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

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.740 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.080 today's episode. My guest this week is Dr. Amanda Smith. Amanda is the director of clinical research

00:00:54.940 at the University of South Florida Health Bird Alzheimer's Center and Research Institute.

00:01:00.240 She is also a professor of psychiatry and behavioral neuroscience at the University of South Florida,

00:01:04.960 and she specializes in the treatment of patients with Alzheimer's disease. She received her MD from

00:01:12.020 Thomas Jefferson University and did her residency and fellowship at the University of South Florida.

00:01:16.720 She specializes in Alzheimer's disease clinical research, along with the diagnosis and treatment

00:01:21.760 of patients with AD and other memory disorders. She's an active member in the memory disorder

00:01:27.920 community, and I actually met her through our shared interest in a nonprofit that you may have

00:01:33.520 heard of, Hilarity for Charity. In this episode, we talk about a number of things, obviously her

00:01:37.860 background and what drew her into a field that many people don't necessarily think of, geriatric

00:01:43.020 psychiatry, as a field pertaining to Alzheimer's disease. We talk a lot about the clinical diagnosis

00:01:49.000 of Alzheimer's disease, which actually is still somewhat elusive, and while it's easier to make

00:01:54.320 the diagnosis today than, say, 20 years ago, it's still far from a perfect diagnosis, and a number of

00:02:00.500 other things need to be ruled out. We get into a pretty good discussion around the pharmacotherapy

00:02:05.900 pipeline. There are, at this time, over 100 drugs in the regulatory pipeline for testing, and we get into

00:02:13.140 a discussion of where they are in that phase and what they're targeting. We discuss specifically,

00:02:18.760 a drug called adecanumab, which is a monoclonal antibody directed at amyloid beta, and at the

00:02:25.040 time of this podcast, it is very tenuously awaiting FDA approval, a decision that should be rendered on

00:02:32.280 June 7th. This is a very important moment for the research community because if approved, it would be

00:02:38.280 the first drug approved, both as a monoclonal antibody and secondly, as a drug that is a disease

00:02:45.120 modifying drug as opposed to a symptom-based drug, which is currently all we have in the quiver.

00:02:52.780 We conclude the discussion by talking about what it means to age in a healthy way, and I think this

00:02:58.760 is the part that probably has the broadest application because even if you don't develop

00:03:02.660 Alzheimer's disease, you will age. That is inevitable, and the insights that Amanda provides

00:03:08.180 here are going to be valuable for everyone. I certainly feel that way myself. So without

00:03:13.460 further delay, please enjoy my conversation with Dr. Amanda Smith.

00:03:22.000 Hey Amanda, thank you so much for making time to chat with me today. From the first time I heard

00:03:28.380 you speak, I knew I wanted to have you on the podcast. You probably don't even remember when that

00:03:31.760 was, do you? Well, I think it was that Zoom thing for HFC, right? That's right. That's right. It was

00:03:38.420 hilarity for charity, and somehow I was considered an expert. You clearly are an expert, and you and me

00:03:45.120 and Richard Isaacson were a part of a discussion in the days when we no longer do physical panel

00:03:50.680 discussions. And I just thought, wow, I was really kind of blown away by a lot of your insights because

00:03:56.420 they went beyond just the obvious topics we discussed, which are the research around what's

00:04:01.960 the cause of Alzheimer's disease? How do you prevent it? What are the treatment? All those

00:04:04.920 things are relevant, and all those things are things that you speak to. But I think what impressed me

00:04:08.980 was the attention you brought to the impact that Alzheimer's disease has on the family just as much

00:04:14.580 as it does the patient. And certainly that's something I want to talk about today. But before we get to

00:04:19.160 that, tell us a little bit about your background. You specialize in geriatric psychiatry, which are

00:04:24.000 not often things you think about, right? People think about psychiatry. They think about forensic

00:04:28.440 psychiatry. They think about more of the DSM-5 type of psychiatry. How did you get interested in that?

00:04:34.560 I grew up in Philadelphia, and I had very active grandparents. They owned a nursing home. A lot of

00:04:43.680 people think grandparents in a nursing home. My own operated a nursing home. And just from a young age,

00:04:50.240 being around them and their friends and, you know, seeing the vibrant lives they led even into their

00:04:57.360 70s and 80s, that to me was normal aging. I never thought of anything different until I was in medical

00:05:06.000 school. And I really saw the pathologic side of aging and the things that can go wrong as we get older,

00:05:13.660 as well as, I want to say, an attitude of ageism among a lot of the attending physicians that we

00:05:20.700 trained under. And there was this sort of epiphany I had one day. I remember I was in Bryn Mawr Hospital

00:05:28.620 in the emergency room, and the attending sent me in to talk to a woman who had come in from a nursing

00:05:36.300 home with chest pain. That was all I knew. So I went in, and I talked to her, and I got the history,

00:05:41.820 and I went and I presented the case to the attending in rounds. And he just laughed at me,

00:05:49.200 and he's like, you went in the wrong room. You know, he's like, the lady I'm talking about doesn't

00:05:53.340 make any sense. And I was like, actually, she does. She just doesn't have her dentures in because the

00:06:01.580 EMTs forgot to bring them. You know, but if you actually sat there and took the time to listen

00:06:06.220 to her, she told a very normal, coherent story about how she was eating lunch, and she felt pain

00:06:12.760 and went to her shoulder, so she called the nurse. That, for me, was so enlightening because I realized

00:06:19.940 how quick people are to brush off the elderly. And it kind of lit a fire in me, so to speak, so that,

00:06:28.700 you know, that became my passion. So for the rest of medical school, I made sure that

00:06:33.860 my elective rotations were geriatrics and working with older people in different aspects of it. And

00:06:41.880 one of my favorite experiences was on the geriatric psychiatry unit, where I got to work with dementia

00:06:49.180 patients and psychotic patients. And I just found that personally, I had more patience for them because

00:06:56.280 of their life stories and the things that they've been through. And, you know, it just sort of led me

00:07:02.340 down this path to where I am now. And there are lots of ways, as you've experienced, I suppose,

00:07:08.400 to interact with patients in a geriatric setting. Obviously, internal medicine, you could go down

00:07:13.840 that path through cardiology. You could certainly go down that path through other subspecialties.

00:07:18.660 When you were doing the psychiatric work, was it understood at the time that a part of dementia is

00:07:28.060 behavioral changes and other things like that? Or how much was it understood that Alzheimer's disease

00:07:35.580 had a behavioral component that would be under the purview of psychiatric care?

00:07:39.360 I think it was fairly well established. The part that was the bigger problem was that there wasn't

00:07:45.820 much that we could do about the cognitive side of things. And fortunately, that's changed some in the

00:07:52.880 time that I've been doing this. So I graduated from med school in 1997, which was actually the year

00:08:00.080 that Dinepazil or Aricept was first approved. So I've kind of witnessed the evolution of Alzheimer's

00:08:07.160 treatments in that time. But certainly from the behavioral standpoint, the behavior problems that can occur

00:08:16.880 are in people with dementia have always been treatable. Anxiety, depression, psychosis. Those

00:08:23.440 have frequently been reasons for hospitalization and often were the reason that we saw people on the

00:08:30.160 geriatric psychiatry unit because they were imagining things that weren't there or, you know, acting out on

00:08:39.200 delusions that they had that people were spying on them and they were taking apart the

00:08:43.760 ceiling tiles in their apartment to find these wires that weren't really there and all that kind

00:08:50.400 of thing. So we've always been able to treat that. And fortunately, there's also been improvement in

00:08:56.720 some of the options there. Not ideally, but to the point where we can control some of those behaviors so

00:09:04.400 people can have a better quality of life and so that caregivers can have a little more peace of mind as well.

00:09:10.640 Is it common that a patient is known to have dementia? And we'll get to how that's diagnosed

00:09:17.840 in such in a moment. But a patient is known to have this diagnosis of dementia, either Alzheimer's

00:09:22.560 dementia or some non-Alzheimer's form. And then they begin to exhibit some of the symptoms you've

00:09:28.560 described so that when they're coming in for evaluation, you're not going through a lengthy

00:09:34.560 differential diagnosis to rule out schizophrenia or other forms of psychoses. Or is it sometimes

00:09:41.200 the case that actually the presenting feature of the dementia can be some of these psychotic

00:09:47.680 symptoms you describe where they feel, hey, someone's talking to me or something like that?

00:09:52.240 Yeah. In fact, the answer is both. Sometimes people will have a course of dementia that after a few

00:10:00.480 years they'll start to develop some of these behavioral symptoms. Some people never get them

00:10:05.600 and some people do actually present with them. Often with the latter, what will usually happen is they'll

00:10:13.040 go be seen by a community psychiatrist or somebody else and get diagnosed with schizophrenia or bipolar

00:10:22.560 illness or something that does not have an onset in the mid-70s. And so usually they'll be misdiagnosed

00:10:30.080 for a couple of years until it becomes really apparent that that's not the primary problem,

00:10:37.120 that there is an underlying neurodegenerative process. I can't sort of imagine, because I haven't

00:10:44.240 been close enough to it, what it's like for a patient in the early stages of dementia. I've seen patients

00:10:52.320 in the later stages where, at least on the outside, it seems that they're quite removed from what's

00:11:01.120 happening. And paradoxically, they don't appear to be suffering very much. But is it safe to assume

00:11:08.480 that it's quite unnerving in the early stages and that that might actually be what's driving some of

00:11:14.160 this behavior? It's a legitimate and understandable fear of something is wrong, but I don't understand what

00:11:19.920 it is. Yeah. I mean, sometimes. So some people are always blissfully unaware throughout the entire

00:11:28.640 course of their illness. I can't tell you how many times I see a patient and they sit down in my office

00:11:35.280 and I'm like, so what brings you in today? And they're like, my wife, there's nothing wrong with

00:11:39.520 me. I'm fine. They have no idea why they're there, even in the very mild stages. Whereas some people are

00:11:47.680 so acutely aware that something's not right. And sometimes they know for two or three years before

00:11:54.960 we can even find any discernible changes on their testing. You know, they're like, I know something's

00:12:00.880 wrong with me. And a lot of times they're right. Sometimes they're just anxious because a family

00:12:07.580 member had it or they're worried. But a lot of times, you know, they're very in tune to what's

00:12:11.840 happening. And I think you're right. Usually those are the people that suffer the most because they

00:12:18.040 know what's happening to them and they don't like it and they know what they're facing. Some patients

00:12:25.400 are extremely insightful and really are aware of what's happening, aware that they're losing things

00:12:32.920 that they used to be able to do or that things aren't coming as quickly. Even yesterday, weirdly,

00:12:39.060 I had two patients with Lewy body dementia, which is a type of dementia that has parts of Alzheimer's,

00:12:47.240 parts of Parkinson's, and some very prominent visual hallucinations. And whereas oftentimes when

00:12:54.640 people have hallucinations or false beliefs to them, they're real and they don't know that they're

00:13:00.520 not real. Both of these patients were like, I see things that aren't there and it drives me crazy.

00:13:06.200 Like they knew this one woman has people all over her living room and she can't find a piece of

00:13:12.860 furniture to sit down on because these people are sitting there and she knows they're not real.

00:13:18.700 But yet she feels like she has to ask them to move in order to sit on her own furniture.

00:13:24.280 But she was insightful enough to be able to say, I know they're not there and I know my family

00:13:29.580 members don't see them. So it's really variable. Let's talk a little bit about how one makes the

00:13:37.620 clinical diagnosis first of dementia and then how one starts to separate out Alzheimer's from Lewy body

00:13:47.080 from presumably an unspecified form of dementia. So starting with the former, what is the clinical

00:13:53.300 definition in the diagnosis of dementia? Dementia is an umbrella term that just sort of describes

00:13:59.400 changes in memory and other areas of cognition. And it represents a change from how you used to be,

00:14:07.000 so you weren't born with it. And it interferes with your day-to-day function. So there are many

00:14:12.140 causes of dementia. Alzheimer's far and away the most common. Although there have been advancements in many

00:14:20.800 of our tests and more sophisticated imaging techniques and blood biomarkers that are coming

00:14:28.340 along, the real crux of diagnosis is a good clinical interview with a patient and with an observer.

