a person gets to you, they can say, hey, there's something wrong with me. Oh, Dr. Smith, that's a so-and-so psychiatrist specializing in geriatrics. I'm going to go see her. And then the primary care doctor can say, look, I have a high enough degree of suspicion that my patient has Alzheimer's, they're going to come to you. Presumably when the neurologist is sending to you, it's not to make the diagnosis, they've made it.

I assume it's then to treat some of the behavioral components. Sometimes, yes. I mean, well, first let me say that I would say fully half of my patients think I'm a neurologist. They don't even differentiate or they'll refer to me as their neurologist and it just is what it is. They assume and it's fine. Or maybe they don't want to say they're going to a psychiatrist. I don't know. Sometimes, I think it varies from place to place. There are a few neurologists

here in town that do specialized in Alzheimer's and treating dementia and focus on that, but a lot of them don't. A lot of them prefer specializing in stroke or headache or MS or seizures. And so when it turns out to be dementia, they're just, oh, we'll go to the Alzheimer's Center. So I don't think it's a question of necessarily psychiatry versus neurology. It's just go to the go to the memory place. But yes, there are definitely a subset of referring providers who do so specifically so that we can manage the behavioral aspect of things.

How long have you been in your current practice in Tampa? Since 2002. In this building, since 2008, but so what happened is I came down to USF in 1997 as an intern to do my residency here. So I did my residency in psychiatry and then a fellowship in geriatric psychiatry. And part of my fellowship time was spent with the Sun Coast Gerontology Center working under Eric Fyfer, who had founded that here in 1980 and really was a leader in the field of geriatric psychiatry and Alzheimer's disease. He was the first president, I think, of the American Association for Geriatric Psychiatry. And it was actually one of

the reasons I chose USF because I knew Sun Coast was here and I was interested in geriatrics and Alzheimer's at that point. So when I finished my fellowship on a Friday, I started working for him on the following Monday, and that was in 2002, and then in 2008, he retired, and I kind of stepped in and took on his role as principal investigator for a lot of the clinical trials he had been doing and kind of directing the center. I'm curious as to how your practice has evolved in nearly 20 years. What is different and what is the same about people showing up with dementia today? Are they older? Are they younger? Are they more metabolically ill? Are they on a faster track or they're progressing quicker? I mean, what are all the differences that you see?

The thing that's the same, I would say, is the fear. You know, people are terrified of losing their minds and losing their memories. And so that continues to be sort of the biggest motivator in terms of people seeking help. I will say that we are seeing people that are both older and younger. I think that there's more of an awareness of Alzheimer's as a disease, as well as an awareness of the fact that there are things that we can do about it, because when I first started, there wasn't a whole lot that we could do. And furthermore, there was sort of this assumption that it was a normal consequence of aging.

There has been a lot of effort put into really educating the public that this is a disease, and that this is not something that you have to live with and this is not a normal consequence of getting older. And because of that, I think there's been success in kind of getting that message across and getting people into the clinic. I think that there's definitely more of a shift towards people seeking baseline, people looking at prevention, people wanting, you know, an evaluation and tips on brain health. And I know, again, you spoke with Richard Isaacson because he runs a prevention clinic at Cornell in terms of the lifestyle modifications and things that people can do earlier.

We often see people who have a parent who have Alzheimer's and want to come in and have an evaluation for themselves or get involved in prevention research so that they don't go down the same path. So I think that's the biggest area where things have shifted. I think there's also a better understanding that people realize that there's more that we can do and that early intervention is key. People often used to be embarrassed by this problem

or isolated by it or not want to tell family members or neighbors and now they understand that if they come and they seek help and we start them on medication, even though our medications are not miracle drugs by any stretch, the ones that are FDA approved. But they can slow down decline. And in some people, they can even

subjectively and objectively help for a period of time. And so knowing that you can preserve your function and stay better longer or stay at home longer, you know, there was one old study way back with Danupozil showing that it delayed nursing home placement by an average of 24 months. That's huge if you're someone that wants to be at home or says, be in a skilled nursing facility or if you're a spouse who wants to keep your loved one home, that makes a difference. Even though the drugs, the people are still going to get worse

on the medication. So anyway, that was a lot of big mouthful just to say. I think there is this better awareness of the things that we are able to do and the help that we're able to provide so that people seek help sooner. We talked about it at the very outset that so many of the things that the patients are experiencing when they show up are, quote unquote, the garden variety, things that a psychiatrist

would see, anxiety and depression, for example. What percentage of the patients that you're taking care of are you prescribing anti-depressants and anxiolytics? And is that standard of care? Is that something that you have the ability to be more bespoke in because you have a greater understanding of how those drugs work and how effective are they?

The answer is, you know, quite a few. I would say the majority of our patients do have some mood or behavioral issue that does require treatment. 90% of people will have some behavioral issue at some point in their illness. It may not be a terribly problematic, psychotic type behavior issue.

