164 - Diagnosing, preventing, & treating Alzheimer’s disease, & life lessons from dementia patients

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Attia.

2. 0:10 – 11:17

   How Amanda developed a passion for geriatric psychiatry;

   1. PAPeter Attia0:10

      Hey, Amanda. Thank you so much for making time to chat with me today. Um, from the first time, um, 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?

   2. ASAmanda Grant Smith0:22

      Well, I think it was that Zoom thing for HFC, right?

   3. PAPeter Attia0:25

      That's right. That's right. It was, it was Hilarity for Charity, and, uh, somehow, uh, I was considered an expert. You clearly are an expert, and, and you and me and Richard Isaacson were a part of a discussion in the, in the days when we no longer do physical panel discussions. And, um, [lip smacks] I just thought, "Wow, I really... I, I, I was really kinda blown away by a lot of your insights," uh, because they went beyond just the, uh, obvious topics we discussed, which are, you know, the, 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, um, I think what impressed me was the, uh, 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 wanna talk about today. But before we get to that, um, t- t- tell us a little bit about your background. You, 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. Um, h- how'd you get interested in that?

   4. ASAmanda Grant Smith1:31

      So 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, my owned and operated a nursing home. And, you know, just from a young age, being around them and their friends and, um, you know, seeing the vibrant lives they led even into their 70s and 80s, you know, that to me was normal aging. Um, I never thought of anything different until I was in medical school, and I really saw, you know, 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 [chuckles] attending physicians that we trained under. And there was this sort of epiphany I had one day. I remember I was in Bryn Mawr 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, you know, presented the case to the attending in, in rounds, and he just laughed at me. And he's 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 [chuckles] , "Actually, she does. She just doesn't have her dentures in because the EMTs forgot to bring them, you know? But if you actually stood, sat there and took the time to listen to her, she told a very, you know, normal, coherent story about how she was eating lunch and she felt pain and it went to her shoulder, so she called the nurse." And so, you know, 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, you know, that became my passion. So for the rest of medical school, I made sure that, you know, my elective rotations were geriatrics and working with older people in, in different aspects of it. And one of my favorite experiences was on the geriatric psychiatry unit, where I got to work with, you know, dementia patients and psychotic patients. And I just found that personally I had more, um, patience 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.

   5. PAPeter Attia4:11

      And there are lots of ways, as you experienced, I suppose, to, um, interact with patients in a geriatric setting. Obviously internal medicine, y- you could go down that path through cardiology. Um, you could certainly go down that path through other subspecialties. Um, [lip smacks] when, 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 was... Uh, uh, I guess I'm struggling with my question because I know what it is and I can't make it come out. How much was it understood that Alzheimer's disease had a behavioral component that would be under the purview of psychiatric care, I guess? [chuckles]

   6. ASAmanda Grant Smith4:57

      I think it was, it, it was fairly well established. Um, you know, the, the part that was the bigger problem was that there wasn't much that we could do about the cognitive side of things.

   7. PAPeter Attia5:09

      Hmm.

   8. ASAmanda Grant Smith5:09

      Um, and f- fortunately, that's changed some [chuckles] in, in the time that I've been doing this. But, um, so I graduated from med school in 1997, which was actually the year that donepezil, or Aricept, was first approved. So kind of witnessed the evolution [chuckles] of Alzheimer's treatments in that time. But certainly from the behavioral standpoint, um, the behavior problems that can occur in people with dementia have always been treatable. Um, anxiety, depression, psychosis, you know, those have frequently been reasons for hospitalization and often were the reasons that we saw people on the geriatric psychiatry unit, um, because they were imagining things that weren't there or, you know, acting out on, um, delusions that they had, you know, that people were spying on them and they were taking apart the, you know, ceiling tiles in their apartment to find these- You know, wires that weren't really there and all that kind of thing. So, so we've always been able to treat that, and, and fortunately there's also been, you know, improvement in some of the options there. Not ideally, but, you know, 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.

   9. PAPeter Attia6:37

      Is it common that a patient is known to have dementia, and we'll get to how that's diagnosed in, in, in such in a moment, but a patient is, is known to have this diagnosis of dementia, either Alzheimer's dementia or some non-Alzheimer'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 rule out schizophrenia or other forms, um, of psychoses. Uh, or is it sometimes the case that actually the presenting feature of the dementia can be some of these, uh, psychotic symptoms you describe where they feel, hey, someone's talking to me or something like that?

   10. ASAmanda Grant Smith7:21

       Yeah, in fact, um, the answer is both. You know, 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, um, 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. Um, and so usually they'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.

   11. PAPeter Attia8:13

       I, I can't sort of imagine, um, 'cause 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. Um-

   12. ASAmanda Grant Smith8:39

       Mm-hmm

   13. PAPeter Attia8:39

       ... 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, is there a, a legitimate and understandable fear of something is wrong, but I don't understand what it is?

   14. ASAmanda Grant Smith8:55

       Yeah, I mean, sometimes. So some people are always blissfully unaware throughout the entire course of their illness. You know, I can't tell you how many times, you know, 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, because there's nothing wrong with me. I'm fine." They have no idea why they're there, um, 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. You know, sometimes they're just anxious because a family member had it or they're worried, but a lot of times, you know, they're very in tune to what's happening. And I, I think you're right. Um, 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. You know, some patients are extremely insightful and really, um, 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. Um, even yesterday weirdly, I had two patients with Lewy body dementia, which is a, a type of dementia that has, um, sort of parts of Alzheimer's, parts of Parkinson's, and, and some very prominent visual hallucinations, and whereas oftentimes when people have hallucinations or false beliefs, to them they're real and they're, 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. You know? This, 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, it's really variable.

3. 11:17 – 21:28

   Defining and diagnosing dementia and Alzheimer’s disease;

   1. PAPeter Attia11:17

      Let's talk a little bit about how one makes the clinical diagnosis, uh, first of dementia, and then how one starts to separate out Alzheimer's from Lewy body from presumably an unspecified form of dementia. So, so starting with the former, what, what is the clinical definition and the diagnosis of dementia?

   2. ASAmanda Grant Smith11:39

      So 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. Um, so the, although there have been advancements in many of our tests, um, and, and more sophisticated imaging techniques and, and blood biomarkers that are coming along, the real crux of Um, 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, um, who has observed changes over time. In interviewing them separately, that's key, separately, because otherwise the most important information is left out, you know, 'cause they don't wanna hurt the loved one's feelings or whatever. So, um, 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, um, as well as some lab tests to rule out reversible causes of memory loss, um, thyroid disturbance, vitamin deficiencies, uh, things like that, syphilis, although frankly, I've stopped really testing for that 'cause it's just tertiary syphilis is so uncommon these days. Um, and once we do all that, generally speaking, you know, we have a pretty accurate diagnostic, you know, chance of getting the right, you know, label for them. Um, sometimes we need formal neuropsych testing with a neuropsychologist. Sometimes we do need PET scanning, um, to look at certain patterns. For example, um, frontotemporal dementia is one where people often present with relatively preserved memory, but significant changes in language or behavior. Um, and usually, you know, 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, um, or, you know, "I'm embarrassed to take him to church because he- he'll get up and take the microphone from the pastor," [laughs] and, you know, you almost know, okay, this is FTD. Um, those are often the people that erroneously get diagnosed with bipolar illness, um, because of these sudden and really profound behavior changes, um, problems with judgment where they get labeled as being manic 'cause they're spending lots of money or they're, you know, responding to every Publisher's Clearing House thing that comes in the mail. Um, you know, so there- there's these typical sort of stories and, and behaviors that we see that kind of support one diagnosis over another.

   3. PAPeter Attia15:11

      So Amanda, there's a lot in there, and I, I kind of wanna go over that in a bit more detail. So to make sure I'm understanding this, and obviously the listener as well, um, the first thing I heard you really say there was the absolute importance of the clinical story. So unlike cancer-

   4. ASAmanda Grant Smith15:26

      Yes

   5. PAPeter Attia15:26

      ... 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. Um, I also didn't hear you talk about CSF sampling, uh, sampling the cerebrospinal fluid to look for amyloid beta or tau. Uh, anything you wanna say about that before we continue down this rabbit hole?

   6. ASAmanda Grant Smith15:55

      Well, yeah, I mean, there are a few things I can say about that. First of all, you know, certainly it is extremely helpful in the diagnostic process to have, you know, formal tests like CSF or, uh, amyloid PET in terms of confirming the diagnosis. You know, although we certainly don't do brain biopsies, unlike when I graduated when you literally could only see amyloid at autopsy under a microscope, we now do have the ability to image amyloid in living patients, um, which has, you know, and I know we're gonna talk about research later, um, allowed us to really go much earlier in the process and, and design some prevention trials, um, based on targeting people who have brain amyloid but don't yet have memory symptoms. Um, so it's been a really amazing revolution as far as that goes. However, from a cost standpoint, um, 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, you know, in the context of a clinical trial, it's really not realistic for many of the patients. Um, as far as CSF goes, you know, there is a, a good correlation between the PET and CSF findings. Um, because I am a geriatric psychiatrist and not a neurologist, I'm not typically doing lumbar punctures as part of my practice. Um, generally speaking between the other markers such as, you know, MRI imaging and PET, FDG PET, uh, 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, um, we're able to make a diagnosis without the additional markers such as CSF. But there are times when it is helpful and when we do refer people, um, to neurology specifically for that.