00:14:39.780 So usually it's a spouse or an adult child or a loved one who has observed changes over time. And in

00:14:47.760 interviewing them separately, that's key, separately, because otherwise the most important information

00:14:54.860 is left out, you know, because they don't want to hurt the loved one's feelings or whatever. So

00:14:59.920 getting a good clinical interview from the patient, informant, doing some cognitive testing to look for

00:15:07.880 patterns that support one diagnosis over another, and then doing some brain imaging to look for certain

00:15:15.860 things like strokes or shrinking in certain parts of the brain, as well as some lab tests to rule out

00:15:22.400 reversible causes of memory loss, thyroid disturbance, vitamin deficiencies, things like that, syphilis,

00:15:30.000 although frankly, I've stopped really testing for that because it's just tertiary syphilis is so

00:15:35.160 uncommon these days. And once we do all that, generally speaking, you know, we have a pretty accurate

00:15:42.360 diagnostic chance of getting the right label for them. Sometimes we need formal neuropsych testing

00:15:50.320 with a neuropsychologist. Sometimes we do need PET scanning to look at certain patterns. For example,

00:15:57.340 frontotemporal dementia is one where people often present with relatively preserved memory, but

00:16:03.820 significant changes in language or behavior. And usually within a minute, I can diagnose them because

00:16:12.520 the loved one will say, well, his memory is not so bad, but, and it's either, you know, he can't really

00:16:18.320 talk anymore, which can also happen in Alzheimer's fairly early in some people, or I'm embarrassed to

00:16:25.940 take him to church because he'll get up and take the microphone from the pastor. And, you know,

00:16:32.640 you almost know, okay, this is FTD. Those are often the people that erroneously get diagnosed with

00:16:39.300 bipolar illness because of these sudden and really profound behavior changes, problems with judgment,

00:16:47.920 where they get labeled as being manic because they're spending lots of money, or they're

00:16:52.460 responding to every publisher's clearinghouse thing that comes in the mail. So there's these typical sort of

00:16:59.300 stories and behaviors that we see that kind of support one diagnosis over another.

00:17:06.520 So Amanda, there's a lot in there, and I kind of want to go over that in a bit more detail. So to

00:17:11.400 make sure I'm understanding this, and obviously the listener as well, the first thing I heard you really

00:17:15.140 say there was the absolute importance of the clinical story. So unlike cancer, where the diagnosis

00:17:21.980 is made typically off imaging and then ultimately through a tissue sample, right, the gold standard is a

00:17:29.180 histological diagnosis. That's not the case in Alzheimer's disease. We don't do biopsies of the brain. I also

00:17:35.180 didn't hear you talk about CSF sampling, sampling the cerebrospinal fluid to look for amyloid beta or tau.

00:17:43.800 Anything you want to say about that before we continue down this rabbit hole?

00:17:47.400 Yeah. I mean, there are a few things I can say about that. First of all, certainly it is extremely

00:17:53.240 helpful in the diagnostic process to have formal tests like CSF or amyloid PET in terms of confirming

00:18:03.820 a diagnosis. Although we certainly don't do brain biopsies, unlike when I graduated, when you literally

00:18:12.120 could only see amyloid at autopsy under a microscope, we now do have the ability to image amyloid in

00:18:19.540 living patients, which has, and I know we're going to talk about research later, allowed us to really

00:18:26.480 go much earlier in the process and design some prevention trials based on targeting people who

00:18:34.700 have brain amyloid but don't yet have memory symptoms. So it's been a really amazing revolution as far as that

00:18:43.580 goes. However, from a cost standpoint, although it's a test I can order, it's not covered by any insurance and

00:18:51.980 would cost a patient about $4,000 out of pocket. So other than doing it in the context of a clinical trial, it's

00:19:00.700 really not realistic for many of the patients. As far as CSF goes, there is a good correlation between

00:19:08.480 the PET and CSF findings. Because I am a geriatric psychiatrist and not a neurologist, I'm not typically

00:19:14.740 doing lumbar punctures as part of my practice. Generally speaking, between the other markers such as

00:19:23.160 MRI imaging and PET, FDG PET, which measures how well the brain is using glucose as its fuel and has

00:19:32.320 different patterns supporting one diagnosis over another, and that is usually covered by some

00:19:37.640 insurance, we're able to make a diagnosis without the additional marker such as CSF. But there are times

00:19:44.920 when it is helpful and when we do refer people to neurology specifically for that.

00:19:51.720 So this clinical diagnosis is so important in a way that it's not really as important in the other

00:19:58.840 major chronic diseases, right? When a patient comes in and they're being diagnosed with diabetes or

00:20:03.060 NAFLD, nobody's really taking a great clinical history. You're sort of assuming you know how they

00:20:07.540 got there. But here you're having that discussion as you described, both with the patient and with

00:20:13.960 someone who can give some of these details you're looking for. So I kind of want to identify some of

00:20:19.720 these patterns. Now, I guess the textbook cases are, first thing is a loss of short-term memory, I'm

00:20:27.740 assuming. Is that the textbook version of Alzheimer's dementia?

00:20:32.500 Yes. I mean, in Alzheimer's disease, usually people start to complain of forgetfulness, repeating. So a loved

00:20:41.420 one might say, well, he asked me what time this appointment was four times since yesterday kind of

00:20:49.560 thing. But he can remember, you know, all the names of his high school football teammates. That's very

00:20:56.600 classic. So the preservation of long-term memory with difficulty with short-term memory.

00:21:02.420 Now, Amanda, how do you differentiate distraction from the path to dementia? Because if there's one

00:21:11.680 thing I've heard so often from patients, it's, I just got introduced to this person and I can't

00:21:17.680 remember their name. And it used to be so easy for me to remember names. Or, you know, my wife told me

00:21:22.480 to do this thing and I just completely spaced on it. And in my practice, most of those patients,

00:21:28.380 when they're saying that, tend to be distracted. There tends to be something else going on. It's really

00:21:32.240 not the prodrome to sort of dementia. But obviously in your practice specifically, that's, one can't

00:21:39.460 assume that. Do you have a way that you try to differentiate that? Well, I think it has to be

00:21:44.040 taken in context with all of the other information. I mean, quite frankly, it happens to me too.

00:21:50.120 Literally yesterday, I thought it was Friday. Because I knew I was, normally on Friday, I wear sweatpants

00:21:59.140 and a USF thing. And I knew I wanted to not wear that for this podcast today. And so I was in my Friday

00:22:05.400 outfit yesterday. And so at one point, I literally was like, oh, it's Friday. And then I was like, oh, no,

00:22:11.620 it's not Friday. But I'm not worried that I have dementia. I was distracted. I'm busy. I have a lot of

00:22:17.320 things going on. And so those kinds of things happen to all of us. So it has to be looked at in the

00:22:25.000 context of, A, the fact that some of this does happen with normal aging. The fact that stress,

00:22:33.700 a bad night's sleep, all that kind of stuff can affect it. And the other part of it is the frequency

00:22:39.380 and intensity of it. If it's the exception rather than the rule, it's probably not dementia. But when

00:22:47.060 that becomes sort of how you are and what happens every day, then it's more concerning.

00:22:53.020 I think you alluded to MRI. And although you didn't state it explicitly, were you talking

00:22:57.860 about hippocampal volume or other brain matter loss? Was that kind of what you were getting at?

00:23:04.280 Yeah. The typical things that we look for in an MRI when evaluating for dementia, A is ruling out

00:23:13.580 vascular disease or quantifying the amount of it. So we all get with aging some amount of tiny little

00:23:21.740 strokes. And I know that sounds scary. But as we get older, for various reasons, high blood pressure,

00:23:29.400 high cholesterol, smoking, diabetes, and even just normal aging, there can be blocking of blood

00:23:34.460 vessels, changes in circulation that cause us to have these tiny little infarcts. These are not

00:23:42.380 anything you would notice. You would never have symptoms. You wouldn't go to the hospital. But

00:23:47.300 there can be an accumulation of them. And there's a certain amount that's sort of normal when it's

00:23:53.980 extremely mild or scattered. But then when they start to coalesce or they start to extend into

00:24:02.300 cortical areas, parts of the brain that sort of matter more in terms of critical thinking,

00:24:08.040 then they can be symptomatic. So that's one of the things that we look at is how much vascular disease.

00:24:14.040 Another thing that we look at is how much shrinking there is, both globally and then, as you mentioned,

00:24:20.760 in the hippocampus, which is where short-term memories are kind of formed and before they go

00:24:27.360 off elsewhere. And so it is known that shrinking in the hippocampus, particularly disproportionately to

00:24:35.800 shrinking elsewhere, can be a biomarker of Alzheimer's disease. Now, there are sometimes people

00:24:41.540 who have hippocampal atrophy and turn out to be amyloid negative. So there are these other

00:24:48.240 pathologies that could be considered, they call it hippocampal sclerosis. Some people have that from

00:24:56.080 a stroke. Some people have it potentially from chronic traumatic encephalopathy and other buildup of

00:25:04.120 other abnormal proteins beside amyloid in the brain that can affect memory as well.

00:25:09.040 I want to come back to the amyloid negative case in a second. Is hippocampal volume a reliable

00:25:17.520 marker to check progress? So for example, if you had a patient that was high risk, theoretically,

00:25:25.660 so I don't know if you're seeing people who are high risk but don't have symptoms yet,

00:25:28.500 but if you had a patient who is high risk, you did an MRI, you got a baseline, so to speak,

00:25:33.940 you had their hippocampal volume, would tracking that over time for changes, reductions, presumably,

00:25:41.040 would that provide any meaningful insight? Sometimes, but not always. So other things

00:25:47.660 can affect hippocampal volume. For example, people who are chronically exposed to elevated levels of

00:25:56.160 cortisol or stress hormone, you know, people who have post-traumatic stress disorder, we know they

00:26:00.800 have smaller hippocampi than people who don't have that. And so there are times when we can track

00:26:10.740 hippocampal volume over the course of progression of Alzheimer's and the shrinking sort of correlates

00:26:18.680 with the amount of cognitive impairment, but sometimes not. You know, sometimes we have people

00:26:24.780 who are very impaired and their brain doesn't really look that bad. And sometimes we have people

00:26:29.220 who look like they shouldn't be able to, you know, put on their own pants based on what the brain looks

00:26:35.720 like, but they seem fine. So it's, again, one of those things that really has to be taken in context

00:26:44.280 with all of the other information and part of the reason why the clinical evaluation and interview

00:26:50.660 and the intangible stuff is so important. And just to be clear, the diagnosis, it requires the clinical

00:26:58.160 story with or without amyloid. And so when you look at the Venn diagram of people with amyloid and

00:27:05.060 people with clinical symptoms suggestive of dementia and you line them up, there's an overlap, but it's not

00:27:10.980 a perfect union. And what that tells us is that amyloid is neither necessary nor sufficient for Alzheimer's

00:27:18.800 disease, correct? Well, amyloid is necessary for Alzheimer's disease. It's not necessary for

00:27:25.620 dementia. But, you know, if you look at the definition pathologically of what Alzheimer's

00:27:31.260 is, it is the amyloid plaques and the tau tangles in the brain. So, you know, that was what's required

00:27:39.080 pathologically to make a diagnosis of Alzheimer's disease. But that diagnosis will only be made post-mortem

00:27:45.560 technically? Technically, yeah. But that's why the advent of amyloid imaging has been so helpful in

00:27:53.160 terms of making that formal diagnosis in living people, which is obviously more helpful for them.

00:28:02.100 You know, the correlation, I believe in one of the studies with amyvid, florbetapir, which was one of

00:28:09.360 the first amyloid imaging ligands that came out, the correlation between the pet and their, these were

00:28:17.360 people who were kind enough to donate their brains after they passed to compare to what their PET scan

00:28:24.460 looked like. And it was a correlation with about 97%. Meaning when they were alive, they had an amyloid

00:28:31.400 PET scan. And an amyloid PET scan, unlike FDG PET, where you're putting radiolabeled glucose, here you're

00:28:41.360 putting an antibody to amyloid as their tracer, correct? Yes. And so they had this scan while they

00:28:48.460 were alive. And you then had a distribution of people that had this much amyloid, that much amyloid,

00:28:54.920 et cetera. But all of them, to be clear, had a diagnosis of Alzheimer's disease based clinically,

00:28:59.540 correct? Right. They had a suspected diagnosis of Alzheimer's and then they underwent the PET and

00:29:06.640 then, then they donated their brains and then the correlation. And then on exam. Yeah. So the,

00:29:13.500 what we're missing there, of course, is the control of people who had amyloid in their brains that would

00:29:19.580 go on to have amyloid on autopsy, but didn't have Alzheimer's disease. Do we have a rough sense of

00:29:24.380 how big a population that is? I've had a hard time finding this, by the way,

00:29:28.200 what percentage of people on autopsy have amyloid in their brain, but did not have dementia during

00:29:35.060 their life? I don't know, honestly, but I think more than you would expect because what we know

00:29:42.560 about amyloid and one of the reasons that amyloid imaging has been so helpful is because it's helped

00:29:48.420 us understand that amyloid starts to build up 10, 15, 20 years before you start to have symptoms of

00:29:57.160 forgetfulness and other cognitive symptoms. And so, you know, it's this process where

00:30:03.660 it's occurring and then it reaches a critical mass. And there's a lot of debate scientifically

00:30:09.380 about what that critical mass is or what the downstream effects of amyloid buildup. There's

00:30:17.700 some people who think that you can have as much amyloid as you want and it's not until you start to

00:30:23.420 have tau, whereas amyloid is sort of widespread kind of from the beginning and builds up all these

00:30:30.360 years beforehand. So the tracking amyloid doesn't correlate to symptoms. Tau, on the other hand,

00:30:37.560 is very different and has a very specific pattern in which it spreads that does indeed correlate with

00:30:45.540 symptoms. So some people feel like it's really the tau that kind of stages where things are and

00:30:51.380 whether you're going to be symptomatic or not. So to answer your question, you know, I think there

00:30:56.780 are a lot of people who start to build up amyloid maybe in their 70s or whatever and then, you know,

00:31:03.460 die of something else. So a way to think about it is it's sort of like saying, and this is a bad

00:31:09.640 example, but I think it's the best one I can think of on the spot. It's like coronary calcification

00:31:13.680 where if somebody dies of cancer and you see calcification in their coronary arteries,

00:31:19.320 you knew they have atherosclerosis, but it never, it may have never clinically manifested itself. And

00:31:24.380 they, if they had not died of cancer, they may have died of an MI 10 years later. That's exactly

00:31:30.000 right. And that's frankly, the analogy we most often like to use. So before 2011, the definition

00:31:38.420 of Alzheimer's was dementia. So there was no place in research for these prodromal patients or, you

00:31:49.740 know, testing these interventions and people before they had full-blown dementia. And that was very much

00:31:56.700 like waiting till someone had a heart attack to say that they had coronary artery disease.