It may be something simple, but nevertheless, they're very common in all types of dementia. The key is understanding that they are equally treatable. Depression in an independent person is just as treatable as depression in a healthy 25-year-old. So there are obviously some adjustments that have to be made for age and renal function and other medications and drug interactions, but we very frequently prescribe the SSRIs, the type of antidepressants because they treat anxiety very well in this population. They're pretty well tolerated. They generally don't

make people fall, which is a big issue in this group as well. We try to stay away from the benzodiazepine type drugs, Alprazolam and lorazapam and all the pams, particularly the diazapam and the longer-acting ones, because they can really increase confusion and have a dramatically high incidence of hip fracture with those drugs used chronically. So a lot of it is identifying the specific problem, treating with the least offensive drug that's going to cause the least amount of collateral damage and stopping them at times when they may no longer be necessary, you know, old people sort of they collect meds like they collect

other things and you know, sometimes you'll see someone was on 15, 17, 18 meds You're like, why are you even on this? people who had 15, 17, 18 meds, you're like, why are you even on this? People who had hypertension when they were 50 and needed three meds to manage it, but now are 90 and they're falling all the time because their blood pressure is so low, but nobody bothered to say, hey, you don't need three meds for your blood pressure anymore. So, we do have to be vigilant and really target symptoms with the safest, lowest dose, and the shortest treatment period that we can. But in doing so, can be very effective in treating these symptoms.

You might not know the answer to this, but do you have a sense of how many patients in the United States, or what fraction of patients in the US with Alzheimer's disease are getting that type of complementary care for the psychiatric component, specifically the depression and the anxiety? Do you think it's the majority or the minority? I would probably say it's the majority. I mean, a lot of them do get treated by their primary doctors for depression. I see a lot of people who come to me already on medication for that. I think doctors are prescribing and people are sharing those.

And certainly from the standpoint of some of the more problematic behaviors, you know, people don't want to live with them. They're difficult. They're difficult for the patient and they can also be problematic and troublesome for the caregivers So they often will seek help for that More acutely than they will for the underlying condition How much are you Provide I mean you're not necessarily treating the family members medically, but

After all you are a psychiatrist, which means you have more tools in your toolkit than simply your prescription pad. How much are you treating the spouse, for example, as you are the patient? The spouse without dementia? Well, in a way, I think we all sort of give free therapy if you want to call it that. I do occasionally medicate caregivers if they register as a patient. You know, I'll say, hey, you know, you really have the severe depression.

We need to treat this, but I won't do it out. You know, I won't do it under the patients. You know, once we're dealing with meds, it's a whole nother story, but obviously there is a lot of support and education, especially with the pandemic. Sometimes I'm the only other person that they will see or talk to, even if it's on telehealth like this.

Oftentimes it's just that opportunity to vent to talk to somebody who can understand what they're going through. Although I have had some experience with family members having dementia lead in life, you know, I was not a primary caregiver. I, most of what I know, comes from the village of patients and caregivers that have shared very personal things with me.

So I have the opportunity to share their insights with others. But I would say quite a lot of, you know, if you wanna call it free therapy or whatever, just that opportunity to listen to make them understand that what they're going through is valid and real, give them pointers and tools and things that they may not have thought of in terms of handling a certain behavior Just that one little pearl that might make their day easier

The other day I was talking to someone who just simply cannot get their loved ones to take a shower I'm like, well, what's their favorite snack? They kind of look to be funny and they're like Cheetos. So I'm like, okay, tell them after they get out of the shower, you'll get them some Cheetos. You know, you'll go to the store, you'll get some Cheetos. And they don't think of it that way because they're just, you know, sort of trying and fighting like, you need to take a bath, you need to take a bath, get in the shower. And I want to take a shower. And there's not that sort of stepping back and like, OK, how can I do this differently?

So sometimes just giving them a little reality check and a break from the constant stress cycle that they're in to kind of look at things through different eyes, really can make a big difference, I think, in their way that they approach things. The other thing that sometimes really difficult for caregivers is a lot of times they'll think that some of these behaviors that their loved ones are showing are intentional.

You know, or he's just doing it to annoy me. It's like, well no, he's not. He's really not. If you knew the answer, you wouldn't ask you again. So instead of saying, don't you remember, just say, answer the question like it's the first time. Take out that sort of personal attack side of it, and not look at it as they're intentionally trying to irritate you, but they have a disease that's making them do this.

And often, you know, that is something that people really need to hear, and it really makes their days better. I mean, it's easy for me to stay here at my desk and tell them it's a lot harder to do, but at least kind of having that reality check can change the way that they approach caregiving. I'm sure people listening are familiar with Elizabeth Kubler-Ross and how she goes through these sort of five stages of grief and how people go through denial and anger, etc, on their way to acceptance. And that model has always sort of been helpful when thinking about something like cancer. And I got to see that a lot firsthand. Is it similar here with Alzheimer's disease,

both for the patient and the caregiver that there's this in some combination or in some order they go through those? Oh, absolutely. I mean, I can't say credit for the phrase, but it's like grieving for someone while there's still a lot. It's the, this can't really be happening, and then being angry that it's happening,

and sort of, well, maybe if we do this, and maybe do that, in fact, I re-listened to your podcast with Lauren Miller, Rogan, and Richard Isaacson last evening, just kind of in preparation for today, and just to make sure we didn't sort of duplicate everything that we talked about. But Lauren in that podcast really gives a very compelling journey

right through those stages, in terms of dealing with her mother, who was my patient, which is how I got to know them in the first place. But it's really a very distinct journey while her mother was still very alive and going through those stages of grief in losing her hopes for what her relationship with her mother would be like as she got older. You know, it's really terribly sad and it's also something that naturally happens as we grieve. You know, I think those stages of grief apply to almost everything. You know, they're sort of

part and parcel of our existence as human beings is that's kind of going to happen. We don't always go through all of them or we don't always resolve all of them or make it through all of them, but it's a very, very real and major part of dealing with this diagnosis. In my experience with oncology patients, once they've progressed through denial and anger and bargaining, et cetera, and they sort progressed through denial and anger and bargaining, etc. and they

sort of get to acceptance, usually the biggest concern, the residual concern, is the amount of suffering at the end. So it actually becomes at least one of the concerns becomes around the mechanism of death. And that's not something a lot of people think about. Most people walking around, if they're level headed, know that they're going to die at some point. There aren't too many people walking around believing that they're immortal. So most people understand in an abstract way,