   7. PAPeter Attia18:15

      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 NAFLD, nobody's really taking a great clinical history. You're sort of assuming you know how they got there. Um, you know- 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, you're looking for. So I kinda wanna identify some of these patterns. Now, I, I guess the textbook cases are first, first thing is a loss of short-term memory, I'm assuming. Is that the, the textbook version of Alzheimer's dementia?

   8. ASAmanda Grant Smith18:57

      Yes. I mean, in Alzheimer's disease, usually people start to complain of forgetfulness, um, repeating. So a, a loved one might say, "Well, he, you know, he asked me what time this appointment was four times since yesterday," kinda thing. Um, but he can remember, you know, all the names of his high school football teammates. That's very classic, so the, the preservation of long-term memory with difficulty with short-term memory.

   9. PAPeter Attia19:29

      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, it's, "I, you know, 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, you know, "My wife told me to do this thing, and I just completely spaced on it." And, you know, my... 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, uh, prodrome 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?

   10. ASAmanda Grant Smith20:10

       Well, I, I think it has to be taken in context with all of the other information. I mean, quite frankly, it happens to me, too. Um, you know, literally yesterday I thought it was Friday [laughs] 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. Um, and so, you know, all... Those kinds of things happen to all of us, so it has to be looked at in the context of, you know, A, the fact that some of this does happen with normal aging, um, the fact that, you know, stress, a bad night's sleep, all that kind of stuff can affect it, and, and the other part of it is the frequency and intensity of it, you know? If it's the exception rather than the rule, it's probably not dementia, but when that becomes sort of how you are and, and what happens every day, then it's more concerning.

4. 21:28 – 32:50

   Medical tests for dementia and their relationship to clinical symptoms;

   1. PAPeter Attia21:28

      You alluded to, um, I think you alluded to MRI, and although you didn't state it explicitly, were you talking about hippocampal volume or other, uh, brain matter loss? Was that kinda what you were getting at?

   2. ASAmanda Grant Smith21:42

      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. Um, but as we get older, you know, for various reasons, high blood pressure, high cholesterol, smoking, diabetes, and even just normal aging, there can be blocking of blood vessels, um, 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, um, there can be an accumulation of them, and there's a certain amount that's sort of normal when it's extremely mild or scattered. But then when they start to, you know, coalesce or they start to extend into cortical areas, um, parts of the brain that sort of matter more in terms of critical thinking, um, 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, um, which is where short-term memories are kind of formed and before they go off elsewhere. And so, um, there is... You know, it is known that, that shrinking in the hippocampus particularly, um, 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, um, so there are these other pathologies, um, that could be considered, um, they call it hippocampal sclerosis. Some people have that from a, a stroke. Some people have it potentially from chronic traumatic encephalopathy and other, other, um, buildup of other abnormal proteins beside amyloid in the brain that can affect memory as well.

   3. PAPeter Attia23:59

      I wanna come back to the amyloid negative case in a second. Um, is hippocampal volume a reliable marker to, um, check progress? So for example-

   4. ASAmanda Grant Smith24:13

      Hmm

   5. PAPeter Attia24:13

      ... 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 was 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, uh, presumably, would that provide any meaningful insight?

   6. ASAmanda Grant Smith24:36

      Sometimes, but not always. So other things can affect hippocampal volume. For example, um, people who are, uh, chronically exposed to elevated levels of cortisol or stress hormone, you know, people who have post-traumatic stress disorder, we know they have smaller hippocampi than people who don't have that. And so it, 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 [laughs] 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, the clinical evaluation and interview and the intangible stuff is so important.

   7. PAPeter Attia25:50

      And just to be clear, the diagnosis is, 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-

   8. ASAmanda Grant Smith26:10

      Correct

   9. PAPeter Attia26:11

      ... is that amyloid is neither necessary nor sufficient for Alzheimer's disease, correct?

   10. ASAmanda Grant Smith26:17

       Well, amyloid is necessary for Alzheimer's disease. It's not necessary for dementia, but, you know, if you look at the definition pathologically of what Alzheimer's is, it is the plaques, the out- the amyloid plaques and the tau tangles in the brain. So, you know, that was what's required pathologically to make a diagnosis of Alzheimer's disease.

   11. PAPeter Attia26:42

       But that diagnosis will only be made postmortem technically?

   12. ASAmanda Grant Smith26:46

       Technically, yeah. Um, but that's why the advent of amyloid imaging has been so helpful in terms of, um, making that formal diagnosis in living people, um, which is obviously more helpful [laughs] for them.

   13. PAPeter Attia27:05

       Mm-hmm.

   14. ASAmanda Grant Smith27:08

       Um, you know, the correlation, I, I believe in one of the studies with, um, Amyvid, uh, florbetapir, which was one of the first amyloid imaging, uh, ligands that came out, the correlation between the PET and their... Th- 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, the correlation was about 97%.

   15. PAPeter Attia27:36

       So meaning when they were alive, they had an amyloid PET scan.

   16. ASAmanda Grant Smith27:40

       Yes.

   17. PAPeter Attia27:41

       And an amyloid PET scan, unlike FDG PET, where you're putting radiolabeled glucose, here you're putting an antibody to amyloid on as their tracer, correct?

   18. ASAmanda Grant Smith27:54

       Yes.

   19. PAPeter Attia27:55

       And so they had this scan while they were alive, and you then had a distribution of people that had ac- you know, this much amyloid, that much amyloid, et cetera. But all of them, to be clear, had a def- had a, had a diagnosis of Alzheimer's disease based clinically, correct?

   20. ASAmanda Grant Smith28:10

       Right. They had a, a suspected diagnosis of Alzheimer's, and then they underwent the PET, and then, then they donated their brains.

   21. PAPeter Attia28:20

       And then on exam-

   22. ASAmanda Grant Smith28:21

       And the correlation between-

   23. PAPeter Attia28:22

       Yeah. So the, 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. Um, what percentage of people on autopsy have amyloid in their brain but did not have dementia during their life?

   24. ASAmanda Grant Smith28:46

       Um, I don't know, honestly. Um, but I think more than you would expect because... So 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 for- forgetfulness and other cognitive symptoms.

   25. PAPeter Attia29:13

       Mm-hmm.

   26. ASAmanda Grant Smith29:14

       And so, um, you know, it's this process where, you know, 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. Um, we're understanding more that tau, w- whereas amyloid is sort of widespread kind of from the beginning and builds up all these years beforehand, um, and so the, the tracking amyloid doesn't correlate to symptoms. Tau, on the other hand, is very different and has a very specific, um, pattern in which it spreads that does indeed correlate with symptoms, so some people feel like it's really the tau that kind of stages where things are and whether you're gonna be symptomatic or not. So to answer your question, you know, I think there are a lot of people, you know, who start to build up amyloid maybe in their 70s or whatever and then, you know, die of something else.

   27. PAPeter Attia30:28

       So, 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-

   28. ASAmanda Grant Smith30:37

       Yeah

   29. PAPeter Attia30:37

       ... where if somebody dies of cancer and you see calcification in their coronary arteries, you knew they have atherosclerosis, but it never, it may have never clinically manifested itself, and they, if they had not died of cancer, they may have died of an MI 10 years later.

   30. ASAmanda Grant Smith30:52

       That's exactly right, and that's frankly the, um, analogy we most often like to use. You know, when-- So before 2011, um, the FDA, you know, the, the definition of Alzheimer's was dementia. So there was no place f- in research for these prodromal 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 when it's like, no, you knew that because they have high 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, you know, 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, um, useful 'cause it has to be made and used within minutes. Um, but, you know, 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, and it allowed, you know, some redefinition, and there were white papers that came out kind of dividing, and I know, um, on a previous podcast, uh, Richard Isaacson did go into this in some detail, but, you know, the preclinical phase of Alzheimer's, then mild cognitive impairment, and then dementia. Um, so it really has allowed us to then kinda take a step back and see if we can intervene before people have these symptoms

5. 32:50 – 44:10

   The pathology of dementia, and the role of the tau and beta-amyloid protein in Alzheimer’s disease;

   1. ASAmanda Grant Smith32:50

      that we may not be able to reverse.

   2. PAPeter Attia32:52

      Yeah. To me, Amanda, that is probably the most exciting part of this field, which is, um, effectively taking from the playbook of the chronic disease we understand most. You know, 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 the-

   3. ASAmanda Grant Smith33:24

      Yeah

   4. PAPeter Attia33:24

      ... uh, the, the basically the distribution from hyperinsulinemia to insulin resistance, NAFLD, 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. You know, we understand what a fatty streak is. We understand what a foam cell is. We understand what leads to calcification. You know, how we go from soft plaque to vulnerable plaque to a ruptured plaque to an MI. And-

   5. ASAmanda Grant Smith33:57

      Right

   6. PAPeter Attia33:57

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

   7. ASAmanda Grant Smith34:31

      Yeah

   8. PAPeter Attia34:31

      ... 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, um, 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?