00:32:03.380 Well, and it's like, no, you knew that because they have high cholesterol and they were building up and

00:32:07.920 you could see on an angioplasty or whatever, you know, that this was happening. And so in 2011,

00:32:15.600 with the advent of amyloid imaging, you know, Pittsburgh compound was the first thing that

00:32:21.020 came out that allowed us to see that, although it's half-life is so terribly short that it really

00:32:25.880 is not clinically useful because it has to be made and used within minutes. But that really allowed

00:32:33.200 us to redefine what Alzheimer's is so that we could see this amyloid building up in patients before

00:32:40.900 they started to have symptoms. And it allowed some redefinition and there were white papers that came

00:32:48.880 out kind of dividing. And I know on a previous podcast, Richard Isaacson did go into this in some

00:32:56.300 detail, but, you know, the preclinical phase of Alzheimer's, then mild cognitive impairment,

00:33:01.640 and then dementia. So it really has allowed us to then kind of take a step back and see if we can

00:33:09.340 intervene before people have these symptoms that we may not be able to reverse.

00:33:16.840 Yeah. To me, Amanda, that is probably the most exciting part of this field, which is effectively

00:33:23.280 taking from the playbook of the chronic disease we understand most. You know, I talk about this with

00:33:28.840 patients, which is like, there's basically these three main chronic diseases, which is Alzheimer's

00:33:34.600 disease, cancer, even though of course that's not one disease. And the atherosclerotic disease is both

00:33:39.840 cerebrovascular and cardiovascular. And those three legs stand on a platform, which is metabolic disease,

00:33:46.620 which is then basically the distribution from hyperinsulinemia to insulin resistance, NAFLD,

00:33:51.400 and type two diabetes. So that becomes the table and you have these legs that stand on it.

00:33:55.920 Of these, I think we have the best understanding of atherosclerosis where lesion by lesion, we can

00:34:02.340 stage them. We understand what a fatty streak is. We understand what a foam cell is. We understand

00:34:08.740 what leads to calcification, how we go from soft plaque to vulnerable plaque to a ruptured plaque to an

00:34:16.580 MI. And we clearly understand, as your point is made, to sit there and wait until someone has a

00:34:24.300 major adverse cardiac event to say, oh, this guy's got heart disease, is nonsensical. I would go one

00:34:30.280 step further and say, waiting until a person's 10-year risk exceeds 5% to intervene is equally

00:34:37.260 nonsensical, yet that is still largely the standard. Because we know from autopsy studies of teenagers,

00:34:44.300 the process begins then. I mean, it probably begins even younger, but we don't have too many autopsies

00:34:49.940 of people below the teen years. But certainly autopsies of people in their late teens and early

00:34:54.560 20s who have died for other reasons already show foam cells, fatty streaks in some cases.

00:35:01.560 So if I'm understanding you correctly, by definition now, based on everything we understand,

00:35:08.300 anyone who clinically classifies as having dementia with amyloid has Alzheimer's disease.

00:35:15.540 Is tau necessarily preceded by amyloid? Or are there scenarios in which tau arrives with minimal

00:35:26.600 to no amyloid beta? So the answer to that question is yes, but I want to kind of go back for a second.

00:35:33.580 So anyone that has dementia and has amyloid does have Alzheimer's, but they may also have other

00:35:41.220 pathology too. So you could have a mixed dementia where you have Alzheimer's and vascular disease,

00:35:49.140 or you could have a mixed Lewy body and Alzheimer's. And we know from the autopsy studies,

00:35:57.000 certainly that are done by Dennis Dixon up in Mayo and Jacksonville, most pathology is actually mixed.

00:36:04.360 I don't have the numbers and I don't remember them quite frankly offhand, but I know that the number

00:36:10.620 of pure Alzheimer's is actually lower than the number of mixed cases. So most people

00:36:18.140 have something else too. Is vascular the most common additional diagnosis?

00:36:26.320 Yes. And so what does that mean? Let's think about that for a second. You may recall,

00:36:30.400 I interviewed Francesco Gonzalez Lima probably two or three years ago. He's here actually in UT Austin,

00:36:36.540 works with Jack Delatorre and they really have a strong point of view that says, look,

00:36:42.840 it's this microvascular disease that is really a big driver here. And there's a very compelling

00:36:48.840 rationale for that. You mentioned it earlier. It's very hard to make it into your seventh, eighth,

00:36:54.140 ninth decade without unbelievable amounts of microvascular damage. And to your point, if a critical

00:37:01.680 mass of that is reached, it's quite likely that that's going to result in the cognitive impairment

00:37:06.940 and ultimately even higher levels of impairment beyond memory, such as executive function.

00:37:12.800 And if, as you said, amyloid is sort of accumulating along the way, it makes sense that you could have

00:37:18.780 this mixed picture where you have the clinical side. So you, you know, you meet the criteria for

00:37:24.060 dementia, you have amyloid beta, and you have a heavy enough burden of vascular disease.

00:37:29.420 I guess it begs the question, if you had a time machine and you could go back in time

00:37:34.600 for that particular patient and you correct the vascular insult. So let's just say in one patient,

00:37:42.460 you aggressively manage their hypertension. In another patient, you kick the smoking cessation

00:37:47.140 in 20 years sooner. In another patient, you manage the dyslipidemia. You're going to impact the vascular

00:37:53.480 stuff. Do you think that has an impact on the amyloid side of the equation? And more importantly,

00:37:58.580 does it impact clinically their development of dementia?

00:38:01.980 I think definitely, yes. I mean, I know when you had your conversation with Richard Isaacson,

00:38:07.660 you know, he stressed the importance of those cardiovascular risk factors and the development

00:38:13.100 of Alzheimer's. The other thing that we know is, and again, it's not exactly the same protein,

00:38:19.520 but it's so closely related. Amyloid is a component of blood vessel walls. So I think there's still room

00:38:28.800 for more understanding in that and what the exact relationship is between normal amyloid and pathologic

00:38:35.660 amyloid. So it's important to say in Alzheimer's, the buildup of amyloid is this abnormal length

00:38:41.840 amyloid that's not the usual thing that we find in our bodies. So it's changed a little bit. But there

00:38:49.580 is normally amyloid that's part of our being. And so because it is part and parcel of blood vessel

00:38:57.780 walls, it's only natural to assume there must be this interplay between the vasculature

00:39:03.660 and the Alzheimer's side of things. I would be lying if I said I knew what that was. You know,

00:39:10.400 I think that still needs to be elucidated. That's why we have floors of people smarter than me upstairs

00:39:16.740 doing experiments. And I'm down here in the clinic. Does amyloid beta exist outside of the

00:39:24.080 blood brain barrier? Does it exist on the other side of the blood brain barrier?

00:39:28.340 Honestly, I don't know.

00:39:29.460 That's interesting. I never actually thought of, you know, until you said what you said

00:39:35.400 about the relationship to the endothelium, I never thought about that. I'm guessing somebody has looked

00:39:41.020 into that. And the answer is probably not enough to matter or else we would simply be doing a blood

00:39:46.820 test to look for enough amyloid, right? Right. Well, that's coming though. So, you know,

00:39:54.200 there are some really exciting, I don't want to forget about your tau question. So, I have like

00:40:00.660 that over here. There are some really exciting developments in terms of looking at blood biomarkers,

00:40:08.480 including plasma amyloid, in terms of potentially having a blood-based test for Alzheimer's.

00:40:16.180 So, there has been progress there. And I think that as time goes on, we're going to be able to

00:40:24.900 do these less invasive tests and really have a better sense of both risk for people who aren't

00:40:34.260 maybe symptomatic yet, as well as diagnosis. So, you had asked about whether you could have

00:40:41.700 other things like tau without amyloid. And the answer is definitely yes. So, frontotemporal

00:40:48.140 dementias, some of them are characterized by abnormal tau buildup in the absence of amyloid.

00:40:55.480 There are some familial genetic frontotemporal brain diseases that are characterized by tau burden,

00:41:03.880 chronic traumatic encephalopathy that we see in football and other boxing and things also have

00:41:11.120 abnormal tau, often in the absence of amyloid. So, yes, that definitely has a role

00:41:18.480 in the development of dementia and in other types of dementia too.

00:41:24.280 We sort of glossed over it, but maybe it is worth explaining what it is that amyloid beta is doing

00:41:30.740 to neurons and what it is that tau is doing to neurons to actually injure them. Do you want to

00:41:37.140 spend just a second kind of outlining those things? To the extent that my blonde self can, I will.

00:41:44.760 To a first order approximation. No, but I mean, I focus on the patient part of things. I let the

00:41:50.640 neuroscientists do their part. But, you know, it is this sort of cascade of damage. There is activation

00:41:58.240 of glial cells, which help protect our brain against intruders, and they can release toxins. They

00:42:07.720 can, it's called autophagy, you know, eating up our own tissue. So, there's damage both inside the

00:42:15.600 neurons and then outside plaques and tangles, and it creates a cascade that eventually leads to cell death.

00:42:25.920 Is it more the death of the neuron itself, or would the injury to the glial cells alone be sufficient

00:42:33.300 to lead to these symptoms? Because the glial cells, of course, when I was in medical school,

00:42:38.500 which was not that long after you, I don't remember that we talked that much about glial cells in our

00:42:44.040 neuroscience classes. I feel like we talked more about the neurons, but I know that in more recent

00:42:49.700 discussions I've had with neuroscientists, they really place almost an equal emphasis on the glial

00:42:55.560 cells. So, I'm curious as to whether or not injuring the glial cells in this particular pathology is

00:43:02.300 equally responsible, or at least to a first order approximation, equally responsible for the damage.

00:43:08.920 I think they're more responsible for the damage. They're part of the cascade that leads to the death of

00:43:15.740 the neurons because they're trying to protect the neurons and, in doing so, injure them.

00:43:24.160 I want to go back to a biomarker question. We're going to talk about the APOE genotype at some point,

00:43:30.120 but of course, one can actually measure APOE in the plasma. You can actually, just like you can

00:43:36.020 measure APO lipoprotein B, which we use obviously extensively in cardiovascular risk stratification.

00:43:42.120 To my knowledge, there's not a commercial assay for measuring APOE, though it can be done. Are you

00:43:49.920 aware of any utility to that? With looking at APOE levels, I read a paper seven or eight years ago,

00:43:57.300 I think suggesting that the lower the level of APOE, the higher the risk, but I could entirely have

00:44:03.520 that backwards and I could entirely be wrong, but is that something you're aware of at all?

00:44:08.060 Not really. I mean, it's really more about the genotyping than the quantification of it. And

00:44:14.800 again, you've talked about it on prior podcasts, the risk that E4 genotype carries compared to the

00:44:22.480 others and the fact that E4 homozygotes have higher risk and also different responses to

00:44:31.000 cardiovascular meds, different risks for other diseases besides dementia. It is typically

00:44:38.140 not something that we check for in the routine day-to-day clinical care for a couple of reasons.

00:44:46.480 One is it's not diagnostic, right? So you can have E4, E4 and not have Alzheimer's, or you can have E2,

00:44:53.300 E3, which might be protective and still have Alzheimer's. So it really just makes people worry.