I'm not going to be alive at a point in time. But it's kind of a vague fuzzy foggy thing, which is I'll have a heart attack at some point that I won't be alive. But to the patient with metastatic cancer, who's, again, accepted that and understands that they've progressed through all standard treatments. So even now we can even take a subset of patients with stage four cancer who are in hospice care. All of a sudden, a big priority is the actual mechanism of death. And certainly for the palliative care physician, and in my opinion, also for the good oncologist, the one who doesn't just sort of abandon the patient when there's no more oncologic care, I think a big part of that is explaining, no, actually, we might not be able to save your life, but we can absolutely prevent discomfort. What is that discussion like for you

What is that discussion like for you once the patient and their family have progressed through all the stages and really understand that this is an irreversible disease and it will result in the end of their life? How do you address the specific fears that remain? That's a great question and I do get asked about it fairly frequently, but yet at the same time we often don't get into it too much because what I try to do is really help people focus on the now. That being said, what I share with them is that a lot of times, you know, people's as they progress, they are going to have more difficulty doing more simple things and more basic things. They will have trouble swallowing, they will need assistance, they will perhaps aspirate on food and get pneumonia. They may lose

mobility and be bedridden, you know, and we go through that conversation when they ask, well, how do you die of Alzheimer's? But the truth is, a lot of people don't ever get to that stage. Many people die of something else. They die of old age, they die of their heart disease, they die because they fell in a parking lot before they ever reach such a terminal stage of dementia. So, we have the conversation, but we also try not to focus on the end game because that's

just miserable. I know a little bit later we're going to be talking about sort of healthy aging and stuff like that. And that's one of the biggest things that I see is not focusing on the end, but focusing on the now, because the truth is with Alzheimer's, that's all people have. You know, they have today, because they may not remember tomorrow what happened today. So they're really living in the moment. So we try not to spend too much time dwelling. I'm obviously extremely honest in terms of what can and will happen if they inquire.

And also in terms of letting them know that support is there through hospice and other things when the time comes, that they don't have to go through that alone. But we try to reroute that thought process into focusing on making each day better. So let's shift gears a little bit and talk about the clinical trial landscape because that's a very big part of what you do, right? You're a clinical psychiatrist who deals with patients on an individual basis, as we've discussed. But you also are heavily involved in another part of this, which is how to do clinical trials. And this is obviously a very important part of this work. Now, all cymbals disease and drugs don't have a great marriage. They don't have a great track record, the way cardiovascular disease does. And even though oncology is not great,

far from perfect, oncology even has a better track record than Alzheimer's disease. And I think you could make the case without being hyperbolic that there is no disease that has a worse track record relative to the inputs on the output side. In other words, there are orphan diseases for which we have no drugs, but there have been

few shots on goal. So the ratio of shots on goal to goals is lower in Alzheimer's disease than probably, not probably, unquestionably any other disease. Okay. On the one level that undoubtedly speaks to the complexity of the disease, some might argue that on another level that speaks to the wrong goal or shooting too late in the game, shooting from too bad an angle at the wrong goal. Like, you could take this metaphor 10 different ways. As it stands today, there are about 120 drugs in the pipeline. If my number crunching has it right, about 27 of them,

if we extracted this correctly off clinicaltrials.gov, are in phase one. So for the listener, meaning these are drugs that are really just being evaluated for safety at this point. So we have some animal data that suggests this is a good idea. We have no idea if it works in humans, but in a very small way with dose escalation, we want to make sure it's safe. About 65 are in phase two, so that means they've passed that bar of being safe, or at least safe enough to proceed to phase two, where now we're looking for some

efficacy, and we'll of course continue to monitor safety. And then 29 or in phase three, which means at a small scale, they've shown efficacy, typically against a placebo. Now we want to see if there's efficacy, again, either versus a placebo or ideally against a current standard in a larger trial, where again, we're always going to continue to monitor safety. But it's really this third stage that is required for FDA approval. Another way to slice the data is to look at it by category of drug. And I found this to be the most interesting. 12 of these are in the space of cognitive enhancement. 12 are in the space of neuropsychiatric and behavioral improvement.

And 97 are in the space of disease modification. Can you explain a little bit what the differences of those three categories mean? And knowing that the next question I'm going to ask you is, how has that evolved over the last 20 years? Because that, to me, has been the big, that was the thing I was most surprised by. Yeah, so the symptomatic treatments are ones that can help slow cognitive decline or help improve memory and thinking, but are not targeting the underlying disease process. So all the drugs that we currently have on the market are ones that are symptomatic treatments, because they're just helping those neurons communicate in the case of Zinephazelle and

Golanthamine and Riveostigmean. They're colonesterase inhibitors, and then there's Mebbenein, which is an NMDA receptor antagonist that normalizes levels of glutamate. But they're just helping with neurotransmitters, and they're not targeting the underlying pathology of amyloid and tau. Then obviously the behavioral drugs are ones that are being targeted for specific behavior problems in Alzheimer's and other dementia patients, things like apathy, agitation, psychosis, sometimes sleep issues, sometimes even appetite and eating problems. So those all kind of fall under the behavioral umbrella. And then these disease modifying treatments are ones that actually target the underlying

pathology in the case of sort of the biggest group of those that are in trials right now are really monoclonal antibodies against primarily Amaloid, but also if you look you know targeting tau and removing them from the brain in the hopes that then there will be cognitive improvement or at least halting cognitive decline. Is it known exactly where amyloid beta is made?