   9. ASAmanda Grant Smith35:13

      Um, so the answer to that question is yes, but I wanna kinda 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, right? So you could have a mixed dementia where you have Alzheimer's and, um, vascular disease, or you could have a mixed Lewy body in Alzheimer's. And, and we know from, um, the autopsy studies, uh, certainly that are done, um, by Dennis Dickson up in Mayo in Jacksonville, you know, most pathology is actually mixed. I, 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.

   10. PAPeter Attia36:10

       And is vascular the most common, um, additional diagnosis?

   11. ASAmanda Grant Smith36:18

       Yes.

   12. PAPeter Attia36:19

       And so what does that mean? Let's, let's think about that for a second. Uh, you may recall I, I interviewed, uh, Francisco Gonzalez-Lima probably two or three years ago. Um, he's here actually in, in UT Austin, um, works with Jack de la Torre, and, and th- they You know, really have a strong point of view that says, "Look, it's this microvascular disease that is really a big driver here." Um, 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. Um, 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, the clinical side, so you, you know, 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, they were, you know, aggressively, you know, you aggressively manage their hypertension, in another patient you, you know, kick the smoking cessation in 20 years sooner, in 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 dementia?

   13. ASAmanda Grant Smith38:01

       I, I think definitely yes. I mean, I know, you know, again, w- when you had your conversation with Richard Isaacson, you know, he stressed the importance of those cardiovascular risk factors in the development of Alzheimer's. The other thing that we know is, a- and again, it's not exactly the same protein, but it's so closely related, you know, amyloid is a component of blood vessel walls, right? So, you know, to what extent ... You know, I, I think there, there's still room for more understanding in that and what the exact relationship is between normal amyloid and pathologic amyloid. So in, it's important to say in Alzheimer's, the buildup of amyloid is this abnormal length amyloid that's not the usual thing that we find in our bodies, right? So it's changed a little bit. Um, 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. Um, I would be lying if I said I knew what that was, you know? I think that still needs to be elucidated. Um, you know, that's why we have floors of people smarter than me upstairs doing experiments. [laughs]

   14. PAPeter Attia39:29

       Does amyloid beta exist outside of the, uh, blood-brain barrier? Does it ex- does it exist on the other side of the blood-brain barrier?

   15. ASAmanda Grant Smith39:36

       Honestly, I don't know.

   16. PAPeter Attia39:39

       Uh, that's interesting. I never actually thought of what, you know, until you said what you said, uh, about the relationship to the endothelium, I never thought about that. I, 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?

   17. ASAmanda Grant Smith39:58

       Right. Well, that's coming, though.

   18. PAPeter Attia40:01

       Yeah.

   19. ASAmanda Grant Smith40:02

       So, you know, there are some really exciting ... I, I don't want to forget about your tau question.

   20. PAPeter Attia40:09

       Yeah, yeah. We'll come back to that.

   21. ASAmanda Grant Smith40:09

       So I have, I have like that over here. Um, you know, there are some really exciting developments in terms of looking at blood biomarkers, including plasma amyloid, um, in terms of, of potentially having a blood-based test for Alzheimer's. Um, so there has been progress there, and I think that, you know, 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.

   22. PAPeter Attia40:53

       One blood-based test-

   23. ASAmanda Grant Smith40:54

       Going back to the-

   24. PAPeter Attia40:54

       Oh, okay. Yep.

   25. ASAmanda Grant Smith40:55

       Oh.

   26. PAPeter Attia40:55

       Yeah. Let's go back to tau, and then I want to ask another blood-based question. [laughs]

   27. ASAmanda Grant Smith40:59

       Okay. So you, you had asked about whether you could have other things like tau without amyloid, and the answer is definitely yes. You know, um, so frontotemporal dementias, some of them are characterized by abnormal tau buildup in the absence of amyloid. Um, there are some familial genetic, um, frontotemporal brain diseases that are characterized by tau burden. Um, chronic traumatic encephalopathy that we see in, in football and other, um, boxing and things also have abnormal tau, often in the am- absence of amyloid. So yes, that definitely has a role in the development of dementia in, in other types of dementia too.

   28. PAPeter Attia41:48

       We sort of glossed over it, but maybe it is worth e- explaining what it is that amyloid, uh, beta is doing to neurons and what it is that tau, uh, is doing to neurons to actually injure them. Do you want to spend just a second kind of outlining those things?

   29. ASAmanda Grant Smith42:06

       Um, to the extent that my blonde self can, I will. [laughs]

   30. PAPeter Attia42:13

       To a first order approximation.
6. 44:10 – 54:44

   The significance of ApoE genotype, and differentiating Alzheimer’s disease from Lewy body dementia;

   1. ASAmanda Grant Smith44:10

      them.

   2. PAPeter Attia44:10

      Mm. I wanna go back to a biomarker question. Um, we're gonna talk about the ApoE genotype at some point, but of course, one can actually measure ApoE in the plasma. You can actually m- just like you can measure Apo lipoprotein B, you, which we use obviously extensively in cardiovascular r- risk stratification. Um, to my knowledge, there's not a commercial, uh, assay for measuring ApoE, though it can be done. Do you... Are you aware of any utility to that? Would that... Would, 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, I could have, I, I could entirely have that backwards, and I could entirely be wrong, but is that something you've, you're aware of at all?

   3. ASAmanda Grant Smith44:58

      Not really. I mean, it's really more about the genotyping than the, the quantification of it. You know, obviously, and again, you've talked about it on prior podcasts, the, um, the risk that E4 genotype carries compared to the others, um, and the fact that E4 homozygotes have higher risk and also different responses to cardiovascular meds, different, um, different risks for other diseases besides dementia. Um, it is typically not something that we check for in the routine day-to-day clinical care, um, 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. [laughs] Um, so it really just makes people worry. Um, 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, um, and helping us understand that carriers, you know, um, 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.

   4. PAPeter Attia46:28

      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're, you used a great example. The 2/3 shows up a lot, and I tell my patients with the 2/3, "You're not off the hook."

   5. ASAmanda Grant Smith46:49

      Right.

   6. PAPeter Attia46:50

      You've got about a 10% risk reduction relative to the 3/3, but the 3/3 is clearly not at risk. Um, and on the flip side, the 3/4 patients or even the 4/4 patients, I say, "Look, it's certainly not a fait accompli, but I would take this a lot more seriously than maybe you otherwise would-

   7. ASAmanda Grant Smith47:07

      Right

   8. PAPeter Attia47:07

      ... in terms of preventative measures." So let's go back to the patient that shows up in clinic. Uh, oh, actually there's one other thing I wanted to clarify. I'm sorry. Let's go back to Lewy body dementia. Most people have heard of this. Uh, there have been some notable, uh, examples in the public, uh, sphere about, you know, folks that have, uh, died from this. Is it still the case that that's a diagnosis that can be made only postmortem?

   9. ASAmanda Grant Smith47:32

      Um, I mean, again, yes, but, uh, it is... You know, there's this sort of classic clinical picture that is so compelling that, you know, it, it, it can be made fairly accurately in the clinic without diagnostic testing.

   10. PAPeter Attia47:52

       And so the clinical distinction between, I hate to use this term, the clinical distinction between classic Alzheimer's dementia and classic Lewy body, so let's exclude the mixed variants of that, h- how would you differentiate those patients?

   11. ASAmanda Grant Smith48:07

       So classic Alzheimer's, you know, would begin with short-term memory loss and slowly but surely over time progress to having difficulty, you know, paying bills and then eventually, um, needing supervision, needing assistance with activities of daily living, cooking, bathing, you know, the, the classic sort of decline. Um, may or may not have behavior issues, may or may not have some changes in walking. Um, Lewy body disease on the other hand presents with a Fairly classic triad of symptoms that occur within two years of 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. Um, there is a Parkinsonism component where they will often be stiff, have trouble rising from a chair, shuffle, uh, they may decrease arm swing when they walk so that they walk and, you know, normally when we walk our arms move, but their arms don't move. They may have more, um, less or I, I should say less expression on their face. Um, they don't necessarily have a tremor, so true Parkinson's disease proper often begins with a tremor, a slow writhing kinda tremor at rest on one side. Um, and often we don't see that in Lewy body disease, but these, they have these other elements of Parkinsonism. And so we've got the, the cognitive impairment, the Parkinsonism, and very often prominent visual hallucinations, um, seeing things that aren't there, fairly elaborate, um, often delusions that go along with it. Um, you know, "There's this family living in my house. There's people and bears living in the trees." You know, people will close their blinds because they don't want these people seeing them and all that kind of stuff. Um, so that classic triad of symptoms with some additional supportive features including restless leg syndrome, um, even many years leading up to it, as well as, uh, 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 'cause he punches me," you know? Um, that's sort of a classic Lewy body picture. And, and furthermore they fluctuate. Both the motor and the cognitive symptoms fluctuate. So today we might be able to go to the mall and walk all around, and tomorrow they might have trouble walking across the room.