00:44:59.020 It does have a lot more utility in the research setting in terms of looking at

00:45:04.920 how carriers versus non-carriers respond to certain treatments and helping us understand that carriers

00:45:14.060 may respond differently to different lifestyle interventions, may have an earlier onset compared

00:45:20.460 to people who don't have it, but ultimately end up with the same disease.

00:45:26.160 Yeah. So when people come to see you in clinic, there's not a lot of utility added by looking at

00:45:34.100 it. I mean, my view is APOE4 is great to help people identify risk early on, but at the same

00:45:40.200 time, nobody gets off the hook. And you used a great example. The 2-3 shows up a lot. And I tell my

00:45:45.860 patients with the 2-3, you're not off the hook. You've got about a 10% risk reduction relative to the

00:45:52.680 3-3, but the 3-3 is clearly not at risk. And on the flip side, the 3-4 patients or even the 4-4

00:45:59.120 patients, I say, look, it's certainly not a fait accompli, but I would take this a lot more seriously

00:46:04.240 than maybe you otherwise would in terms of preventative measures. Let's go back to Lewy

00:46:09.620 body dementia. Most people have heard of this. There have been some notable examples in the public

00:46:14.760 sphere about folks that have died from this. Is it still the case that that's a diagnosis that can

00:46:20.800 be made only post-mortem? Again, yes, but there's this sort of classic clinical picture

00:46:28.000 that is so compelling that it can be made fairly accurately in the clinic without diagnostic

00:46:36.940 testing. And so the clinical distinction between, I hate to use this term, the clinical distinction

00:46:43.040 between classic Alzheimer's dementia and classic Lewy body, so let's exclude the mixed variants of that,

00:46:49.740 how would you differentiate those patients? Classic Alzheimer's would begin with short-term memory loss

00:46:57.340 and slowly but surely over time progress to having difficulty, you know, paying bills and then

00:47:06.620 eventually needing supervision, needing assistance with activities of daily living, cooking, bathing,

00:47:12.900 having the classic sort of decline. May or may not have behavior issues, may or may not have some

00:47:20.660 changes in walking. Lewy body disease, on the other hand, presents with a fairly classic triad of

00:47:28.460 symptoms that occur within two years of one another. One is an Alzheimer's-like cognitive impairment

00:47:35.860 component that can notably fluctuate so that some days people seem really good and some days they seem

00:47:42.860 really, really bad. There is a Parkinsonism component where they will often be stiff, have trouble rising

00:47:52.260 from a chair, shuffle. They may decrease arm swing when they walk so that they walk and, you know, normally when

00:47:59.060 we walk our arms move but their arms don't move. They may have less expression on their face.

00:48:05.300 They don't necessarily have a tremor so true Parkinson's disease proper often begins with a tremor, a slow

00:48:14.740 writhing kind of tremor at rest on one side and often we don't see that in Lewy body disease but these,

00:48:23.140 they have these, they have these other elements of Parkinsonism and so we've got the the cognitive

00:48:28.900 impairment, the Parkinsonism and very often prominent visual hallucinations, seeing things that aren't

00:48:36.900 there, fairly elaborate, often delusions that go along with it. There's this family living in my house,

00:48:44.340 there's people and bears living in the trees, people will close their blinds because they don't want

00:48:50.340 these people seeing them and all that kind of stuff. So that classic triad of symptoms with some

00:48:57.380 additional supportive features including restless leg syndrome, even many years leading up to it,

00:49:06.660 as well as REM sleep behavior disturbances. So people who often act out in their dreams or a spouse who

00:49:15.220 says I have to sleep in the other room because he punches me, that's sort of a classic Lewy body

00:49:20.580 picture. And furthermore, they fluctuate. Both the motor and the cognitive symptoms fluctuate. So

00:49:28.340 today we might be able to go to the mall and walk all around and tomorrow they might

00:49:33.140 have trouble walking across the room. From the time of diagnosis, Amanda, until those patients are

00:49:39.540 either in hospice or incapacitated or dead is typically how long. Is that a quicker disease?

00:49:46.820 Sometimes. I mean, it's usually about eight years, but for some, you know, my experience,

00:49:52.660 I've had a lot of Lewy body patients who have sort of this precipitous decline and then kind of hit a

00:49:59.860 plateau for a while and then really drop off. This is anecdotal, this is not based on any data, but it's just my

00:50:08.020 experience with them and having seen enough of them to see that that's frequently kind of how it goes.

00:50:14.340 But it's usually about an eight to 10 year process. And there it's less often as protracted as

00:50:22.900 Alzheimer's can be, even though the average for Alzheimer's is still also eight to 10 years. It can

00:50:29.380 be significantly longer. How hereditary is Lewy body dementia, either with respect to

00:50:35.540 Lewy body itself or being predictive of the next generation's risk for Alzheimer's disease or

00:50:42.660 Parkinson's for that matter? I honestly don't know. I don't think it's terribly genetic.

00:50:47.940 You know, we don't have well-established as with early onset Alzheimer's, which does have

00:50:54.020 some specific mutations that cause it. I don't know that we know of specific mutations for Lewy body

00:51:00.580 disease, but I may be just not informed. I mean, that makes in some ways Lewy body

00:51:07.060 a bit more of a mystery because as you said, for Alzheimer's disease on the very early onset side,

00:51:12.740 we have the PSEN1 to APP mutations, which are about as close to deterministic as you get. And then you

00:51:21.300 have the APOE4 gene, which is not deterministic, but is highly suggestive for the more typical

00:51:28.260 variant. And we also have known risk factors, diabetes, microvascular disease, dyslipidemia.

00:51:35.460 I mean, these things are absolutely known risk factors. We seem to have none of that on the side

00:51:40.740 of Lewy body, correct? As far as I know. Yeah. What's the relative incidence of Alzheimer's

00:51:46.180 versus Lewy body dementia? Is it like eight, 10 to one, or how much more prominent is Alzheimer's?

00:51:52.340 Well, it depends, I guess, if you're looking at the autopsy confirmed versus sort of what we see

00:52:00.180 in the clinic. I honestly don't have the numbers specifically for you, but I do know that,

00:52:06.420 you know, it's diagnosed less, but found more on autopsy that people do have Lewy bodies that we

00:52:14.260 may not have expected. I got it. And just in your experience in your clinic,

00:52:19.220 what's the approximate distribution of those? It's about, I would say, 50 to 60

00:52:26.580 plus percent Alzheimer's, about 20 percent true vascular, about 20 percent Lewy body. And then

00:52:36.100 the rest is FTD and some of these Parkinson's plus syndromes, progressive supranuclear palsy,

00:52:43.540 and some of these other less common things that we only see once in a while. Back to kind of the

00:52:48.660 way your practice works. Presumably, people are coming to you at the referral of a neurologist,

00:52:54.260 correct? Not necessarily, no. Okay. We get people referred from their primary doctors. We get people

00:53:01.060 that are self-referred. We get people that are referred by neurology. It varies widely.

00:53:07.940 That in and of itself is actually quite interesting, right? If you think about the different paths that a

00:53:12.100 person gets to you, they can say, hey, there's something wrong with me. Oh, Dr. Smith, that's a

00:53:18.580 so-and-so psychiatrist specializing in geriatrics. I'm going to go see her. And then the primary care

00:53:24.260 doctor can say, look, I have a high enough degree of suspicion that my patient has Alzheimer's. They're

00:53:28.820 going to come to you. Presumably, when the neurologist is sending to you, it's not to make

00:53:33.380 the diagnosis. They've made it. I assume it's then to treat some of the behavioral components?

00:53:39.460 Sometimes, yes. I mean, well, first, let me say that I would say fully half of my patients think

00:53:45.060 I'm a neurologist. They don't even differentiate or they'll refer to me as their neurologist. And

00:53:53.460 it just is what it is. You know, they assume and it's fine. Or maybe they don't want to say they're

00:53:58.500 going to a psychiatrist. I don't know. Sometimes I think it varies from place to place. There are a few

00:54:06.260 neurologists here in town that do specialize in Alzheimer's and treating dementias and focus on

00:54:12.100 that. But a lot of them don't. A lot of them prefer specializing in stroke or headache or MS or seizures.

00:54:21.860 And so when it turns out to be dementia, they just say, oh, we'll go to the Alzheimer's Center.

00:54:27.060 So I don't think it's a question of necessarily psychiatry versus neurology. It's just go to the

00:54:34.020 go to the memory place. But yes, there are definitely a subset of referring providers

00:54:43.300 who do so specifically so that we can manage the behavioral aspect of things.

00:54:48.180 How long have you been in your current practice in Tampa?

00:54:53.700 Since 2002. In this building since 2008. So what happened is I came down to USF in 1997 as an intern

00:55:05.140 to do my residency here. So I did my residency in psychiatry and then a fellowship in geriatric

00:55:11.740 psychiatry. And part of my fellowship time was spent with the Suncoast Gerontology Center working

00:55:19.100 under Eric Pfeiffer, who had founded that here in 1980 and really was a leader in the field of

00:55:26.940 geriatric psychiatry and Alzheimer's disease. He was the first president, I think, of the

00:55:32.220 American Association for Geriatric Psychiatry. And it was actually one of the reasons I chose USF

00:55:38.620 because I knew Suncoast was here and I was interested in geriatrics and Alzheimer's at that

00:55:44.860 point. So when I finished my fellowship on a Friday, I started working for him on the following

00:55:51.820 Monday. And that was in 2002. And then in 2008, he retired and I kind of stepped in and took on his

00:56:00.380 role as principal investigator for a lot of the clinical trials he had been doing and kind of directing

00:56:06.140 the center. I'm curious as to how your practice has evolved in nearly 20 years. What is different

00:56:12.700 and what is the same about people showing up with dementia today? Are they older? Are they younger? Are

00:56:18.780 they more metabolically ill? Are they on a faster track? Are they progressing quicker? I mean, what are all

00:56:25.820 the differences that you see? The thing that's the same, I would say, is the fear. You know,

00:56:32.300 people are terrified of losing their minds and losing their memories. And so that continues to be

00:56:40.940 sort of the biggest motivator in terms of people seeking help. I will say that we are seeing people

00:56:49.100 that are both older and younger. I think that there's more of an awareness of Alzheimer's as a disease,

00:56:57.740 as well as an awareness of the fact that there are things that we can do about it. Because when I first

00:57:06.060 started, there wasn't a whole lot that we could do. And furthermore, there was sort of this assumption

00:57:14.460 that it was a normal consequence of aging. There has been a lot of effort put into really educating

00:57:21.020 the public that this is a disease and that this is not something that you have to live with. And this

00:57:27.020 is not a normal consequence of getting older. And because of that, I think there's been success in kind

00:57:34.620 of getting that message across and getting people into the clinic. I think that there's definitely more

00:57:42.060 of a shift towards people seeking a baseline, people looking at prevention, people wanting,

00:57:51.580 you know, an evaluation and tips on brain health. And I know, again, you spoke with Richard Isaacson

00:57:57.500 because he runs a prevention clinic at Cornell in terms of the lifestyle modifications and things

00:58:03.500 that people can do earlier. You know, we often see people who have a parent who have Alzheimer's and

00:58:11.020 want to come in and have an evaluation for themselves or get involved in prevention research so that they

00:58:18.060 don't go down the same path. So I think that's the biggest area where things have shifted. I think

00:58:23.980 there's also a better understanding that people realize that there's more that we can do and that early

00:58:30.860 intervention is key. People often used to be embarrassed by this problem or isolated by it or not

00:58:39.900 want to tell family members or neighbors. And now they understand that if they come and they seek help

00:58:45.340 and we start them on medication, even though they're, you know, our medications are not miracle drugs by any

00:58:51.180 stretch, the ones that are FDA approved, but they can slow down decline. And then in some people they

00:58:57.020 can even subjectively and objectively help for a period of time. And so knowing that you can preserve

00:59:05.420 your function and stay better longer or stay at home longer, you know, there was one old study way

00:59:12.220 back with Dinepazil showing that it delayed nursing home placement by an average of 24 months. That's

00:59:19.740 huge. If you're someone that wants to be at home versus being a skilled nursing facility, or if you're

00:59:25.260 you're a spouse who wants to keep your loved one home, you know, that makes a difference. Even though the

00:59:30.540 drugs not, you know, the people are still going to get worse on the medication. So anyway, you know,

00:59:35.500 that was a lot, a big mouthful just to say that, you know, I think there is this better awareness of

00:59:42.140 the things that we are able to do and the help that we're able to provide so that people seek help

00:59:47.420 sooner. We talked about it at the very outset that so many of the things that the patients are

00:59:53.660 experiencing when they show up are, quote unquote, the garden variety things that a psychiatrist would

00:59:59.260 see anxiety and depression, for example. What percentage of the patients that you're taking

01:00:05.020 care of, are you prescribing antidepressants and anxiolytics? And is that standard of care? Is that

01:00:11.980 something that you have the ability to be more bespoke in because you have a greater understanding

01:00:16.780 of how those drugs work and how effective are they?