Is it understood how from where the transcription takes place or is this all post translational modification. There's a whole science dedicated to that. It actually is different points along the cascade. So there's the Amaloid precursor protein, which is on chromosome 21, which is why people with Down syndrome who have three copies of chromosome 21, which is why people with Down syndrome who have three copies of chromosome 21 almost inevitably will get Alzheimer's if they live long enough because they're making a third more amyloid than the rest of us. So anywhere from the very beginning of our DNA all the way through some of the enzymes that cleave amyloid. So part of the problem is that the amyloid gets cleaved

a length of 40 or 42 amino acids, rather than whatever it's supposed to be, which I don't remember. And then the abnormal amyloid kind of folds and there's fibrils and the plaque itself is a conglomeration of a series of folds in the protein and so there are even differences among the antibodies as to what part of that cascade they target. And amyloids not necessary. In other words, if you could wave a magic wand and pull amyloid out of a person,

is there any ill consequence? Well, like I said, it is part of blood vessel walls normally. So, this pathologic amyloid, you know, these abnormal lanes of a beta 40 and 42, yeah, I mean those could be pulled out without consequence because they shouldn't be there in the first place. So if you wanted to target the system, you would not target the creation of Amaloid, you would probably target the enzymes that abnormally cleave. That is one area that has been studied. The gamma-secretase inhibitors, for example, are ones that have been studied. The gamma-secretase inhibitors, for example,

are ones that have been studied. And the base inhibitors, these are things that are being looked at, because these are responsible for cleaving. But a lot of times those have had side effects that we didn't really want. Yeah, I wonder if, has anybody looked at something like in any sense, all they go nucleotide

that goes straight after the enzyme in a laser precision? Basically says, you can't make this enzyme and you don't have to carpet bomb the enzyme and everything around it. You're literally going after the transcription of the enzyme. Yeah, I honestly don't know. That's where the scientist is. I mean, I'm sure somebody has thought of it and declined. There's I'm sure there's a reason that hasn't been done. Yeah, I mean,

the thing is, you know, sometimes they have thought of it if they've tried it, but then they don't realize what the downstream effects of doing so may be. And that's been a problem with several of these medications, you know, whether it's a great idea a great idea, they've identified a target, they've identified compounds that seek out that target, but they cause liver toxicity, or they cause some other significant medical issue, or they cause cardiac arrhythmias, or things that medically are not safe to continue.

The thing that surprised me, Amanda, when I looked at the distribution of drugs, just again, this is available on clinicaltrails.gov, is that 80% of the drugs are disease-modifying drugs, which is a good sign, of course, because the other 20%, as you said, are symptomatic. Now, that's not the way the drugs are currently represented. How many drugs, six approved drugs for Alzheimer's disease right now? Well, there's technically five. Well, there's six, but one of them is a combination of the other two. Two existing, right, right. Yeah. All of these are symptomatic drugs, right? We don't have a disease modifying agent out there.

We're gonna obviously talk about biogen in a moment, which is an important, almost watershed moment in the field. I assume that it's from your standpoint, a great sign that 80% of the pipeline is actually focusing on the underlying cause as opposed to just the symptoms. Right, and a lot of that has to do with what I mentioned earlier with regard to that 2011 sort of major moment where we were allowed to redefine what Alzheimer's is and our understanding that the amyloid pathology building up for many years is was a key factor.

I'm not saying it's a B factor, but it's a key factor in the development of Alzheimer's disease symptoms. Now some of the disease modifying drugs that were initially tested were tested in people with mild to moderate Alzheimer's disease. And we're negative. They did not seem to work or help. And it may have been because targeting amyloid at that stage of the disease may be too late to help. People who already are significantly impaired.

But that 2011 shift into understanding that there's MCI, and that even before that preclinical Alzheimer's, allowed us to then design trials that are currently ongoing, looking at both prevention by amyloid removal before cognitive symptoms start. And then also treating people with mild cognitive impairment who do have some symptoms of memory loss but are not yet demented because they're still functional in their day-to-day.

What was the typical duration of those failed studies? So if you look at the earlier studies that we're trying to remove amyloid late in the game that failed, do you recall on average with the duration, these like four year studies, three year, five year studies? No, they were usually about 18 months. Wow, so really short. So yeah, you could definitely make the case that that's again, just going back to the disease

I understand best. That's like saying, we're gonna take patients who have the most aggressive form of cardiovascular disease. They've got multivessel disease, huge stenosis, vulnerable plaque everywhere. And for 18 months, let's see what happens if we employ lipid lowering therapy. And we see that it has kind of a minor impact. And you can make the case. Well, you probably should have done it earlier and for longer. Right. And well, I mean, the earlier is definitely key. I mean, I don't know if that, so, well,

yes, for longer, but not in that particular group. You know, there would not have been any benefit. I don't think to doing a Three or four-year study of that moderately-demanded group with these therapies because they were just gonna go keep getting worse You know, that's the thing they kept getting they were their disease had Was progressing the train had left the station and it was gonna do what it was gonna do so you know traditionally 18 months has been a standard length for Alzheimer's trials, because it's the amount of time you have to remember, these trials cost lots of money. People often complain and rightfully so that certain drugs are extremely expensive.