   12. PAPeter Attia51:08

       And from the time of diagnosis, Amanda, until those patients are either in hospice or incapacitated or dead is typically how long? Is that a quicker disease?

   13. ASAmanda Grant Smith51:21

       Sometimes. I mean, it's usually about eight years. Um, but for some it... You know, my experience, I've had a lot of Lewy body patients who have sort of this precipitous decline and then kind of hit a plateau for a while and then really drop off. Um, you know, this is not, this is anecdotal. This is not based on [laughs] 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 there are, it's less often as protracted as Alzheimer's can be. Even though the average for Alzheimer's is still also eight to 10 years, um, it can be significantly longer.

   14. PAPeter Attia52:11

       How hereditary is Lewy body dementia, either with respect to Lewy body itself or being predictive of the next generation's risk for Alzheimer's disease or Parkinson's for that matter?

   15. ASAmanda Grant Smith52:24

       Um, I honestly don't know. I don't think it's terribly genetic. You know, we don't have well-established, um, you know, as, as with early onset Alzheimer's, which does have some specific mutations that cause it, I don't know that we know of, of specific mutations for Lewy body disease, but I, I may be just not informed.

   16. PAPeter Attia52:47

       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, 2, 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, you know, microvascular disease, dyslipidemia. I mean, these things are absolutely known, uh, risk factors. Uh, we seem to have none of that on the side of Lewy body, correct?

   17. ASAmanda Grant Smith53:27

       As far as I know, yeah.

   18. PAPeter Attia53:28

       What's the relative incidence of Alzheimer's versus Lewy body dementia? Is it like eight, 10 to one or h- how, how, how much more prominent is Alzheimer's?

   19. ASAmanda Grant Smith53:38

       Um, well it depends I guess if you're looking at, uh, you know, the autopsy confirmed-

   20. PAPeter Attia53:48

       Yeah

   21. ASAmanda Grant Smith53:49

       ... versus sort of what we see in the clinic. Um, you know, I think that I, I honestly don't have the numbers specifically for you, but I, I do know that, you know, it's diagnosed less but found more on autopsy, that people do have Lewy bodies that we may not have expected.

   22. PAPeter Attia54:08

       I got it. And in, just in your experience in your clinic, what's the approximate, uh, distribution of those?

   23. ASAmanda Grant Smith54:16

       Uh, the, the... It's about, I would say, um, you know, 50 to 60-plus percent Alzheimer's, about 20% true vascular, about 20% Lewy body, and then the rest is FTD and some of these Parkinson's-plus syndromes, um, progressive supranuclear palsy and some of these other less common things that we only see once in a while.

7. 54:44 – 1:06:14

   The evolution of Alzheimer’s disease prevention, care, and medications over the last 20 years;

   1. PAPeter Attia54:44

      So back to kind of the way your practice works, presumably people are coming to you at the referral of a neurologist, correct?

   2. ASAmanda Grant Smith54:53

      Not necessarily, no.

   3. PAPeter Attia54:54

      Okay

   4. ASAmanda Grant Smith54:54

      Um, we, we get people referred from their primary doctors, we get people that are self-referred, um, we get people that are referred by neurology. It, it varies widely.

   5. PAPeter Attia55:08

      Th- th- 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, you know, psychiatrist specializing in geriatrics. I'm gonna go see her." And then the, the primary care doctor can say, "Look, I'm, I have a high enough degree of suspicion that my patient has Alzheimer's. They're gonna 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?

   6. ASAmanda Grant Smith55:41

      Um, sometimes yes. I mean, well, first let me say that I would say fully half of my patients think I'm a neurologist. Like, they don't even sort of differentiate or, you know, they'll refer to me as their neurologist, and it, it just is what it is. You know, they assume, and it's fine, or maybe they don't wanna say they're going to a psychiatrist. [laughs] I don't know. Um, sometimes, y- you know, I think it varies from place to place. There are a few neurologists here in town that do specialize in Alzheimer's and treating dementias and focus on that, but a lot of them don't. Um-

   7. PAPeter Attia56:20

      Hmm

   8. ASAmanda Grant Smith56:20

      ... a lot of them prefer specializing in stroke or headache or, you know, MS or seizures. And so, um, when it turns out to be dementia, they just say, "Well, go to the Alzheimer's center." Um, 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. [laughs]

   9. PAPeter Attia56:45

      Yeah.

   10. ASAmanda Grant Smith56:46

       Um, but yes, there are definitely a subset of referring providers who do so specifically so that we can manage the behavioral aspect of things.

   11. PAPeter Attia56:58

       How long have you, um, been in your current practice in Tampa?

   12. ASAmanda Grant Smith57:03

       Since 2002. Um, in this building since 2008, but so what happened is I, um, I came down to USF in 1997 as an intern to do my residency here. So I did my residency in psychiatry and then, um, a fellowship in geriatric psychiatry. And part of my fellowship time was spent with the Suncoast Gerontology Center working under Eric Pfeiffer, um, who had founded that here in 1980 and, um, really was a, 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, um, it was actually one of the reasons I chose USF because I knew Suncoast was here and I was interested in geriatrics and Alzheimer's at that point. Um, so when I finished my fellowship on a Friday, I started working for him on the following Monday. Um, and, and that was in 2002, and then in 2008, he retired and I kinda 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.

   13. PAPeter Attia58:24

       S- so I'm curious as to how your practice has evolved in nearly 20 years. Um, what, 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, are they on a, on a faster track? Are they progressing quicker? I mean, what, what are all the differences that you see?

   14. ASAmanda Grant Smith58:48

       So that's a really great question, and, um, you know, the, 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. Um, I will say that we are seeing people that are both older and younger, you know? I think that there's more of an awareness of Alzheimer's as a disease as well as an awareness of, um, the fact that there are things that we can do about it 'cause 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, you know? There, there has been a lot of, um, 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. Um, I think that, you know, there's definitely more of a shift, um, towards people seeking baseline, people looking at prevention, people, um, wanting, you know, an evaluation and, and tips on brain health. And I know, you know, again, you spoke with Richard Isaacson 'cause he runs a prevention clinic at Cornell, um, in terms of the lifestyle modifications and things that people can do earlier. You know, we, we often see people who have a parent who have Alzheimer's and wanna 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 that, I think that's the biggest area where things have shifted. Um- I think there's also a better understanding that people, um, realize that there's more that we can do and that early intervention is key. You know, people often used to be embarrassed by this problem or isolated by it or not wanna 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 they're, you know, our, our medications are not miracle drugs by any stretch [laughs] , the ones that are FDA approved, um, but they can slow down decline and then in some people they can, can even subjectively and objectively help f- for a period of time. And so knowing that you can preserve your function and stay better longer or stay at home longer, um, you know, there was one old study way back with donepezil showing that it delayed nursing home placement by an average of 24 months. You know, that's huge if you're someone that wants to be at home versus being [laughs] in a skilled nursing facility or if you're, you're a spouse who wants to keep your loved one home. You know, that makes a difference even though the drug's not, you know, the people are still gonna get worse on the medication. Um, so anyway, you know, that was a lot, a big mouthful just to say that [laughs] , you know, I think there is this better, um, 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.

   15. PAPeter Attia1:02:31

       Um, we talked about it at the very outset that so many of the things that the patients are experiencing when they show up are, you know, quote-unquote, "the garden variety things that a psychiatrist would see," anxiety and depression, for example.

   16. ASAmanda Grant Smith1:02:46

       Mm-hmm.

   17. PAPeter Attia1:02:46

       Um, what percentage of the patients that you're taking care of are you prescribing antidepressants and anxiolytics, and, um, 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?

   18. ASAmanda Grant Smith1:03:05

       So the answer is, y- you know, quite a few. Q- I would say the majority of our patients do have some mood or behavioral issue that does require treatment. Um, 90% of people will have some behavioral issue at some point in their illness. Um, it may not be a, you know, terribly problematic psychotic type behavior issue. It may be, you know, something simple, but nevertheless, um, they're very common in all types of dementia. The key is understanding that they are equally treatable. You know, depression in a demented person is just as treatable as depression in a healthy 25-year-old. Um, so there are obviously some, um, adjustments that have to be made for age and, and renal function and other medications and drug interactions, but, um, we very frequently prescribe the SSRIs, um, the type of antidepressants, because they treat anxiety very well in this population. They're pretty well-tolerated. Um, they generally don't make people fall, which is a big issue in this group as well. Um, you know, we try to stay away from the benzodiazepine tri- type drugs, you know, alprazolam and lorazepam and all the pams [laughs] . Um, particularly diazepam and the longer acting ones, but, um, you know, because they can really increase confusion and, and have a dramatically high incidence of hip fracture, uh, with those drugs in, used chronically. So, um, a lot of it is, you know, identifying the specific problem, treating with the least sort of offensive drug that's gonna cause the least amount of collateral damage, um, and, you know, stopping them at times when they may no longer be necessary. You know, old people sort of [laughs] , they collect meds like they collect other things and, you know, sometimes you'll see someone who's on 15, 17, 18 meds and you're like, "Why are you even on this?" Um, 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 'cause their blood pressure's so low, but nobody bothered to say, "Hey, you don't need three meds for your blood pressure anymore." Um, so, you know, we do have to be vigilant and, and really s- 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.