01:00:19.740 The answer is, you know, quite a few. I would say the majority of our patients do have some

01:00:27.100 mood or behavioral issue that does require treatment. 90% of people will have some behavioral

01:00:33.100 issue at some point in their illness. It may not be a terribly problematic, psychotic type behavior

01:00:39.260 issue. It may be, you know, something simple, but nevertheless, they're very common in all types of

01:00:46.060 dementia. The key is understanding that they are equally treatable. Depression in a dependent person

01:00:53.740 is just as treatable as depression in a healthy 25-year-old. So there are obviously some adjustments

01:01:03.020 that have to be made for age and renal function and other medications and drug interactions.

01:01:10.060 But we very frequently prescribe the SSRIs, the type of antidepressants, because they treat anxiety

01:01:18.860 very well in this population. They're pretty well tolerated. They generally don't make people fall,

01:01:26.140 which is a big issue in this group as well. You know, we try to stay away from the benzodiazepine

01:01:32.700 type drugs, you know, alprazolam and lorazepam and all the PAMs, particularly diazepam and the longer

01:01:40.540 acting ones, because they can really increase confusion and have a dramatically high incidence of

01:01:45.900 hip fracture with those drugs and used chronically. So a lot of it is, you know, identifying

01:01:54.620 the specific problem, treating with the least offensive drug that's going to cause the least

01:02:03.020 amount of collateral damage, and stopping them at times when they may no longer be necessary. You

01:02:11.420 know, old people sort of, they collect meds like they collect other things. And, you know, sometimes

01:02:19.020 you'll see someone who's on 15, 17, 18 meds, and you're like, why are you even on this? People who had

01:02:26.700 hypertension when they were 50 and needed three meds to manage it, but now are 90 and they're falling

01:02:33.660 all the time because their blood pressure is so low, but nobody bothered to say, hey, you don't need

01:02:37.980 three meds for your blood pressure anymore. So we do have to be vigilant and really target symptoms with the

01:02:46.700 safest, lowest dose and the shortest treatment period that we can. But in doing so can be very

01:02:55.580 effective in treating these symptoms. You might not know the answer to this,

01:02:59.420 but do you have a sense of how many patients in the United States or what fraction of patients in

01:03:04.620 the US with Alzheimer's disease are getting that type of complementary care for the psychiatric component,

01:03:11.820 specifically the depression and the anxiety? Do you think it's the majority or the minority?

01:03:15.420 I would probably say it's the majority. I mean, a lot of them do get treated by their primary doctors

01:03:21.420 for depression. I see a lot of people who come to me already on medication for that. I think doctors

01:03:28.380 are prescribing and people are sharing those. And certainly from the standpoint of some of the more

01:03:35.420 problematic behaviors, you know, people don't want to live with them. They're difficult. They're

01:03:40.220 difficult for the patient and they can also be problematic and troublesome for the caregivers.

01:03:45.980 So they often will seek help for that more acutely than they will for the underlying condition.

01:03:53.820 How much are you providing? I mean, you're not necessarily treating the family members

01:04:00.620 medically, but after all, you are a psychiatrist, which means you have more tools in your toolkit than

01:04:07.580 simply your prescription pad. How much are you treating the spouse, for example, as you are the

01:04:13.020 patient, the spouse without dementia? Well, in a way, I think we all sort of give free therapy,

01:04:18.940 if you want to call it that. I do occasionally medicate caregivers if they register as a patient.

01:04:25.500 You know, I'll say, hey, you know, you really have a severe depression. We need to treat this.

01:04:30.220 But I won't do it out. You know, I won't do it under the patients. You know, once we're dealing with

01:04:36.300 meds, it's a whole nother story. But obviously, there is a lot of support and education, especially with

01:04:44.140 the pandemic. Sometimes I'm the only other person that they will see or talk to, even if it's on

01:04:50.460 telehealth like this. Oftentimes, it's just that opportunity to vent, to talk to somebody who can

01:04:57.900 understand what they're going through. Although I have had some experience with family members having

01:05:04.700 dementia late in life, you know, I was not a primary caregiver. Most of what I know comes from the

01:05:13.260 village of patients and caregivers that have shared very personal things with me. So I have the

01:05:20.060 opportunity to share their insights with others. But I would say quite a lot of, you know, if you want to

01:05:26.940 call it free therapy or whatever, just that opportunity to listen, to make them understand that

01:05:37.100 what they're going through is valid and real, give them pointers and tools and things that they may

01:05:44.140 not have thought of in terms of handling a certain behavior. Just that one little pearl that might make

01:05:50.140 their day easier. The other day, I was talking to someone who just simply cannot get their loved

01:05:56.300 one to take a shower. And I'm like, well, what's their favorite snack? And they kind of looked at me

01:06:02.540 funny. And they're like, Cheetos. So I'm like, okay, tell them after they get out of the shower,

01:06:08.700 you'll give them some Cheetos. You know, you'll go to the store, you'll get some Cheetos. And

01:06:14.140 they don't think of it that way, because they're just, you know, sort of trying and fighting,

01:06:17.900 like, you need to take a bath, you need to take a bath, get in the shower. I don't want to take a

01:06:21.260 shower. And there's not that sort of stepping back and like, okay, how can I do this differently?

01:06:27.820 So sometimes just giving them a little reality check and a break from the constant stress cycle

01:06:34.540 that they're in to kind of look at things through different eyes really can make a big difference,

01:06:40.460 I think, in their, the way that they approach things. The other thing that's sometimes really

01:06:45.900 difficult for caregivers is a lot of times they'll think that some of these behaviors that their

01:06:51.660 loved ones are showing are intentional, you know, or he's just doing it to annoy me.

01:06:59.420 It's like, well, no, he's not. Like if he's really not, if he knew the answer,

01:07:06.380 he wouldn't ask you again. So instead of saying, don't you remember, just say, answer the question

01:07:11.420 like it's the first time. Take out that sort of personal attack side of it, you know, and not look

01:07:19.420 at it as they're intentionally trying to irritate you. But, you know, they have a disease that's

01:07:24.460 making them do this. And often, you know, that is something that people really need to hear,

01:07:30.460 and it really makes their days better. I mean, it's easy for me to sit here at my desk and tell them,

01:07:36.780 it's a lot harder to do, but at least kind of having that reality check can change the way that

01:07:44.300 they approach caregiving. I'm sure people listening are familiar with Elizabeth Kubler-Ross and how she

01:07:50.460 goes through these sort of five stages of grief and how people go through denial and anger, et cetera,

01:07:57.500 on their way to acceptance. And that model has always sort of been helpful when thinking about

01:08:03.260 something like cancer. And I got to see that a lot firsthand. Is it similar here with Alzheimer's

01:08:10.380 disease, both for the patient and the caregiver, that there's this, in some combination or in some

01:08:16.540 order they go through those? Oh, absolutely. I mean, I can't take credit for the phrase,

01:08:21.660 but it's, you know, it's like grieving for someone while they're still alive. You know, it's the,

01:08:26.460 this can't really be happening and then being angry that it's happening and, you know, sort of,

01:08:31.100 well, maybe if we do this and maybe do that. In fact, I, I re-listened to your podcast with Lauren

01:08:38.460 Miller Rogan and Richard Isaacson last evening, just kind of in preparation for today and just to

01:08:45.740 make sure we didn't sort of duplicate everything that we talked about. But Lauren in that podcast

01:08:51.660 really gives a very compelling journey right through those stages in terms of dealing with her mother,

01:08:59.020 who was my patient, which is how I got to know them in the first place. But it's really a very

01:09:06.380 distinct journey while her mother was, was still very alive and going through those stages of grief in

01:09:15.100 losing her hopes for what her relationship with her mother would be like as she got older. You know,

01:09:24.500 it was really terribly sad and it's also something that naturally happens as we grieve. You know,

01:09:31.780 I think those stages of grief apply to almost everything. You know, they're sort of part and

01:09:37.780 parcel of our existence as human beings is that's kind of going to happen. We don't always go through

01:09:43.700 all of them or we don't always resolve all of them or make it through all of them. But it's a very,

01:09:52.100 very real and major part of dealing with this diagnosis. In my experience with oncology patients,

01:10:00.980 once they've progressed through denial and anger and bargaining, et cetera, and they sort of get to

01:10:07.060 acceptance, usually the biggest concern, the residual concern is the amount of suffering at the end.

01:10:14.660 So it, it actually becomes at least one of the concerns becomes around the mechanism of death.

01:10:21.700 And that's not something a lot of people think about. Most people walking around,

01:10:26.100 if they're level headed, know that they're going to die at some point. There aren't too many people

01:10:29.700 walking around believing that they're immortal. So most people understand in an abstract way,

01:10:34.100 I'm not going to be alive at a point in time, but it's kind of a vague, fuzzy, foggy thing,

01:10:40.180 which is, yeah, I'll have a heart attack at some point, then I won't be alive. But,

01:10:43.140 but to the patient with metastatic cancer, who's again, accepted that and understands that they've

01:10:50.100 progressed through all standard treatments. So even now we can even take a subset of patients

01:10:54.900 with stage four cancer who are in hospice care. All of a sudden, a big priority is the actual mechanism

01:11:01.620 of death. And certainly for the palliative care physician, and in my opinion, also for the good

01:11:06.980 oncologist, the one who doesn't just sort of abandon the patient when there's no more oncologic

01:11:11.860 care. I think a big part of that is explaining, no, actually, we might not be able to save your

01:11:17.540 life, but we can absolutely prevent discomfort. What is that discussion like for you once the

01:11:24.660 patient and their family have progressed through all the stages and really understand that this is

01:11:30.900 an irreversible disease and it will result in the end of their life? How do you address the specific

01:11:38.180 fears that remain? That's a great question. And I do get asked about it fairly frequently,

01:11:44.420 but yet at the same time, we often don't get into it too much because what I try to do is really help

01:11:53.220 people focus on the now. That being said, what I share with them is that a lot of times, you know,

01:11:59.460 people as they progress, they are going to have more difficulty doing more simple things and more basic

01:12:06.820 things. They will have trouble swallowing. They will need assistance. They will perhaps aspirate on food

01:12:14.900 and get pneumonia. They may lose mobility and be bedridden, you know, and we go through that

01:12:23.940 conversation when they ask, you know, well, how do you die of Alzheimer's? But the truth is a lot of

01:12:32.020 people don't ever get to that stage. You know, many people die of something else. They die of old age.

01:12:38.340 They die of their heart disease. They die because they fell in a parking lot

01:12:42.340 before they ever reach such a terminal stage of dementia. So we have the conversation, but we also

01:12:53.060 try not to focus on the end game because that's just miserable. I know a little bit later,

01:13:02.180 we're going to be talking about sort of healthy aging and stuff like that. And that's one of the

01:13:06.820 biggest things that I see is not focusing on the end, but focusing on the now. Because the truth

01:13:14.020 is with Alzheimer's, that's all people have. You know, they have today because they may not remember

01:13:20.100 tomorrow what happened today. So they're really living in the moment. So we try not to spend too

01:13:27.460 much time dwelling. I'm obviously extremely honest in terms of what can and will happen if they inquire,

01:13:35.220 and also in terms of letting them know that support is there through hospice and other things

01:13:42.740 when the time comes, you know, that they don't have to go through that alone.

01:13:46.900 But we try to reroute that thought process into focusing on making each day better.