And obviously you coming from Canada have a whole different perspective on that than the American side of it, where it's just all about money all the time. That being said, there is some validity to the price of some of these drugs because of the vast amount of resources that have been spent. You know, it takes on average, I read a statistic that 10 to 15 years and a billion dollars for any one drug to get from development and discovery to FDA approval. That's right, it's probably higher today actually. It's probably closer to about 1.3, 1.4 billion,

and you're absolutely correct. So if you look at that pipeline of 120 odd drugs, again, it's not gonna be 120 billion because some of them will get weeded out in phase one. But there's no question that the United States subsidizes the rest of the world in drug pricing. So there's basically an understanding, quid pro quo in my mind that says, look, in exchange for having the best drugs available first, you will pay a premium for the development of the drug.

That's effectively what's happening in the US. Yeah, and then it's also important to point out though that for every one drug that makes it all the way through, there's literally four or five thousand that don't. Some get squashed in the very beginning and some make it to animal models, you know, but it's a very, very, very expensive process for the drug companies. And so, going back to my point, they have to find that sweet spot in terms of length of a trial that will be worth their investment, but at the same time not spend extra resources, but also give the information that they need. And so knowing how Alzheimer's progresses, particularly in that group, 18 months is a spot where you're going to see, okay, so in 18 months,

if they're better, well, that's crazy, because that doesn't happen. If they're stable, well that's good because it's usually there's some drop off in that period of time and if they're worse than clearly it's not working. Yeah, and if you look at the oncology playbook here, you understand the challenge of this space which is you have the same economics, right, which is a billion to a billion and a half to get a drug from inception into a clinic. And truthfully, you have kind of a gray area of utility, right? There are drugs that are getting approved that make very little sense. So they extend median survival by two months without extending overall survival and

They're gonna cost a hundred thousand dollars and we can debate the merits of that and that's where you'll see differences between the US the UK Canada, etc But you see one of the issues here that I find most interesting and I'm not as familiar with it in Alzheimer's disease But I'm intimately familiar with it in cardiovascular disease and in oncology, is the importance of patient selection study design. It's everything. Let's use cardiovascular disease in this example. I always found the Fourier trial and the Odyssey trial, which were the two major trials used to test

the PCSK-9 inhibitors. I found them to be very elegant and very complimentary. So the Fourier trial took patients who were maximally statinized. These are patients that had an LDL cholesterol that was typically south of 70 milligrams per deciliter or in about that neighborhood. So these are people at the fifth percentile

of LDL cholesterol and then added a PCSK9 inhibitor to them. The study was stopped after two to three years. I believe it was intended for four or five, and it demonstrated an improvement. And again, in cardiovascular disease, what are your outcomes? It's usually MACE, major adverse cardiac events, so heart attack, stroke, re-vascularization, death. So you have heart outcomes. That's an important thing, right? They're not tracking. Nobody cares how much it lowers your cholesterol. The biomarker means nothing anymore.

It's only, does it prevent an outcome. You had a complimentary study in Odyssey, which did not take heavily statinized patients, but patients who were, if I recall, equally at risk. And again, it was major adverse cardiac event. And there's all, usually include all cause mortality. This is a challenge that I see in Alzheimer's diseases, and I'm saying this not as an absolute challenge, just as a challenge to me as an outsider,

I struggle to understand these endpoints sometimes, and I just don't understand how valid they are, not because I think that the people measuring them are nefarious, but because they just seem very soft and squishy at times. Like, well, did the person cognitively get better? Maybe yes, no, I'm not sure. And yeah, we use this test and it has a five point scoring system and we square the boxes and such and such. But in the end, it's a harder disease to measure definitive outcomes to your point

at the duration of time we wanna study them. So that's a lot to unpack. And I guess where I'm going with that is, how do you think about, let's start with one element. How do you think about patient selection? Who is the right patient to be studying? Where on that progress from preclinical to MCI to disease?

I think we've ruled out bucket three, right? I think if I've heard you earlier, it's we don't wanna be studying patients for disease modification that already have significant dementia. So would you say the same is true of MCI and we should be looking at the preclinical, which means we, by definition, are making an imaging diagnosis, or is it early MCI and we should be looking at the preclinical, which means we, by definition, are making an imaging diagnosis, or is it early MCI?

So I think the jury is still out with regard to MCI. There still are a lot of trials, and I think there may be opportunity for mild cognitive impairment as well as mild dementia to benefit from these disease modifying therapies. The prevention trials are definitely, you know, if we're looking at a cure, because that's what everybody wants, right, a cure, I think the prevention trials are really going to be the way to go, because then you're stopping it before it starts. We know that these anti-amolade drugs remove amolade. We know this. They successfully reduce amolade to a point where people go from having positive amolade pet to negative amolade pet. In fact, we had an occasion once

where we had a patient who was in a trial, an anti-amoled trial for some time, and then that study stopped, and then she wanted to enroll in another study. And it was actually an anti-tow antibody, and they did allow people with previous exposure to anti-amoled drugs after a certain window of time. Sometimes they don't. So when she had her new amyloid pet for that study, she screen-failed because she was amyloid negative. So that's been shown in numerous trials with more than one compound that it definitely removes amyloids. If you look at the pet outcomes for these drugs, they're great. What are the clinical outcomes?