8. 1:06:14 – 1:19:03

   Psychiatric support for dementia patients (and caregivers) with depression and anxiety;

   1. PAPeter Attia1:06:15

      You, you might not know the answer to this, but, um, 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 complimentary care for the psychiatric component, specifically the depression and the anxiety? Do you think it's the majority or the minority?

   2. ASAmanda Grant Smith1:06:34

      I would probably say it's the majority. I mean, a lot of them do get, um, treated by their primary doctors for depression. I see a lot of people who come to me already on medication for that.

   3. PAPeter Attia1:06:45

      Mm-hmm.

   4. ASAmanda Grant Smith1:06:46

      Um, you know, I, I think doctors are prescribing and people are sharing those and, and certainly from the standpoint of, um, some of the more problematic behaviors, you know, people don't wanna 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, you know, more acutely than they will for the underlying condition.

   5. PAPeter Attia1:07:18

      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. Um, how much are you treating the, the spouse, for example, as you are the patient, the, the spouse without dementia?

   6. ASAmanda Grant Smith1:07:40

      Well, in a way I think [laughs] we all sort of give, you know, free therapy, if you wanna call it that. You know, we, uh, I, I do occasionally medicate caregivers if they register as a patient. You know, I'll say, "Hey, you know, you really have the, a severe depression. We need to treat this." Um, but I won't do it out, you know, I won't do it under the patient's-

   7. PAPeter Attia1:08:02

      Yep

   8. ASAmanda Grant Smith1:08:02

      ... you know, o- once we're, we're dealing with meds, it's a whole 'nother story. But, um, obviously there's a lot of support and education. Sometimes, I mean, especially with the pandemic, um, you know, sometimes I'm the only other person that they will see or talk to, even if it's on telehealth like this, you know. Oftentimes it's just that opportunity to vent, to talk to somebody who can understand what they're going through. Um, you know, although I have had some experience with family members having dementia late in life, you know, I was not a primary caregiver. Um, I, most of what I know comes from, you know, 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. Um, but I, I would say quite a lot of, you know, if you wanna call it free therapy or whatever, um, you know, just that opportunity to, you know, listen, to make them understand that, you know, what they're going through is valid and real, um, give them pointers and tools and, and, um, 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. You know, the other day I was talking to someone who just simply cannot get their loved one to take a shower. And I'm like, "Well, what's their favorite snack?" And they kinda looked at me funny, and I said, you know... They were like, "Cheetos." So I'm like, "Okay, tell them after they get out of the shower you'll give them some Cheetos." You know [laughs] , you'll go to the store and you'll get some Cheetos. And they're like, you know, they, they don't think of it that way 'cause 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." "I don't wanna take a shower." And there's not that sort of stepping back and like, "Okay, how can I do this differently?" So sometimes just, you know, kind of giving them a little reality check and a break from the, the constant stress cycle that they're in to kinda look, look at things through different eyes, um, really can, can make a big difference, I think, in their, the way that they approach things. You know, the other, the other thing that's sometimes really difficult for caregivers is, you know, a lotta times they'll think that some of these behaviors that their loved ones are, um, showing are intentional, you know, or, "He's just doing it to annoy me." It's like, "Well, no, he's not."

   9. PAPeter Attia1:10:59

      [laughs]

   10. ASAmanda Grant Smith1:10:59

       Like, if [laughs] "He's really not. If he knew the answer, he wouldn't ask you again. So instead of saying, 'Don't you remember?' just say, answer the question like it's the first time," you know? And, and take out that sort of personal attack side of it, you know, and, and not look at it as they're intentionally trying to irritate you, but, you know, 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, it's, it's easy for me to sit here at my desk and tell them. It's a lot harder to do, but at least kind of having that reality check can, can change the, the way that they approach caregiving.

   11. PAPeter Attia1:11:49

       Um, I'm sure people listening are familiar with Elisabeth Kubler-Ross and how she goes through these sort of five stages, um, of, of grief and how people go through, you know, denial and anger, et cetera, on their way to acceptance. And, uh, that model, um, has always sort of been helpful when thinking about something like cancer. Um, and [clears throat] I got to see that a lot firsthand. Um, is it similar here with Alzheimer's disease, uh, both for the patient and the caregiver, that they, that there's this, you know, in some combination or in some order they go through those?

   12. ASAmanda Grant Smith1:12:31

       Oh, absolutely. I mean, you know, other, you know, I can't take credit for the phrase, but it's, you know, it's like grieving for someone while they're still alive, you know? It, it's the, um, you know, this can't really be happening, and then being angry that it's happening, and, you know, sort of, well, maybe if we do this and maybe do that. In fact, I, I re-listened to your podcast with Lauren Miller Rogin and, uh, Richard Isaacson last evening just kind of in preparation for today and just to make sure we didn't sort of duplicate everything [laughs] that we talked about. Um- But, you know, Lauren in that podcast really gives a very compelling journey right through those stages, you know, in terms of dealing with her mother, um, who was my patient, which is how I got to know them in the first place. Um, but, you know, it, it's really a, a very distinct journey while her mother was, was still very alive and, you know, going through those stages of grief and losing her hopes for what her relationship with her mother would be like as she got older. Um, you know, and it's really terribly sad, and it- 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, our, you know, existence as human beings, is that's kinda gonna happen. Um, we don't always go through all of them or we don't always resolve all [laughs] of them, um, or, or make it through all of them. Uh, but it's a very, very real and major part of, of dealing with this diagnosis.

   13. PAPeter Attia1:14:28

       Um, in, in my experience with oncology patients, once they've progressed through denial and anger and bargaining, et cetera, and they sort of get to acceptance, the... usually the biggest concern, the residual concern, [clears throat] is the amount of suffering at the end. Uh, so it, it actually becomes, um, a- at least one of the concerns becomes around the mechanism of death. Um, and that's not something a lot of people think about. Uh, 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. Um, but it's still, it's kind of a vague, fuzzy, foggy thing, which is, "Yeah, I'll have a heart attack at some point, then I, I won't be alive." But, but to the patient with metastatic cancer who's, again, accepted that and understands that they've progressed through all standard treatments, um, 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. Um, and, a- and, and certainly for the palliative care physician and, uh, a- and, and, 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, uh, 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." Um, 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, uh, and it will result in the end of their life? How do you address the specific fears that remain?

   14. ASAmanda Grant Smith1:16:22

       Um, that's a great question, and I do get asked about it fairly frequently. Um, but yet at the same time we often don't get into it too much because, you know, what I try to do is really help people focus on the now. Um, that being said, you know, uh, what I share with them is that a lot of times, you know, people's... uh, as they progress, they are gonna have more difficulty doing more simple things and more basic things. Um, they will have trouble swallowing. They will need assistance. They will perhaps aspirate on food and get pneumonia. Um, they may lose mobility and be bedridden, you know? And, and we go through that conversation when they ask, you know, "Well, how, how do you die of Alzheimer's?" Um, but the truth is, a lot of people don't ever get to that stage, you know? Many people die of something else. They die of old age. They die of their heart disease. They die 'cause they fell in a parking lot, um, you know, before they ever reach such a terminal stage of dementia. Um, and so, you know, we have the conversation, but we also try not to focus on the end game because that's just miserable, you know? And then, um, I know a little bit later, you know, we- we're gonna be talking about sort of healthy aging and stuff like that, and, and, you know, that's one of the biggest things that I see is, 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. They have... you know, 'cause they may not remember tomorrow what happened today. So, um, they're really living in the moment. So, you know, we try not to spend too much time dwelling on... You know, I, 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, uh, through hospice and other things, um, when the time comes, you know, that they don't have to go through that alone. But, you know, we try to reroute that thought process into focusing on making each day better.

9. 1:19:03 – 1:29:15

   Drug pipeline, clinical trials, and major challenges to overcome;

   1. PAPeter Attia1:19:04

      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. Um, but you also are heavily involved in another part of this, which is How to do clinical trials-

   2. ASAmanda Grant Smith1:19:23

      Yes

   3. PAPeter Attia1:19:23

      ... and this is obviously a very important part of this work. Now, um, Alzheimer's disease and drugs don't have a great marriage. They don't have a great track record-

   4. ASAmanda Grant Smith1:19:32

      Uh-huh

   5. PAPeter Attia1:19:32

      ... the way cardiovascular disease does. Um, and even though oncology is not, you know, great, far from perfect, uh, oncology even has a better track record than Alzheimer's disease. And, uh, I think you could make the case without being hyperbolic that there is no disease that has a worse track record, um, relative to the inputs, uh, on the output side. In other words, there are, you know, there are orphan diseases for which we have no drugs.