01:13:54.500 So let's shift gears a little bit and talk about the clinical trial landscape, because that's a very

01:13:59.300 big part of what you do, right? You're a clinical psychiatrist who deals with patients on an

01:14:04.340 individual basis, as we've discussed. But you also are heavily involved in another part of this,

01:14:10.820 which is how to do clinical trials. And this is obviously a very important part of this work. Now,

01:14:15.860 Alzheimer's disease and drugs don't have a great marriage. They don't have a great track record the way

01:14:22.020 cardiovascular disease does. And even though oncology is not great, far from perfect,

01:14:28.580 oncology even has a better track record than Alzheimer's disease. And I think you could make

01:14:32.580 the case without being hyperbolic, that there is no disease that has a worse track record relative to

01:14:38.340 the inputs on the output side. In other words, there are orphan diseases for which we have no drugs,

01:14:44.260 but there have been few shots on goal. So the ratio of shots on goal to goals is lower in Alzheimer's

01:14:49.460 disease than probably, not probably, unquestionably any other disease. Okay. On the one level,

01:14:55.460 that undoubtedly speaks to the complexity of the disease. Some might argue that on another level,

01:15:01.540 that speaks to the wrong goal or shooting too late in the game, shooting from too bad an angle at the

01:15:08.740 wrong goal. You could take this metaphor 10 different ways. As it stands today, there are about 120 drugs

01:15:15.460 in the pipeline. If my number crunching has it right, about 27 of them, if we extracted this

01:15:22.900 correctly off clinicaltrials.gov are in phase one. So for the listener, meaning these are drugs that are

01:15:29.140 really just being evaluated for safety at this point. So we have some animal data that suggests

01:15:34.100 this is a good idea. We have no idea if it works in humans, but in a very small way with dose escalation,

01:15:40.100 we want to make sure it's safe. About 65 are in phase two. So that means they've passed that bar

01:15:46.500 of being safe or at least safe enough to proceed to phase two, where now we're looking for some

01:15:51.860 efficacy and we'll of course continue to monitor safety. And then 29 are in phase three, which means

01:15:59.220 at a small scale, they've shown efficacy typically against a placebo. Now we want to see if there's

01:16:05.140 efficacy again, either versus a placebo or ideally against a current standard in a larger trial where,

01:16:11.940 again, we're always going to continue to monitor safety, but it's really this third stage that is

01:16:17.940 required for FDA approval. Another way to slice the data is to look at it by category of drug. And I

01:16:24.340 found this to be the most interesting. 12 of these are in the space of cognitive enhancement. 12 are in

01:16:31.460 the space of neuropsychiatric and behavioral improvement and 97 are in the space of disease

01:16:37.540 modification. Can you explain a little bit what the differences of those three categories mean? And

01:16:43.460 knowing that the next question I'm going to ask you is how has that evolved over the last 20 years?

01:16:48.260 Because that to me has been the biggest, that was the thing I was most surprised by.

01:16:51.860 Yeah. So the symptomatic treatments are ones that can help slow cognitive decline or help improve

01:17:00.420 memory and thinking, but are not targeting the underlying disease process. So all the drugs that

01:17:05.620 we currently have on the market are ones that are symptomatic treatments because they're just helping

01:17:12.180 those neurons communicate. In the case of denepazil and galantamine and rivastigmine, they're, you know,

01:17:19.220 cholinesterase inhibitors. And then there's memantine, which is an NMDA receptor antagonist that

01:17:25.940 that normalizes levels of glutamate. But they're just, they're helping with neurotransmitters and

01:17:30.500 they're not targeting the underlying pathology of amyloid and tau. Then obviously the behavioral drugs

01:17:39.940 are ones that are being targeted for specific behavior problems in Alzheimer's and other dementia

01:17:46.740 patients. Things like apathy, agitation, psychosis, sometimes sleep issues, sometimes even appetite and

01:17:55.140 eating problems. So those all kind of fall under the behavioral umbrella. And then these disease

01:18:01.700 modifying treatments are ones that actually target the underlying pathology in the case of sort of the

01:18:09.940 biggest group of those that are in trials right now are really monoclonal antibodies against primarily

01:18:18.420 amyloid. But also if you look, you know, targeting tau and removing them from the brain in the hopes that

01:18:26.340 then there will be cognitive improvement or at least halting cognitive decline.

01:18:32.580 Is it known exactly where amyloid beta is made? Is it understood how from where the transcription takes

01:18:42.580 place or is this all post-translational modification?

01:18:46.660 There's a whole science dedicated to that. It actually is different points along the cascade.

01:18:54.900 So there's the amyloid precursor protein, which is on chromosome 21, which is why people with

01:19:03.060 Down syndrome who have three copies of chromosome 21 almost inevitably will get Alzheimer's if they

01:19:08.740 live long enough because they're making a third more amyloid than the rest of us.

01:19:14.260 So anywhere from the very beginning of our DNA all the way through some of the enzymes that cleave

01:19:22.660 amyloids. So part of the problem is that the amyloid gets cleaved at a length of 40 or 42

01:19:30.100 amino acids rather than whatever it's supposed to be, which I don't remember.

01:19:34.580 And then the abnormal amyloid kind of folds and there's fibrils and the plaque itself is a

01:19:46.580 conglomeration of a series of folds in the protein. And so there are even differences among the antibodies

01:19:58.020 as to what part of that cascade they target.

01:20:01.860 And amyloid's not necessary. In other words, if you could wave a magic wand and pull amyloid out of

01:20:07.380 a person, is there any ill consequence?

01:20:10.020 Well, like I said, it is part of blood vessel walls normally. So this pathologic amyloid,

01:20:19.700 you know, these abnormal lengths of A-beta 40 and 42, yeah, I mean, those could be pulled

01:20:25.700 out without consequence because they shouldn't be there in the first place.

01:20:28.740 So if you wanted to target the system, you would not target the creation of amyloid,

01:20:32.980 you would probably target the enzymes that abnormally cleave.

01:20:37.140 That is one area that has been studied. The gamma secretase inhibitors, for example,

01:20:45.460 are ones that have been studied. And the base inhibitors, these are things that are being looked

01:20:53.300 at because these are responsible for cleaving. But a lot of times those have had side effects

01:21:01.380 that we didn't really want.

01:21:02.340 Yeah. I wonder if, has anybody looked at something like an antisense oligonucleotide

01:21:06.580 that goes straight after the enzyme in a laser precision, basically says, you can't make this

01:21:11.380 enzyme and you don't have to carpet bomb the enzyme and everything around it. You're literally going

01:21:17.060 after the transcription of the enzyme. Yeah. I honestly don't know. That's for the scientists.

01:21:24.900 I mean, I'm sure somebody has thought of it and declined. I'm sure there's a reason that hasn't

01:21:28.420 been done. Yeah. I mean, the thing is, you know, sometimes they have thought of it or they've tried

01:21:32.980 it, but then they don't realize what the downstream effects of doing so may be. And that's been a problem

01:21:40.420 with several of these medications, you know, where they, it's a great idea. You know, they've identified

01:21:46.980 a target, they've identified compounds that seek out that target, but they cause liver toxicity or

01:21:55.460 they cause, you know, some other significant medical issue or they cause cardiac arrhythmias or

01:22:03.300 things that medically are not safe to continue.

01:22:07.060 The thing that surprised me, Amanda, when I looked at the distribution of drugs, just again,

01:22:12.580 this is available on clinicaltrials.gov is that 80% of the drugs are disease modifying drugs,

01:22:18.900 which is a good sign, of course, because the other 20%, as you said, are symptomatic. Now that's

01:22:24.660 not the way the drugs are currently represented. There are, are there, how many drugs, six approved

01:22:29.700 drugs for Alzheimer's disease right now? Well, there's technically five. Well, there's six,

01:22:36.740 six, but one of them is a combination of the other two. Two existing. Right, right. Okay. Yeah.

01:22:41.620 All of these are symptomatic drugs, right? We don't have a disease modifying agent out there. We're

01:22:48.180 going to obviously talk about Biogen in a moment, which is an important, almost watershed moment in

01:22:53.860 the field. I assume that it's from your standpoint, a great sign that 80% of the pipeline is actually

01:23:01.540 focusing on the underlying cause as opposed to just the symptoms. Right. And a lot of that has to do

01:23:07.060 with what I mentioned earlier with regard to that 2011 sort of major moment where we were allowed to

01:23:16.260 redefine what Alzheimer's is. And our understanding that the amyloid pathology building up for many

01:23:23.780 years is was a key factor. You know, I'm not saying it's a V factor, but it's a key factor in the

01:23:30.260 development of Alzheimer's disease symptoms. Now, some of the disease modifying drugs that were

01:23:37.700 initially tested were tested in people with mild to moderate Alzheimer's disease and were negative.

01:23:44.420 You know, they did not seem to work or help. And it may have been because targeting amyloid

01:23:51.140 at that stage of the disease may be too late to help people who already are significantly impaired.

01:24:00.100 But that 2011 shift into understanding that there's MCI and that even before that preclinical Alzheimer's

01:24:09.140 allowed us to then design trials that are currently ongoing, looking at both prevention by amyloid removal

01:24:18.260 before cognitive symptoms start. And then also treating people with mild cognitive impairment

01:24:25.060 who do have some symptoms of memory loss, but are not yet demented because they're so functional in

01:24:31.220 their day to day.

01:24:32.100 What was the typical duration of those failed studies? So if you look at the earlier studies

01:24:39.140 that were trying to remove amyloid late in the game that that failed, do you recall on average

01:24:45.940 with the duration of these like four year studies, three year, five year studies?

01:24:49.220 No, they were usually about 18 months.

01:24:51.460 Wow. So really short. So yeah, you could definitely make the case that that's again,

01:24:56.500 just going back to the disease I understand best. That's like saying we're going to take

01:25:00.900 patients who have the most aggressive form of cardiovascular disease. They've got multi-vessel

01:25:10.660 disease, huge stenosis, vulnerable plaque everywhere. And for 18 months, let's see what happens if we

01:25:19.220 employ lipid lowering therapy. And we see that it has kind of a minor impact and you can make the case,

01:25:24.900 well, you probably should have done it earlier and for longer.

01:25:28.180 Right. And well, I mean, the earlier is definitely key. I mean, I don't know that. So, well, yes,

01:25:36.100 for longer, but not in that particular group. You know, there would not have been any benefit,

01:25:43.380 I don't think, to doing a three or four year study of that moderately demented group with these therapies,

01:25:50.660 because they were just going to keep getting worse. You know, that's the thing. They kept getting,

01:25:55.300 they were, their disease had, was progressing. The train had left the station and it was going to do

01:26:02.180 what it was going to do. So, you know, traditionally 18 months has been a standard length for Alzheimer's

01:26:10.740 trials because it's the amount of time. You have to remember these trials cost lots of money.

01:26:20.260 You know, people often complain and rightfully so that certain drugs are extremely expensive. And,

01:26:27.460 and, you know, obviously you coming from Canada have a whole different perspective on

01:26:32.820 that than the American side of it, you know, where it's just all about money all the time.

01:26:38.740 That being said, there is some validity to the price of some of these drugs because of the vast

01:26:46.260 amount of resources that have been spent. You know, it takes on average, I read a statistic that 10 to 15

01:26:53.860 years and a billion dollars for any one drug to get from development and discovery to FDA approval.

01:27:06.340 That's right. It's probably higher today, actually. It's probably closer to about 1.3,

01:27:11.300 1.4 billion. Uh, and you're absolutely correct. So if you look at that pipeline of 120 odd drugs,

01:27:20.340 again, it's not going to be 120 billion because some of them will get weeded out in phase one,

01:27:24.900 but there's no question that the United States subsidizes the rest of the world in drug pricing.

01:27:32.420 So there's basically an understanding quid pro quo in my mind that says, look, in exchange for having

01:27:39.540 the best drugs available first, you will pay a premium for the development of the drug. That's

01:27:46.340 effectively what's happening in the US. Yeah. And then it's also important to point out though,

01:27:51.220 that for every one drug that makes it all the way through, there's literally four or 5,000 that don't.

01:28:00.980 Some get squashed in the very beginning and some make it to animal models, you know, but

01:28:07.780 it's a very, very, very expensive process for the drug companies. And so going back to my point,

01:28:16.820 they have to find that sweet spot in terms of length of a trial that will be worth their investment,

01:28:25.380 but at the same time, not spend extra resources, but also give the information that they need. And

01:28:30.820 so knowing how Alzheimer's progresses, particularly in that group, 18 months is a spot where you're

01:28:37.140 going to see, okay, so in 18 months, if they're better, well, that's crazy because that doesn't

01:28:42.580 happen. If they're stable, well, that's good because it's usually there's some drop off in that

01:28:49.220 period of time. And if they're worse, then clearly it's not working.

01:28:52.500 Yeah. And if you look at the oncology playbook here, you understand the challenge of this space,

01:28:59.540 which is you have the same economics, right? Which is a billion to a billion and a half to get a drug

01:29:05.380 from inception into a clinic. And truthfully, you have kind of a gray area of utility, right? There are

01:29:14.420 drugs that are getting approved that make very little sense. So they extend median survival by two

01:29:22.180 months without extending overall survival. And they're going to cost a hundred thousand dollars,

01:29:29.940 and we can debate the merits of that. And that's where you'll see differences between the US, the UK,

01:29:34.500 Canada, et cetera. But you see, one of the issues here that I find most interesting, and I'm not as

01:29:40.740 familiar with it in Alzheimer's disease, but I'm intimately familiar with it in cardiovascular disease

01:29:45.540 and in oncology is the importance of patient selection and study design. It's everything.