Yeah, just like you said, nobody cares about a marker or cholesterol. You care about the clinical outcomes and symptoms. And so none of that matters if you're removing amyloid, if the people aren't any better, or if they're continuing to get worse. And so that's what was happening with the mild to moderate group, you know, the original solanasmab trials, people just kept getting worse because they already had enough

neurodegeneration and other pathology now going on in the brain that the whether the amelite was there anymore didn't matter. I do think in MCI that there's opportunity for these drugs to work and the FDA is considering the adjucanumab data right now. There was just last or actually at the beginning of this week data for Don Anumab, which is a lily study that came out at the ADPD meeting showing that it met end points on almost all of the mark, you know all the primary and secondary outcome measures that they had set forth. So I wouldn't rule out the MCI group at this point,

but in terms of sort of the ideal, I think prevention ultimately is gonna be the way to go as far as disease modification. And just like you'll go to the doctor and see you have high cholesterol and intervene then before you get to these bad cardiac or stroke outcomes, you know, you'll go to the doctor and perhaps have a test that shows you have amyloid and then intervene then so that you don't then develop cognitive impairment. That's our hope and our goal. Yeah, that makes hands down the most sense.

And again, I'm obviously stating the obvious, but the more we can model this after a disease where we've had unbelievable success like cardiovascular disease, rather than a disease where we've had very little success, which is cancer, because we have to wait until you have cancer. Now, of course, I think liquid biopsies

are gonna change that. And we are really on the cusp of that. In fact, that's going to be a super exciting discussion. We're gonna have on the podcast in the next couple of months. So the goal, of course, is to turn cancer into cardiovascular disease. It's to turn Alzheimer's disease into the same. Let's talk a little bit about adochemimab,

as you mentioned it. So one of the most promising versions of these monoclonal antibodies to amyloid is adoch chemimab, as you mentioned it. So one of the most promising versions of these monoclonal antibodies to Ameloid is adicana-mab, which is a drug manufactured by a company called Biogen. And it's been in the news a lot lately. I think for several reasons. One is it's a drug that made it to phase three and it was running two parallel studies,

emerge and engage. And to my understanding, very little difference between them, obviously different sites, and maybe a slight difference in some dosing, but effectively the same trial, which is not uncommon for how a drug like this would be tested in phase three, because of the size that you need to have,

the number of participants you need. Where I think it got interesting was how the results were interpreted for the two arms, and then what a re-evaluation looked like. So do you want to explain the story of, I guess, let's start with the beginning. This was a well-done study in that it had pre-specified endpoints, and that's very important for people when they're evaluating clinical trials. Let's start with the beginning. This was a well done study in that it had pre-specified endpoints. That's very important for people when they're evaluating clinical trials. You have to pre-specify your primary endpoint. You got to call your shot before you go to bat.

What was the end point in this study and how did they go about evaluating? Honestly, I don't remember what the specific primary outcome measure was. It was cognitive, but yeah, yeah, yeah, but it wasn't like, it wasn't an imaging study. It was a cognitive study, right? So normally, I don't remember if it was the 8S cog or not to be perfectly honest. So the story of the embarking gate studies,

and I'm sorry, the emergent engage. We're doing embark now, which is the follow-up for the people that had previously been in emergent engage. The bottom line is that the study was going along, and at some point they do what's called a futility analysis to see if it's worthwhile to continue spending their resources on the drug or to abandon it. And when they did the futility analysis, they were not meeting

their primary endpoints. But after further analysis and looking at sort of a cohort of people who had dose escalated kind of in the interim, they realized that the people in the high dose group actually were meeting those endpoints. And so they went back and looked at all the data and in a very unusual turn of events, they were like, actually, we were wrong and this is helping. So they ended up going back and putting people back in the study who had previously been on it in this new embark study as well as submitting to the FDA for approval. The numbers aren't necessarily relevant, but the highest dose, if I recall, was like 10

milligrams per kilogram, and there was also a stratification for apoi and non-apoi, which I didn't understand because they were giving a lower dose to the apoi for carriers than a higher dose. And are they currently just giving everybody the highest dose in the revisit trial? I don't know if I'm allowed to talk about the current protocol. Okay. If it's comfortable at all or not. But what's interesting is that there's

something that's going to happen on June 7th. What is that? We're waiting for on June 7th. I just want to go back and touch on a point that you mentioned. You know, one of the reasons that they give the 8.0 E4 carriers a lower dose is because of the risk of RIA, our amyloid-related imaging abnormalities. So we know that with these amyloid drugs that remove amyloid, we often will see changes in MRI, either edema or swelling or micro-hemorrhages. So RE for edema, REH for hemorrhages, often asymptomatic, but certainly,

we're very significant in some of the earlier iterations of anti-MLA drugs and drug trials that were going on, and there was a distinct difference between the risk of ARIA in E4 carriers versus not. So that would have been the reason at the beginning that they would have been on a lower dose. I believe, and I don't want to speak incorrectly, but I do believe that subsequently, they did find with this drug that that was not happening. So they may have allowed the E4 carriers to go to the higher dose.

Yeah, there was a protocol amendment. They did amend the protocol for E4 to go to 10 Migs per Kig. So June 7th. Yeah, what's going to have, what are we waiting for on June 7th? Everybody's anticipating this. Yeah, so the FDA is supposed to render a decision about whether they're going to approve this or not. And what did the advisory board say earlier in the year? There were two different things.

So there was one group that recommended approval, and then there was another panel that was like, yeah, the data is not so compelling and recommended not. So we really do not know which way the FDA is going to go. There is a very large push on the part of families and patients who have gone without any new treatment for this disease for almost 20 years. To say, it's better lot of that going on. Then there's some very strict science people who are saying, if the data doesn't support it, don't do it. So we really have no idea which way they're gonna go. Let's assume the FDA concludes, there's insufficient data and they do not approve it.