   6. ASAmanda Grant Smith1:19:57

      Right.

   7. PAPeter Attia1:19:57

      Uh, but there have been few shots on goal. So the ratio of shots on goals, uh, shots on goal to goals is, uh, 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. Um, some might argue that on another level, that speaks to the wrong goal or shooting too late in the game, you know, shooting from too bad an angle at the wrong goal. Like there, you could-

   8. ASAmanda Grant Smith1:20:26

      Right

   9. PAPeter Attia1:20:26

      ... you could take this metaphor 10 different ways.

   10. ASAmanda Grant Smith1:20:28

       Right.

   11. PAPeter Attia1:20:29

       Um, as it stands today, there are about 120 drugs in the pipeline. Um, 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, in a very small way with dose escalation, we wanna make sure it's safe. About 65 are in phase two, so that means they've passed that bar of being safe, um, 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 are 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 gonna continue to monitor safety. Um, 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, uh, knowing that the next question I'm going to ask you is, that how has that evolved over the last 20 years? 'Cause that to me has been the bigge- that was the thing I was most surprised by.

   12. ASAmanda Grant Smith1:22:13

       Yeah. So the, um, the symptomatic treatments are ones that, you know, 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, um, are ones that are symptomatic treatments because they're just helping those neurons communicate. Um, in the case of donepezil and galantamine and rivastigmine, they're, you know, cholinesterase inhibitors. And then there's memantine, which is an NMDA receptor antagonist that, that normalizes levels of glutamate. But they're just, they're helping with neurotransmitters and they're not, um, targeting the underlying pathology, um, of amyloid and tau. Um, then obviously the, the behavioral drugs are ones that are being targeted for specific behavior problems in Alzheimer's and other dementia patients, things like apathy, agitation, um, 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. Um, in the case of sort of the biggest group of those that are in trials right now are really, um, monoclonal antibodies against primarily amyloid, but also if you look, you know, targeting tau, um, and removing them from the brain in the hopes that then there will be cognitive improvement or at least s- halting cognitive decline. Um-

   13. PAPeter Attia1:24:04

       Can I interject for a second mechanistically? Um, is it known exactly where amyloid beta is made? Is it, is it understood how, you know, from wh- where the, where the transcription takes place, or is this all post-translational modification?

   14. ASAmanda Grant Smith1:24:23

       Well, so there, there's a whole science dedicated to that, you know, and there it actually is, is different points along the cascade, you know? So there's the amyloid precursor protein, which is on chromosome 21, um, 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 'cause they're making a third more amyloid than the rest of us. Um, 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 at a length of 40 or 42 amino acids rather than whatever it's supposed to be, which I don't remember [laughs] . Um, and then the abnormal amyloid kind of folds and, you know, there's fibrils and there, there's Pla- you know, the plaque itself is a conglomeration of, um, a series of folds in the protein. And so, um, there are even differences among the antibodies as to what part of that cascade they target.

   15. PAPeter Attia1:25:50

       And amyloid's not necessary. In other words, if you could wave a magic wand and pull amyloid out of a person, is there any ill consequence?

   16. ASAmanda Grant Smith1:26:00

       Well, like I said, it is part of blood vessel walls normally. So th- this pathologic amyloid, you know, th- these abnormal lengths of Aβ40 and 42, um, yeah, I mean, those could be pulled out without consequence 'cause they shouldn't be there in the first place.

   17. PAPeter Attia1:26:20

       So if you wanted to target the system, you would not target a-- You would not target the creation of amyloid, you would probably target the enzymes that abnormally cleave.

   18. ASAmanda Grant Smith1:26:31

       Well, that, that is one area that has been studied. Um, the, uh, gamma secretase inhibitors, for example, are ones that have been studied. Um, there, there's, there's... And the BACE inhibitors, these are, are things that are being looked at 'cause these are responsible for cleaving.

   19. PAPeter Attia1:26:54

       Mm-hmm.

   20. ASAmanda Grant Smith1:26:55

       But a lot of times those have had side effects that we didn't really want.

   21. PAPeter Attia1:27:02

       Yeah. I wonder if-- Has anybody looked at something like an antisense oligonucleotide 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.

   22. ASAmanda Grant Smith1:27:22

       Yeah, I honestly don't know.

   23. PAPeter Attia1:27:23

       Mm.

   24. ASAmanda Grant Smith1:27:23

       You know, that's, that's for the scientists. [chuckles]

   25. PAPeter Attia1:27:28

       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.

   26. ASAmanda Grant Smith1:27:31

       Yeah. I mean, the thing is, you know, sometimes they have thought of it or they've tried it, but then they don't realize what the downstream effects-

   27. PAPeter Attia1:27:39

       Yeah

   28. ASAmanda Grant Smith1:27:39

       ... of doing so may be.

   29. PAPeter Attia1:27:41

       Yeah.

   30. ASAmanda Grant Smith1:27:41

       Um, and that's been a problem with several of these medications, you know, where the-- it's a great idea. You know, they've identified a target, they've identified compounds that seek out that target, but they cause liver toxicity, or they cause, you know, some other significant, um, medical issue, or they cause cardiac arrhythmias or, um, things that medically are not safe to continue.
10. 1:29:15 – 1:41:21

    Redefining Alzheimer’s disease and designing effective trials;

    1. PAPeter Attia1:29:15

       the symptoms.

    2. ASAmanda Grant Smith1:29:16

       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, the amyloid pathology building up for many years is, was a key factor. You know, I'm not saying it's the factor, but it's a key factor in the development of Alzheimer's disease symptoms. Um, now, some of the disease-modifying drugs that were initially tested were tested in people with mild to moderate Alzheimer's disease, um, and were negative. You know, they, 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. Um, but that 2011 shift into understanding, uh, that there's MCI and that even before that pre-clinical 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 'cause they're so functional in their day-to-day.

    3. PAPeter Attia1:30:50

       What was the typical duration of those failed studies? Um, so if you look at the earlier studies that were trying to remove amyloid, uh, late in the game that, that failed, do, do you recall on average what the duration-- Are these like four-year studies, three-year, five-year studies?

    4. ASAmanda Grant Smith1:31:08

       No, they were usually about 18 months.

    5. PAPeter Attia1:31:10

       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, you know, have the most aggressive form of cardiovascular disease. They've got multi-vessel disease, huge stenoses, um you know, vulnerable plaque everywhere, and for 18 months, let's see what happens if we employ lipid-lowering therapy, uh, and we see that it has kind of a minor m- impact," and you can make the case, "Well, you probably should have done it earlier and for longer."

    6. ASAmanda Grant Smith1:31:51

       Right. And well, I mean, the, 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, um, benefit, I don't think, to doing a three or four-year study of that moderate, you know, moderately demented group with these therapies 'cause they were just gonna get, keep getting worse.

    7. PAPeter Attia1:32:18

       Mm-hmm.

    8. ASAmanda Grant Smith1:32:19

       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. Um, so, you know, traditionally, 18 months has been a standard length for Alzheimer's trials 'cause it's the amount of time... You know, you have to remember, these trials cost lots of money. [laughs] Um, you know, people often complain, and rightfully so, that certain drugs are extremely expensive and, and, you know, obviously you coming from Canada have a whole different perspective on, um, that than, you know, the American side of it, you know, where it's just all about money all the time. Um, that being said, you know, 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, you know, 10 to 15 years and a billion dollars for any one drug to get from development and discovery to FDA approval.

    9. PAPeter Attia1:33:40

       Yeah, that, that's right. It, it's pro- it's probably higher today, actually. It's probably closer to about 1.3, 1.4 billion. Uh, and you're absolutely correct. Uh, so if you look at that pipeline of 120 odd drugs, um, a- again, it's not gonna be 120 billion 'cause some of them will get, you know, weeded out in phase one. Um, but there's no question that the United States, um, subsidizes the rest of the world in drug pricing. So what, w- it, 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 U.S.

    10. ASAmanda Grant Smith1:34:28

        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 4,000 or 5,000 that don't. Um, you know, some get squashed in the very beginning, and some make it to animal models, you know, but, you know, so, so it's a very, very, very expensive-

    11. PAPeter Attia1:34:53

        Yeah

    12. ASAmanda Grant Smith1:34:53

        ... um, process for the drug companies. And so [laughs] my, going back to my point, you know, they have to find that sweet spot in terms of length of a trial that will sort of 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, you know, 18 months is a spot where you're gonna see, okay, so in 18 months, if they're better, well, that's crazy 'cause that doesn't happen. [laughs] Um, if they're stable, well, that's good 'cause it's usually there's some drop-off in that period of time. And if they're worse, then clearly it's not working.

    13. PAPeter Attia1:35:40

        Yeah, and if you, if you look at the oncology playbook here, um, y- 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. Um, and truthfully, you have kind of a, a, a gray area of utility, right? There are drugs that are getting approved that make very little sense. Um, so they extend median survival by two months without extending overall survival, and they're gonna cost $100,000, and we can debate the merits of that, and that's where you'll see differences between the U.S., the UK, Canada, et cetera.