01:29:51.620 Let's use cardiovascular disease in an example. I always found the Fourier trial and the Odyssey

01:29:57.540 trial, which were the two major trials used to test the PCSK9 inhibitors. I found them to be

01:30:05.380 very elegant and very complimentary. So the Fourier trial took patients who were maximally statinized.

01:30:12.100 These are patients that had an LDL cholesterol that was typically south of 70 milligrams per deciliter

01:30:17.380 or in about that neighborhood. So these are people at the fifth percentile of LDL cholesterol

01:30:22.740 and then added a PCSK9 inhibitor to them. The study was stopped after two to three years. I believe it

01:30:29.540 was intended for four or five and it demonstrated an improvement. And again, in cardiovascular disease,

01:30:34.500 what are your outcomes? It's usually MACE, major adverse cardiac events. So heart attack,

01:30:39.300 stroke, revascularization, death. So you have hard outcomes. That's an important thing, right? They're

01:30:46.020 not tracking. Nobody cares how much it lowers your cholesterol. The biomarker means nothing anymore.

01:30:51.460 It's only does it prevent an outcome. You had a complementary study in Odyssey, which did not take

01:30:57.380 heavily statinized patients, but patients who were, if I recall, equally at risk. And again, it was major

01:31:03.540 adverse cardiac event. And they usually include all-cause mortality. This is a challenge that I

01:31:09.540 see in Alzheimer's disease is, and I'm saying this not as an absolute challenge, just as a challenge to

01:31:15.220 me as an outsider. I struggle to understand these endpoints sometimes, and I just don't understand how

01:31:22.260 valid they are. Not because I think that the people measuring them are nefarious, but because they just

01:31:28.260 seem very soft and squishy at times. Like, well, did the person cognitively get better? Maybe,

01:31:34.420 yes, no, I'm not sure. And yeah, we use this test and it has a five-point scoring system and we square

01:31:40.420 the boxes and such and such. But in the end, it's a harder disease to measure definitive outcomes,

01:31:47.780 to your point, at the duration of time we want to study them. So that's a lot to unpack. And I guess

01:31:53.140 where I'm going with that is, how do you think about, let's start with one element. How do you

01:31:58.420 think about patient selection? Who is the right patient to be studying? Where on that progress

01:32:03.940 from preclinical to MCI to disease? I think we've ruled out bucket three, right? I think if I've heard

01:32:10.580 you earlier, it's, we don't want to be studying patients for disease modification that already have

01:32:17.060 significant dementia. So would you say the same is true of MCI and we should be looking at the preclinical,

01:32:23.140 which means we, by definition, are making an imaging diagnosis or is it early MCI?

01:32:28.340 So I think the jury's still out with regard to MCI. There still are a lot of trials and I think there

01:32:33.620 may be opportunity for mild cognitive impairment as well as mild dementia to benefit from these

01:32:43.140 disease modifying therapies. The prevention trials are definitely, you know, if we're looking at

01:32:49.940 a cure because that's what everybody wants, right? A cure. I think the prevention trials are really

01:32:55.380 going to be the way to go because then you're stopping it before it starts. We know that these

01:33:04.580 anti-amyloid drugs remove amyloid. We know this. They successfully reduce amyloid to a point where

01:33:12.660 people go from having positive amyloid PET to negative amyloid PET. In fact, we had an occasion

01:33:20.260 once where we had a patient who was in a trial, an anti-amyloid trial for some time and then that

01:33:26.900 study stopped and then she wanted to enroll in another study and it was actually an anti-tau antibody

01:33:34.740 and they did allow people with previous exposure to anti-amyloid drugs after a certain window of

01:33:41.460 time. Sometimes they don't. So when she had her new amyloid PET for that study, she screen failed

01:33:48.820 because she was amyloid negative. So that's been shown in numerous trials with more than one compound

01:33:57.220 that it definitely removes amyloid. So if you look at the PET outcomes for these drugs, they're great.

01:34:03.620 What are the clinical outcomes?

01:34:05.460 Yeah. Just like you said, nobody cares about a marker or cholesterol. You care about the clinical

01:34:10.660 outcomes and symptoms. And so none of that matters if you're removing amyloid if the people aren't any

01:34:16.900 better or if they're continuing to get worse. And so that's what was happening with the mild to moderate

01:34:25.220 group. The original solanazumab trials, people just kept getting worse because they already had enough

01:34:32.100 neurodegeneration and other pathology now going on in the brain that whether the amyloid was there

01:34:38.820 anymore didn't matter. I do think in MCI that there's opportunity for these drugs to work and

01:34:47.060 the FDA is considering the aducanumab data right now. There was just last or actually at the beginning

01:34:54.340 of this week data for donanumab, which is a Lilly study that came out at the ADPD meeting showing

01:35:01.780 that it met endpoints on almost all of the mark, you know, the primary and secondary outcome measures

01:35:07.860 that they had set forth. So yeah, I wouldn't rule out the MCI group at this point. But in terms of

01:35:15.060 sort of the ideal, I think prevention ultimately is going to be the way to go as far as disease

01:35:21.940 modification. And just like you'll go to the doctor and see you have high cholesterol and intervene then

01:35:29.540 before you get to these bad cardiac or stroke outcomes, you know, you'll go to the doctor and

01:35:35.620 perhaps have a test that shows you have amyloid and then intervene then so that you don't then

01:35:40.020 develop cognitive impairment. That's our hope and our goal. Yeah, that makes hands down the most sense.

01:35:45.700 And again, I'm obviously stating the obvious, but the more we can model this after a disease where

01:35:51.300 we've had unbelievable success like cardiovascular disease rather than a disease where we've had very

01:35:57.780 little success, which is cancer, because we have to wait until you have cancer. Now, of course,

01:36:02.580 I think liquid biopsies are going to change that. And we are really on the cusp of that. In fact,

01:36:06.580 that's going to be a super exciting discussion we're going to have on the podcast in the next

01:36:10.900 couple of months. So the goal, of course, is to turn cancer into cardiovascular disease. It's to turn

01:36:16.740 Alzheimer's disease into the same. Let's talk a little bit about adecanumab as you mentioned it. So

01:36:22.580 one of the most promising versions of these monoclonal antibodies to amyloid is adecanumab,

01:36:29.300 which is a drug manufactured by a company called Biogen. And it's been in the news a lot lately,

01:36:34.900 I think for several reasons. One is it's a drug that made it to phase three and it was running two

01:36:42.180 parallel studies, Emerge and Engage. And to my understanding, very little difference between

01:36:50.260 them, obviously different sites and maybe a slight difference in some dosing, but effectively the same

01:36:56.100 trial, which is not uncommon for how a drug like this would be tested in phase three because of

01:37:01.220 the size that you need to have of the number of participants you need. Where I think it got

01:37:06.900 interesting was how the results were interpreted for the two arms and then what a reevaluation looked

01:37:16.180 like. So do you want to explain the story of, I guess, let's start with the beginning.

01:37:21.700 This was a well done study in that it had pre-specified endpoints. And that's very important

01:37:26.660 for people when they're evaluating clinical trials. You have to pre-specify your primary endpoint. You

01:37:30.660 got to call your shot before you go to bat. What was the endpoint in this study and how did they go

01:37:36.660 about evaluating? Honestly, I don't remember what the specific primary outcome measure was.

01:37:44.180 It was cognitive, but yeah, yeah, yeah. But it wasn't like, it wasn't an imaging study. It was a

01:37:49.300 cognitive study, right? So normally it's the, I don't remember if it was the ADAS cog or not,

01:37:55.620 to be perfectly honest. So the story of the Embark and Engage studies is, I'm sorry,

01:38:04.740 the Emerge and Engage. We're doing Embark now, which is the follow-up for the people that had previously

01:38:10.100 been in Emerge and Engage. The bottom line is that the study was going along and at some point

01:38:19.380 they do what's called a futility analysis to see if it's worthwhile to continue spending their

01:38:24.180 resources on the drug or to abandon it. And when they did the futility analysis, they were not meeting

01:38:31.700 their primary endpoints. But after further analysis and looking at sort of a cohort of people who had

01:38:40.340 dose escalated kind of in the interim, they realized that the people in the high dose group

01:38:46.740 actually were meeting those endpoints. And so they went back and looked at all the data

01:38:51.940 data. And in a very unusual turn of events, they were like, actually, we were wrong and this is

01:38:58.500 helping. So they ended up going back and putting people back in the study who had previously been on

01:39:07.540 it in this new Embark study, as well as submitting to the FDA for approval.

01:39:15.140 The numbers aren't necessarily relevant, but the highest dose, if I recall,

01:39:19.220 was like 10 milligrams per kilogram. And there was also a stratification for APOE and non-APOE,

01:39:25.140 which I didn't understand because they were giving a lower dose to the APOE-4 carriers than a higher

01:39:30.500 dose. And are they currently just giving everybody the highest dose in the revisit trial?

01:39:36.660 I don't know if I'm allowed to talk about the current protocol.

01:39:40.340 Okay.

01:39:41.460 If it's confidential or not.

01:39:44.020 But what's interesting is that there's something that's going to happen on June 7th.

01:39:48.020 What is that? What are we waiting for on June 7th?

01:39:50.740 I just want to go back and touch on a point that you mentioned. One of the reasons that

01:39:53.940 they give the APOE-4 carriers a lower dose is because of the risk of ARIA or amyloid-related

01:40:00.980 imaging abnormalities. So we know that with these amyloid drugs that remove amyloid,

01:40:06.900 we often will see changes in MRI, either edema or swelling, or micro hemorrhages. So ARIA-E for

01:40:17.620 edema, ARIA-H for hemorrhages, often asymptomatic, but certainly were very significant in some of the

01:40:25.940 earlier iterations of anti-amyloid drugs and drug trials that were going on. And there was a distinct

01:40:33.300 difference between the risk of ARIA in E4 carriers versus not. So that would have been the reason

01:40:39.780 at the beginning that they would have been on a lower dose. I believe, and I don't want to speak

01:40:45.860 incorrectly, but I do believe that subsequently they did find with this drug that that was not

01:40:52.420 happening. So they may have allowed the E4 carriers to go to the higher dose.

01:40:57.780 Yeah, there was a protocol amendment. They did amend the protocol for E4 to go to 10 migs per kg.

01:41:03.700 So June 7th.

01:41:05.320 Yeah. What's going to happen? What are we waiting for on June 7th? Everybody's anticipating this.

01:41:09.320 Yeah. So the FDA is supposed to render a decision about whether they're going to approve this or not.

01:41:15.880 And what did the advisory board say earlier in the year?

01:41:20.260 There were two different things. So there was one group that recommended approval. And then there was

01:41:27.960 another panel that was like, yeah, the data is not so compelling and recommended not. So we really do

01:41:35.680 not know which way the FDA is going to go. There is a very large push on the part of families and

01:41:46.980 patients who have gone without any new treatment for this disease for almost 20 years to say,

01:41:54.880 it's better than nothing. Please approve it. I know, you know, from an advocacy standpoint,

01:42:01.220 there's a lot of that going on. You know, then there's some, you know, very strict science people

01:42:07.680 who are saying, you know, if the data doesn't support it, don't do it. So we really have no idea

01:42:13.460 which way they're going to go. Let's assume the FDA concludes there's insufficient data

01:42:19.160 and they do not approve it. Does anything prevent Biogen from, aside from the destruction of shareholder

01:42:24.600 value, is anything preventing Biogen from running another clinical trial at phase three to try to

01:42:30.340 seek approval with a better protocol that might be able to yield a better outcome?

01:42:36.240 No, there's nothing preventing that. You know, obviously it's just a question of

01:42:40.000 having the funds and inclination to do so, you know, but that's, I think you touched on a little

01:42:46.120 bit earlier, part of the problem that we have is that the outcomes, the primary outcome measures

01:42:52.880 for these trials aren't that great. These are sort of longstanding, well-established cognitive tests,

01:43:00.180 but how much they move in the right period of time may not be as good as we hope. The ones that

01:43:09.540 focus on the CDR, the clinical dementia rating, you know, there is a subjective component to that

01:43:17.160 because that's not just a test that is an interview and a rating that a rater makes based on what both

01:43:25.180 the patient says and what an informant says. And the CDR is the primary endpoint for this drug.

01:43:32.060 Okay. And that's the thing. I mean, the CDR has flaws, you know.

01:43:37.840 I think it has six dimensions to it, but it's subjective, as you said.