Does anything prevent biogen from, aside from the destruction of shareholder value, is anything preventing biogen from running another clinical trial at phase three to try to seek approval with a better protocol that might be able to yield a better outcome? No, there's nothing preventing that. Obviously, it's just a question of having the funds and inclination to do so. But that's's I think you touched on a little bit earlier part of the problem that we have is that the outcomes the primary outcome measures for these trials aren't that great These are sort of long-standing well-established cognitive tests, but how much they move in the right period of time

may not be as good as we hope. The ones that focus on the CDR, the clinical dementia rating, you know, there is a subjective component to that because that's not just a test, that is an interview, and a rating that a radar makes based on what both the patient says and what an

informant says. And the CDR is the primary endpoint for this drug. Okay. And that's the thing. I mean, the CDR has flaws, you know. I think it has six dimensions to it, but it's subjective, as you said. It is subjective and prone to bias from, let's say, a depressed caregiver who sees everything worse than it is. There have been studies looking at that kind of thing, and a lot of times a caregiver who

is highly stressed and depressed will overreport symptoms leading to higher scores, you know, on the sum of boxes. So the CDR looks at memory, it looks at judgment, it looks at home and hobbies and some other things and a radar will interview the subject. Well, they're interviewing the informant and then they'll'll interview the subject. And they'll ask about recent events. Tell me something you did last week. Tell me something you did in the last month. And then part of the rating is based on what the patient remembers compared to what the

informant said. And there is that sort of intangible part where, you know, if you're kind of on the fence, you could go either way. Even though there are very well-established scoring parameters and hours of training videos and things on how to do the CDR, there still is that sort of, it feels like a one or it feels like a 0.5 that plays into it that's not just an objective measure, like an LDL level. That, to me, is the biggest challenge here is

cancer progresses quickly enough, and at least currently we study it in a very clear sense. I mean, we can debate that there are actually some limitations in how we study cancer progression. And that's been, I think, gamified a little too much. Cardiovascular disease we've already discussed. It seems that the best hope for a disease in which subjective evaluation is so important is to have biomarkers that are so predictive of clinical outcome that you can rely on

those in combination potentially with a clinical evaluation. You can't do a long enough study to get hard outcomes. There's really two enormous challenges in drug development for Alzheimer's disease. There's the technical challenge of how do you develop a good enough drug, and then there's the operational challenge of how do you actually study it. Right. So going back to your question, you know, biogen could very well go back and do another study and use a different primary outcome measure, whether it's the ADAS cog or there was a cognitive

composite score that was recently used by ESI for a different trial. You know, they got a lot of flack for it, because people accused them of kind of cherry picking things that worked, but at the same time, as you also mentioned earlier, these were things that were predefined. You know, it's not like they went and just chose the best things or the things that showed change. They defined in the beginning that these are the measures that we're going to look at and made this cognitive composite based on years and thousands of patients' worth of data showing what specific cognitive tests may be better predictors or may change more during a certain period than those that won't. So I personally didn't have a problem with that cognitive composite

because I thought that it was a thoughtful way of kind of rethinking and getting good data that might be useful. The A-DES cog is just so ingrained in this field. And although it certainly has a lot of utility, it also has limitations. So finding some of these better objective primary outcome measures from a cognitive standpoint, in addition to the biomarkers, I think certainly will be useful for drugs moving forward. So I want to kind of close our discussion Amanda with something you alluded to earlier, which is,

what does it mean to undergo healthy aging? It's inevitable, we're all aging, we're all going to die and unfortunately many of us are going to die with some form of cognitive impairment even if it is not dementia. So in your 20 years of practice, what wisdom have you gleaned and what might someone who is seemingly far from that learn? So, you know, it's interesting, and I knew we were going to talk about this, so I've actually been, you know, more contemplative in the last few days kind of thinking about it. You know, there are a lot of different frameworks for aging, you stuff that we learned in psychology class and some of these classic structured approaches

to aging both psychological and sociological, but I'm never want to kind of fit into one neat category. I like to kind of be eclectic and take a little bit of this and a little bit of that. But at the end of the day, it really has to do with, how people see themselves, how people interact with the world, what kind of relationships they have, how able they are to let go of things that they've lost, and how able they are to focus on the positive. I think that's where I see people struggle the most as a psychiatrist and people develop

the most depression is when they spend so much time looking down the road at what's going to happen or what might happen that they can't enjoy now. And it's very interesting. I can have two patients, maybe both of whom were marathon runners, and now both have Parkinson's disease. And while they both have disability, one of them centers their whole identity around this new disability and focuses on the fact, well, I used to be able to do this. I used to be able to do that. Now, I can't do this. I can't do that. Whereas the other one is like, well, okay, so I can't run anymore, or I might fall if I go to the beach, but I can still enjoy the sunset and a special wheelchair, or focusing on what I still can do and trying to make the most of each day. And those are the people that I think age successfully, even in the face of having illness. We all will age. We all have changes in our physical strength and our

mental alertness and you know, acuity, but it doesn't necessarily disable us. And even if it does, the key for me really is how that shapes our attitude or how much we let it affect our attitude. I want to run an idea by you and I'm curious as to your thoughts. I describe health span or quality of life as having broadly three dimensions, a physical one, a cognitive one, an emotional one. And I think it's safe to say that as sure as God made little green apples, the first two decline with age. Now, if you're really lucky, they don't decline too, too much, assuming you live a long life. So if you talk about someone who's going to live into their 90s, there's a physical decline that is undeniable.