    14. ASAmanda Grant Smith1:36:27

        Right.

    15. PAPeter Attia1:36:28

        But you see, one of the issues here that, that I find most interesting, and I'm not famili- 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 in study design. Um, it's everything, right? So to me, let's use cardiovascular disease as an example. I always found the FOURIER trial and the ODYSSEY trial, which were the two major trials used to test the PCSK9 inhibitors, I found them to be very elegant and very complementary. So the FOURIER trial took patients who were maximally statinized. Uh, 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. Um, and then added a PCSK9 inhibitor to them. Um, the study was stopped after two to three years. I believe it was intended for four or five, and it demonstrated an improvement. Um, and again, in cardiovascular disease, what are your outcomes? It's usually MACE, uh, major adverse cardiac event, so heart attack, stroke, revascularization, death. So you have hard 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 complementary 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 al- they usually include all-cause mortality. This is a challenge that where I see in Alzheimer's disease is, and I'm, 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. Um, 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, um, in the end, it's a harder disease to measure definitive outcomes at the-- at, to your point, at the duration of time we wanna study them. So, um, that's a lot to unpack and, and, and I, 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 we're, we're-- If I've heard you earlier, it's we, we don't wanna be studying patients for disease modification that already have significant dementia. So are you-- would you say the same is true of MCI and we should be looking at the preclinical, or with- which means we by definition are making an imaging diagnosis, um, or is it early MCI?

    16. ASAmanda Grant Smith1:39:33

        So I think, you know, the, the jury's still out with regard to MCI. There still are a lot of trials, and I think there may be, um, opportunity for, um, mild cognitive impairment as well as mild dementia to benefit from these disease-modifying therapies. Um, you know, if we're looking at a cure, 'cause that's what everybody wants, right? A cure. Um, I think the prevention trials are really gonna be the way to go because then you're stopping it before it starts. You know, we know that these anti-amyloid drugs remove amyloid. We know this. They successfully reduce amyloid to a point where people go from having positive amyloid PET to negative amyloid PET. Um, in fact, we had a, an occasion once where we had a patient who was in a trial, um, an anti-amyloid trial for some time, and then that study stopped, and then she wanted to enroll in another study, and it was actually an anti-tau antibody and, and they did allow people with previous exposure to anti-amyloid drugs after a certain window of time. Sometimes they don't. Um, so when she had her new amyloid PET for that study, she screen failed 'cause she was amyloid negative. And so, um, you know, that's been shown in, in numerous trials with more than one compound that, that it definitely removes amyloid. So if you look at the PET outcomes for these drugs, they're great. Um-

    17. PAPeter Attia1:41:19

        What are the clinical outcomes?

    18. ASAmanda Grant Smith1:41:20

        But nobody cares

11. 1:41:21 – 1:50:47

    The promise of monoclonal antibody treatments for Alzheimer’s disease;

    1. ASAmanda Grant Smith1:41:21

       what-- Yeah. Yeah, just like, like you said, nobody cares about a m- a mar- a marker cholesterol. You care about the clinical outcomes and symptoms. And so none of that matters if, if you're removing amyloid, if the people aren't any better-

    2. PAPeter Attia1:41:35

       Mm-hmm

    3. ASAmanda Grant Smith1:41:35

       ... or if they're continuing to get worse. You know, that's what was happening with the mild to moderate group, um, you know, the original solanezumab trials. Um, you know, people just kept getting worse 'cause they're-- they already had enough neurodegeneration and other pathology now going on in the brain that the, whether the amyloid was there anymore didn't matter. Um, I do think in MCI that there's opportunity for these drugs to work and, and, you know, the FDA is considering the aducanumab data right now. Um, the-- There was just, um, last or actually at the beginning of this week, data for donanemab, which is a Lilly study that came out at the, um, ADPD meeting showing that it met endpoints on almost all of the mark, you know, the, the primary and secondary outcome measures that they had set forth. So, um, yeah, 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, you know, just like you'll go to the doctor and see you have high cholesterol and intervene then before you get to these, you know, 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.

    4. PAPeter Attia1:43:10

       Yeah. That make-- That makes hands down the most sense. And again, I, 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-

    5. ASAmanda Grant Smith1:43:27

       Right

    6. PAPeter Attia1:43:27

       ... until you have cancer. Uh, now, of course, I think-

    7. ASAmanda Grant Smith1:43:30

       Right

    8. PAPeter Attia1:43:30

       ... 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, um, discussion we're gonna have on the podcast in the next, you know, couple of months. Um, so the goal, of course, is to turn cancer into cardiovascular disease. It's to, to turn, uh, Alzheimer's disease into the same. So one of the most promising versions of these monoclonal antibodies to, uh, amyloid is aducanumab-

    9. ASAmanda Grant Smith1:43:55

       Mm-hmm

    10. PAPeter Attia1:43:55

        ... which is a drug manufactured by a company called Biogen, and it's been in the news a lot lately. Um- I think for several reasons. One is it's a drug that made it to phase three, and it was running two parallel studies, uh, emerge and what was the other one called?

    11. ASAmanda Grant Smith1:44:13

        Engage.

    12. PAPeter Attia1:44:14

        Engage. Yeah.

    13. ASAmanda Grant Smith1:44:15

        Mm-hmm.

    14. PAPeter Attia1:44:15

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

    15. ASAmanda Grant Smith1:45:07

        Right

    16. PAPeter Attia1:45:08

        ... what was the, what was the endpoint in this study, and how did they go about evaluating?

    17. ASAmanda Grant Smith1:45:13

        Um, honestly, I don't [laughs] remember what, what the specific primary outcome measure was.

    18. PAPeter Attia1:45:20

        So it, it was co- it was cognitive, but it wasn't like, it wasn't an imaging study. It was a cognitive study, right?

    19. ASAmanda Grant Smith1:45:27

        I don't remember if it was the ADAS-Cog or not, to be perfectly honest. The story of the EMBARC and ENGAGE studies is... Or I'm sorry, the EMERGE and ENGAGE.

    20. PAPeter Attia1:45:40

        Yeah.

    21. ASAmanda Grant Smith1:45:40

        We're doing EMBARC now, which is the, uh, follow-up for the people that had previously been in EMERGE and ENGAGE. Um, so the, 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. Um, and when they did the futility analysis, they were not meeting their primary endpoints. Um, 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." And so they ended up going back and, and putting people back in the study who had previously been on it, um, in this new EMBARC study as well as submitting to the FDA for approval.

    22. PAPeter Attia1:46:57

        And the, the, 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 ApoE and non-ApoE, uh, which I didn't understand because they were giving a lower dose to the ApoE4 carriers than a higher dose. And are they currently just giving everybody the highest dose in the revisit trial?

    23. ASAmanda Grant Smith1:47:21

        Um, I don't know if I'm allowed to talk about the current protocols.

    24. PAPeter Attia1:47:24

        Okay.

    25. ASAmanda Grant Smith1:47:24

        [laughs]

    26. PAPeter Attia1:47:26

        No, that's okay.

    27. ASAmanda Grant Smith1:47:26

        If it's confidential or not.

    28. PAPeter Attia1:47:27

        So, but, but what's interesting is that there's something that's gonna happen on June 7th. What is that? What are, what are we waiting for on June 7th?

    29. ASAmanda Grant Smith1:47:35

        Well, I, I just wanna go back and touch on a point that you mentioned. You know, one of the reasons that they give the ApoE4 carriers a lower dose is because of the risk of ARIA or 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 microhemorrhages. So ARIA-E for edema, ARIA-H for hemorrhages. Um, often asymptomatic, but certainly, um, were very significant in some of the earlier iterations of anti-amyloid-

    30. PAPeter Attia1:48:15

        Mm
12. 1:50:47 – 2:02:45

    How we should measure outcomes in dementia trials and define “healthy aging”;

    1. ASAmanda Grant Smith1:50:47

       that's, I think you touched on a little bit earlier, part of the problem that we have is that, you know, the outcomes, the primary outcome measures for these trials aren't that great. Um, you know, there's... 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. Um, the ones that focus on the CDR, the clinical dementia rating, you know, there is a subjective component-

    2. PAPeter Attia1:51:24

       Mm-hmm

    3. ASAmanda Grant Smith1:51:24

       ... to that, 'cause that's not just a test. That is a, an interview and a rating that a rater makes based on, um, what both the patient says and what an informant says.

    4. PAPeter Attia1:51:37

       And the CDR is the primary endpoint for this drug.

    5. ASAmanda Grant Smith1:51:41

       Okay. So, and that's the thing. I mean, the CDR has, um-

    6. PAPeter Attia1:51:46

       I think it has six dimensions to it, but it's subjective, as you said.