01:43:41.780 It is subjective and prone to bias from, let's say, a depressed caregiver who sees everything worse

01:43:51.740 than it is. There have been studies looking at that kind of thing. And a lot of times a caregiver

01:43:59.080 who is highly stressed and depressed will over-report symptoms leading to higher scores,

01:44:07.700 you know, on the sum of boxes. So the CDR looks at memory, it looks at judgment, it looks at

01:44:13.880 home and hobbies and some other things. And a rater will interview the subject. Well,

01:44:20.960 they'll interview the informant and then they'll interview the subject and they'll ask about recent

01:44:25.900 events. Tell me something you did last week. Tell me something you did in the last month. And then

01:44:30.040 part of the rating, you know, is based on what the patient remembers compared to what

01:44:37.240 the informant said. And there is that sort of intangible part where, you know, if you're kind

01:44:44.400 of on the fence, you could go either way. Even though there are very well-established scoring

01:44:48.780 parameters and hours of training videos and things on how to do the CDR, there still is that sort of,

01:44:57.340 eh, it feels like a 1 or it feels like a 0.5 that plays into it that's not just an objective measure

01:45:04.740 like an LDL level. That to me is the biggest challenge here is cancer progresses quickly enough.

01:45:12.900 And at least currently we study it in a very clear sense. I mean, we can debate that there are

01:45:18.720 actually some limitations in how we study cancer progression. And that's been, I think, gamified a

01:45:24.540 little too much. Cardiovascular disease, we've already discussed. It seems that the best hope for

01:45:30.440 a disease in which subjective evaluation is so important is to have biomarkers that are so predictive

01:45:39.300 of clinical outcome that you can rely on those in combination, potentially, with a clinical

01:45:45.720 evaluation. You can't do a long enough study to get hard outcomes. There's really two enormous

01:45:52.900 challenges in drug development for Alzheimer's disease. There's the technical challenge of how

01:45:58.060 do you develop a good enough drug? And then there's the operational challenge of how do you actually study

01:46:02.820 it? Right. So going back to your question, you know, Biogen could very well go back and do

01:46:08.900 another study and use a different primary outcome measure, whether it's the ADAS-COG or there is a

01:46:15.160 cognitive composite score that was recently used by ESI for a different trial. You know, they got a lot

01:46:23.000 of flack for it because people accused them of kind of cherry picking things that worked. But at the same

01:46:31.180 time, as you also mentioned earlier, these were things that were predefined. You know, it's not like

01:46:37.840 they went and just chose the best things or the things that showed change. They defined in the

01:46:43.400 beginning that these are the measures that we're going to look at and made this cognitive composite

01:46:49.540 based on years and thousands of patients' worth of data showing what specific cognitive tests may be

01:46:58.300 better predictors or may change more during a certain period than those that won't. So I personally

01:47:06.280 didn't have a problem with that cognitive composite because I thought that it was a thoughtful way of

01:47:11.580 kind of rethinking and getting good data that might be useful. You know, the ADAS-COG is just so ingrained

01:47:19.400 in this field. And although it certainly has a lot of utility, it also has limitations. So finding some of

01:47:27.180 these better objective primary outcome measures from a cognitive standpoint, in addition to the

01:47:34.680 biomarkers, I think certainly will be useful for drugs moving forward.

01:47:39.340 So I want to kind of close our discussion, Amanda, with something you alluded to earlier, which is

01:47:43.220 what does it mean to undergo healthy aging? It's inevitable. We're all aging. We're all going to die.

01:47:50.240 And unfortunately, many of us are going to die with some form of cognitive impairment, even if it is not

01:47:56.100 dementia. So in your 20 years of practice, what wisdom have you gleaned and what might someone who

01:48:04.900 is seemingly far from that learn? So, you know, it's interesting. And I knew we were going to talk

01:48:11.980 about this. So I've actually been, you know, more contemplative in the last few days kind of thinking

01:48:17.060 about it. You know, there are a lot of different frameworks for aging. You know, the stuff that we

01:48:23.180 learned in psychology class and, you know, some of these classic structured approaches to aging,

01:48:30.040 both psychological and sociological. But, you know, I'm never one to kind of fit into one neat

01:48:37.400 category. I like to kind of be eclectic and take a little bit of this and a little bit of that. But

01:48:43.220 at the end of the day, you know, it really has to do with, you know, how people see themselves,

01:48:50.220 how people interact with the world, what kind of relationships they have, how able they are to

01:48:58.000 let go of things that they've lost, and how able they are to focus on the positive. I think that's

01:49:08.960 where I see people struggle the most as a psychiatrist and people develop the most depression

01:49:16.360 is when they spend so much time looking down the road at what's going to happen or what might

01:49:22.420 happen that they can't enjoy now. And it's very interesting. I can have two patients, maybe both

01:49:31.500 of whom were marathon runners, and now both have Parkinson's disease. And while they both have

01:49:39.800 disability, one of them centers their whole identity around this new disability and focuses

01:49:48.760 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.

01:49:53.160 I can't do that. Whereas the other one is like, well, okay, so I can't run anymore, or I might fall

01:50:02.060 if I go to the beach, but I can still enjoy the sunset in a special wheelchair, or focusing on what

01:50:10.820 I still can do and trying to make the most of each day. And those are the people that I think

01:50:16.740 age successfully, even in the face of having illness. We all will age. We all have changes in

01:50:26.980 our physical strength and our mental alertness and, you know, acuity, but it doesn't necessarily

01:50:35.040 disable us. And even if it does, the key for me really is how that shapes our attitude or how much

01:50:43.640 we let it affect our attitude. I want to run an idea by you, and I'm curious as to your thoughts.

01:50:49.440 I describe health span or quality of life as having broadly three dimensions, a physical one.

01:50:56.980 A cognitive one and an emotional one. And I think it's safe to say that as sure as God made little

01:51:04.320 green apples, the first two decline with age. Now, if you're really lucky, they don't decline

01:51:11.000 too, too much, assuming you live a long life, right? So if you talk about someone who's going to live

01:51:14.980 into their nineties, there is a physical decline that is undeniable. Even if you are fortunate to be

01:51:22.300 spared dementia, there is a cognitive decline, but it doesn't have to be that sharp. And for the lucky

01:51:28.580 ones, you've got the Charlie Mungers of the world who are literally in their nineties and appear to

01:51:33.900 be just as sharp as ever. But the one that doesn't appear to have an age component to it is the emotional

01:51:40.760 one. And so the question I've been pondering is, are the most miserable people going to be the people

01:51:48.760 whose identity is wrapped up in the things that inevitably decline? And therefore, should we be

01:51:56.000 putting more of our identity in the one thing that really has no tie to age, which is basically our

01:52:04.760 emotional health, which I believe is most a function of the quality of our relationship? So a person who

01:52:11.260 has wonderful quality relationships is generally an emotionally healthy person. And that doesn't mean

01:52:17.560 it's a person who doesn't get sad and a person who doesn't get angry and a person that doesn't

01:52:21.840 struggle, but they have an emotional strength to them that I think comes from this tethering to

01:52:27.420 other people. So does that framework make sense? Absolutely. I think it's spot on and exactly true.

01:52:35.360 You know, that is so important in terms of wellbeing is having people feeling loved, feeling

01:52:45.220 that there are people you can rely on, feeling that there are people who can share experiences with

01:52:52.240 you. You know, social isolation is a huge problem for some people and a definite determinant of quality

01:52:59.960 of life versus not. I definitely see that people that struggle the most are the ones that are constantly

01:53:08.300 comparing themselves to their former selves. I used to be able to do this. I used to be able to

01:53:15.120 tell you that. I used to, if I did that, I would just be, you know, hiding under my covers. I mean, I didn't

01:53:21.980 used to need these, but I do. So it's like, well, I might as well buy cute ones because you got to have

01:53:28.720 them.

01:53:29.460 It's so hard though, Amanda. Like I, I think about it, like we're about the same age and it's true.

01:53:36.220 We've already experienced a decline, but it's going to get steeper, right? Like it's when you

01:53:42.920 look at what it means to be 90 for most people, at least it's, it's going to be a far greater

01:53:51.600 loss over the previous two decades than maybe we've experienced in the previous two decades.

01:53:57.020 There's a real non-linearity to it, but I guess it's as good a time as any to begin rehearsing that.

01:54:02.440 And I've been very deliberate about this for the past two to three years in anticipation of

01:54:07.700 hopefully a long life. Cause you know, look, I think there was a day when all of my identity was

01:54:13.300 wrapped up in these things that are inevitably going to decline and none of it was wrapped up

01:54:19.560 in the other. And, and I'm undergoing an asset reallocation, which I guess the point is we should

01:54:25.440 be doing this when we still have a chance to.

01:54:27.080 No, you're absolutely right. And, and that, that actually is a great point, not just doing

01:54:34.240 the asset reallocation, but just doing things when you still have a chance. You know, one of the things

01:54:38.980 as we were talking earlier, another big thing that I think contributes to quality of life

01:54:45.160 and you sort of, whether people age well or not is regret and how much regret they live with.

01:54:51.240 And so very often I see people who come in and, you know, have worked really hard throughout their

01:54:59.240 lives and put off this and put off that. And we're just about to retire and do X, Y, Z. And then now,

01:55:07.280 well, now I have this devastating disease. And so part of what I do is educating them. Well,

01:55:13.320 you can still do X, Y, and Z. You just might have to do it a little bit differently. But it also,

01:55:18.860 I mean, personally has affected me, you know, my happy place is the beach. I love the beach. I have

01:55:25.600 dreamed my whole life of being able to see the horizon from my bed. And so as soon as we were able

01:55:34.400 to afford it, we got, you know, a condo at the beach. It was old, built in 1972 and, you know,

01:55:42.720 quite frankly, hideous at the time when we got it. But it meant that I could wake up and see

01:55:48.820 the Gulf of Mexico, especially through the pandemic. We've gone there almost every weekend

01:55:53.800 just because what else are you going to do? And, you know, but that's something I learned

01:55:59.060 from my patients. You know, don't wait. Don't wait until I retire to get that beach condo because

01:56:03.780 I might not be able to use it. You know, I'm living now. So do it now. And that's A, something I've

01:56:12.200 learned and B, something I really try to impart to these people that are coming in that sort of

01:56:17.200 feel like that's a hard stop. Like, oh, well, I can't do this now because of this diagnosis.

01:56:23.180 And it's like, well, no, you still can. You just have to be a little more careful or

01:56:26.700 you can still take that cruise, but you just wear, you know, I actually, anytime I go to a meeting,

01:56:32.720 I haven't been to a meeting in, you know, a year and a half, but I save all of my name tag

01:56:37.540 lanyard things and I give them out to people. I say, here, take this on your cruise and just put your

01:56:43.460 room number or cabin number or whatever in it and your cell phone number so that if, you know,

01:56:49.020 your loved one wanders off on a ship, at least they can call you or they can find out what cabin

01:56:53.640 you're in. And so it's making those adjustments, but still, you know, doing the things that you

01:57:00.060 enjoy with the people you enjoy doing it with. I think that's incredibly well said, Amanda. You

01:57:06.200 know, I've really enjoyed our discussion today. And I know that everyone listening to this has as well,

01:57:10.260 because I just think people are becoming more and more aware of this condition. And as you said,

01:57:14.940 it's less taboo. It's something that people are talking about. And I do believe that people are

01:57:20.980 cautiously optimistic that the next decade looks better than the last decade in terms of actual

01:57:26.840 medical treatments we have. I'm still firmly in the camp of Richard, which is not to say that

01:57:32.380 you're not saying that, but that says, look, prevention is the best medicine for chronic disease,

01:57:39.180 be it cardiovascular disease, cancer, or Alzheimer's disease. But inevitably, a number

01:57:44.380 of us are going to slip through the fingers and the grasp of prevention and are going to need

01:57:49.480 treatments. And I'm hopeful that these monoclonal antibodies that can target amyloid beta or tau

01:57:55.200 can be a step in the right direction. So thanks very much for all of your insights today.

01:57:59.820 Oh, my pleasure. And of course, exercise.

01:58:02.880 You don't need to tell this audience.

01:58:06.300 No, I know. That's what I'm saying. You know, it's even if you've passed the point of prevention,

01:58:12.780 and I know you've gotten into this in other podcasts, but the data, the growing body of data

01:58:19.080 shows that even in people who have cognitive impairment or have full-blown dementia,

01:58:24.620 aerobic activity can actually improve scores on cognitive testing. Some of the research that some of

01:58:31.720 our colleagues do through all of these prevention trials and then through these intervention trials

01:58:38.440 in MCI and AD, Silver Sneakers Program at the YMCA, Laura Baker at Wake Forest is doing a lot of great

01:58:47.180 stuff with this and showing that even if you have dementia, your scores will go up if you do aerobic

01:58:55.600 exercise. So that's what gets me going in the afternoon.

01:58:59.620 All right, Amanda. Well, thanks so much. And I hope you get to see the sunset this weekend.

01:59:06.040 Thank you. I really appreciate it. It was great talking with you.

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The Peter Attia Drive - June 07, 2021

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

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