Even if you are fortunate to be spared dementia, there is a cognitive decline, but it doesn't have to be that sharp. And for the lucky ones, you've got the Charlie Mungers of the world who are literally in their 90s and appear to be just as sharp as ever. But the one that doesn't appear to have an age component to it is the emotional one. And so the question I've been pondering is, are the most miserable people going to be the people whose identity is wrapped up in the things that inevitably decline? And therefore, should we be putting more of our identity in the one thing that really has no tie to age, which is basically our emotional health, which I believe is most a function of the quality of our relationship.

So a person who has wonderful quality relationships is generally an emotionally healthy person. And that doesn't mean it's a person who doesn't get sad and a person who doesn't get angry and a person that doesn't struggle, but they have an emotional strength to them that I think comes from this tethering to other people. So does that framework make sense? Absolutely. I think it's spot on and exactly true. That is so important in terms of well-being is having people feeling loved, feeling that there are people you can rely on,

feeling that there are people who can share experiences with you. Social isolation is a huge problem for some people and a definite determinant of quality of life versus not. I definitely see the people that struggle the most are the ones that are constantly comparing themselves to their former selves. I used to be able to do this. I used to be able to do that. If I did that, I would just be hiding under my covers. I mean, I didn't use to need these, but I do. So it's like, well, I might as well buy cute ones

because you gotta have them. It's so hard though, Amanda. Like I think about it. Like we're about the same age and it's true. We've already experienced a decline, but it's gonna get steeper, right? Like it's when you look at what it means to be 90, for most people at least, it's going to be a far greater loss over the previous two decades than maybe we've experienced in

the previous two decades. There's a real non-linearity to it. But I guess it says, good time is any to begin rehearsing that. And I've been very deliberate about this for the past two to three years in anticipation of hopefully a long life. Because look, I think there was a day when all of my identity was wrapped up in these things that are inevitably going to decline. And none of it was wrapped up in the other.

And I'm undergoing an asset reallocation which I guess the point is we should be doing this when we still have a chance to. No you're absolutely right and that that actually is a great point not just doing the asset reallocation but just doing things when you still have a chance. You know one of the things as we were talking earlier another big thing that I think contributes to quality of life and you sort of whether people age well or not is regret and how much regret they live with.

And so very often I see people who come in and you know have worked really hard throughout their lives and put off this and put off that and we're just about to retire and do XYZ. And then now well now I have this devastating disease. And so part of what I do is educating them, well you can still do XYZ. You just might have to do it a little bit differently. But it also, I mean personally has affected me, you know, my happy place is the beach. I love the beach. I have dreamed my whole life of being able to see the horizon from my bed. And so as soon as we were able to afford it, we got, you know, a condo at the beach. It was old built in 1972 and, you know, quite frankly, hideous at the time when we got hit but it meant that

I could wake up and see the Gulf of Mexico especially through the pandemic we've gone there almost every weekend just because what else are you going to do and you know but that's something I learned from my patients you know don't wait don't wait until I retire to get that beach condo because I might not be able to use it. You know, I'm living now, so do it now. And that's A, something I've learned, and B, something I really try to impart to these people that are coming in that sort of feel like

that's a hard stop. Like, oh, I can't do this now because of this diagnosis. And it's like, well, no, you still can. You just have to be a little more careful. You can still take that cruise, but you just wear, I actually, any time I go to a meeting, I haven't been to a meeting, and you're in a half, but I save all of my name tag, Lannard Things,

and I give them out to people. I say, here, take this on your cruise and just put your room number, or cabin number, number or whatever in it and your cell phone number. So if you know your loved one wanders off on a ship, at least they can call you or they can find out what cabin you're in. And so it's making those adjustments, but still, you know, doing the things that you enjoy with the people, you enjoy doing it. I think that's incredibly well said, Amanda. You know, I've really enjoyed our discussion today.

And I know that everyone listening to this has as well, because I just think people are becoming more and more aware of this condition. And as you said, it's less taboo. It's something that people are talking about. And I do believe that people are cautiously optimistic that the next decade looks better than the last decade in terms of actual medical treatments we have.

I'm still firmly in the camp of Richard, which is not to say that you're not saying that, but that says, look, prevention is the best medicine for chronic disease, be it cardiovascular disease, cancer or Alzheimer's disease. But inevitably, a number of us are going to slip through the fingers and the grasp of prevention and are going to need treatments. And I'm hopeful that these monoclonal antibodies that can target amyloid beta or tau can be

a step in the right direction. So thanks very much for all of your insights today. Oh, my pleasure. And of course, exercise. You don't need to tell this audience. No, I know. That's what I'm saying. Even if you've passed the point of prevention, and I know you've gotten into this another podcast, but the data, the growing body of data, shows that even in people who have cognitive impairment or have full-blown dementia,

aerobic activity can actually improve scores on cognitive testing. Some of the research that some of our colleagues do through all of these prevention trials and then through these intervention trials in MCI and AD, Silver Sneakers program at the YMCA, Laura Baker, that Wake Forest is doing a lot of great stuff with this and showing that even if you have dementia your scores will go up if you do a aerobic exercise. So that's what gets me going in the afternoon.

All right Amanda. Well, thanks so much and I hope you get to see the sunset this weekend. Thank you, I really appreciate it. It was great talking with you. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription.

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