    7. ASAmanda Grant Smith1:51:50

       It, it is subjective and, and prone to, um, bias from, let's say, a depressed caregiver who sees everything worse than it is, you know. Um, we, there have been studies looking at that kind of thing and, you know, a lot of times a caregiver who is highly stressed and depressed will over-report 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, you know, some other things and, you know, a, a rater will interview the subject. Well, they'll, they'll interview the informant, and then they'll interview the subject and, um, you know, 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, you know, is based on what the patient remembers compared to what the informant said. Um, and, 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, eh, it feels like a one or it feels like a .5, you know, that, that plays into it that, that's not, you know, just an objective measure like an LDL level, you know? Um-

    8. PAPeter Attia1:53:25

       Yeah, I mean, that's, 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. Um, 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-

    9. ASAmanda Grant Smith1:54:00

       Right

    10. PAPeter Attia1:54:01

        ... in combination, potentially, with a clinical evaluation.

    11. ASAmanda Grant Smith1:54:05

        Yeah.

    12. PAPeter Attia1:54:05

        I don't think we're g- you're not gonna... You can't do a long enough study to get hard outcomes.

    13. ASAmanda Grant Smith1:54:11

        Right.

    14. PAPeter Attia1:54:11

        Um, so I- I mean, there's really two enormous challenges-

    15. ASAmanda Grant Smith1:54:16

        Mm-hmm

    16. PAPeter Attia1:54:16

        ... 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.

    17. ASAmanda Grant Smith1:54:26

        Right. And, you know, 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, um, whether it's the ADAS-Cog, or there was a, a cognitive, um, composite score that was recently used by Eisai for a different trial. You know, they got a lot of flack for it, um, 'cause 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, um, measures that we're gonna 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, um, you know, I personally didn't have a problem with that cognitive composite because I thought that it was a thoughtful way of kind of rethinking, um, and getting good data that might be useful, you know. The, the ADAS-Cog is just so ingrained in this field, and although it certainly has a lot of utility, it also has limitations. And so, um, 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, for drugs moving forward.

    18. PAPeter Attia1:56:12

        So I wanna kind of close our discussion, Amanda, with something you alluded to earlier, which is what does it mean to, to, to undergo healthy aging? Um, it's in- it's inevitable.

    19. ASAmanda Grant Smith1:56:23

        Yeah.

    20. PAPeter Attia1:56:23

        We're all aging. We're all going to die, and unfortunately, many of us are going to die, um, with some form of cognitive impairment, even if it is not dementia.

    21. ASAmanda Grant Smith1:56:34

        Yeah.

    22. PAPeter Attia1:56:34

        So in your 20 years of practice, what, what, what wisdom have you gleaned, and, and what might someone who is, you know, seemingly far from that learn?

    23. ASAmanda Grant Smith1:56:49

        So, you know, it's, it's interesting, and I, I knew we were gonna talk about it, so I've actually been, you know, more contemplative in the last few days kind of thinking about it. Um, you know, there, there are a lot of different frameworks for aging, you know, the stuff that we learned in psychology class and, you know, some of these classic structured approaches to aging, both psychological and, and sociological. But, you know, I'm never one to kind of, um, 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, you know, but at the end of the day, you know, it really has to do with, you know, 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, um, and, you know, how able they are to focus on the positive. Um, 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 gonna happen or what might happen that they can't enjoy now. And, you know, it's, it's very interesting. I can have two patients, you know, maybe both of whom were marathon runners, and now both have Parkinson’s disease. And while they both have disability, one of them sort of 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 in a special wheelchair," or, you know, focusing on what I still can do and trying to make the most of each day. Um, and those are the people that I think age successfully, even in the face of having illness. You know, we all will age. We all have, um, changes in our physical strength and our, you know, 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, how that shapes our attitude or how much we let it affect our attitude.

    24. PAPeter Attia1:59:44

        I want to run an idea by you, and I, I'm curious as to your thoughts. Um, I describe healthspan or quality of life as having broadly three dimensions, uh, a physical one, a cognitive one, and 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. Um, now, if you're really lucky, they don't decline too, too much, assuming you live a long life, right? So if you talk about someone who's gonna 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 not-- It, it, it doesn't have to be that sharp. And for the lucky ones, you do hear... You know, you, you 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, I believe is most a function of the quality of our relationships. 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, you know, they, they have an emotional strength to them that I think comes from this tethering to other people. So, so do- does that framework make sense?

    25. ASAmanda Grant Smith2:01:37

        Absolutely. I think it's, it's spot on and, and exactly true, you know. That is so important in terms of, um, you know, well-being is, is having people... You know, feeling loved, feeling that there are people you can rely on, feeling that there are people who can share experiences with you. You know, social isolation is a huge problem for some people and, and a definite, um, determinant of quality of life versus not. Um, I definitely see the people that struggle the most are the ones that are constantly comparing themselves to their former selves. You know? Um, I used to be able to do this, I used to be able to do that, I used to, you know. If I did that, I would just be, you know, hiding under my covers. I mean, I didn't used to need these, but I do, so it's like, well, I might as well buy cute ones because you gotta have 'em, you know? And, and so it's-

13. 2:02:45 – 2:11:30

    How understanding dementia can reshape our life philosophy;

    1. PAPeter Attia2:02:46

       It's so hard though, Amanda. Like, I, I, I, I, you know, 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, um, for most people at least, it's, it's gonna be a, a far greater, uh, 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's as good a time as any to begin rehearsing that. And I, and I, and I've, I've been very deliberate about this for the past two to three years, um, in anticipation of hopefully a long life, um, which ... 'Cause, you know, look, I think there was a day when all of my identity was wrapped up in the, in these things that are inevitably going to decline, and none of it was wrapped up in the other. And, and, uh, there [laughs] I'm undergoing an asset reallocation, uh, which I guess the point is we should be doing this when we still have a chance to.

    2. ASAmanda Grant Smith2:03:54

       No, you're absolutely right. And, and that, that actually is a, 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 I, you know, I, I, as we were talking earlier, um, another big thing that I think contributes to quality of life and sort of whether people age well or not is regret and how much regret-

    3. PAPeter Attia2:04:20

       Mm-hmm

    4. ASAmanda Grant Smith2:04:20

       ... 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 were just about to retire and do X, Y, Z, and then now, "Well, now I have this devastating disease." And so, you know, part of what I do is educating them, "Well, you can still do X, Y, and Z. You just might have to do it a little bit differently." Um, 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, you know, the horizon from my bed. And so, you know, 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 [laughs] got it, but it meant that I could wake up and see the Gulf of Mexico. Um, and, you know, we, especially through the pandemic, we've gone there almost every weekend just because what else are you gonna do? And, you know, I, 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, 'cause I might not be able to use it, you know? I'm living now, so do it now. And, and that's, you know, 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 it's a hard stop. Like, "Oh, well, 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," or, "You can still take that cruise, but you just wear ... " You know, I actually, any time I go to a meeting, I haven't been to a meeting in, you know, a year and a half, but you know, I save all of my name tag, you know, lanyard 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 or whatever in it, and your cell phone number so that if, you know, your loved one wanders off on the ship, at least they can call you or they can find out what cabin you're in." Um, and so it, it's, it's making those adjustments, but still, you know, doing the things that you enjoy with the people you enjoy doing it with.

    5. PAPeter Attia2:06:42

       Uh, I think, I think that's incredibly well said, Amanda. Um, you know, I've really enjoyed our discussion today, and I know that everyone listening to this has as well because, um, I, I just think people are becoming more and more aware of this condition. Um, and as you said, it's less taboo. It's something that people are talking about. And I, I do believe that, um, people are cautiously optimistic that the next decade looks better than the last decade in terms of actual medical treatments we have. Uh, I'm still firmly in the camp, um, of Richard, which is not to say that y- you're not saying that, but that, that, 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 in the grasp of prevention and are going to need treatments. Um, and I'm hopeful that these, uh, monoclonal antibodies that can target amyloid beta or tau, uh, can be a step in the right direction. So thanks very much for all of your insights today.

    6. ASAmanda Grant Smith2:07:45

       Oh, my pleasure. And of course, exercise. [laughs]

    7. PAPeter Attia2:07:50

       You don't need to tell this audience.

    8. ASAmanda Grant Smith2:07:53

       No, I know. That's what I'm saying. That, you know, it, it's, even if you've passed the point of prevention, you know? And, and I know you've gotten into this in other podcasts, but you know, 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. Um, you know, st- some of the, um, research that some of our colleagues do through all of these prevention trials and then through these intervention trials in MCI and AD, um, Silver Sneakers program at the YMCA. Um, Laura Baker, uh, at Wake Forest is doing a lot of great stuff with this and, and showing that even if you have dementia, your scores will go up if you do aerobic exercise. So-

    9. PAPeter Attia2:08:50

       I'm glad you said it

    10. ASAmanda Grant Smith2:08:51

        ... that's what gets me going in the afternoon. [laughs]

    11. PAPeter Attia2:08:55

        All right, Amanda. Well, thanks so much, and I, I hope you get to, uh, to see the sunset, uh, this weekend.

    12. ASAmanda Grant Smith2:09:02

        Thank you. I really appreciate it. It was great talking with you.

    13. PAPeter Attia2:09:07

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Episode duration: 2:11:30