The Peter Attia Drive - #138 - Lauren Miller Rogen and Richard Isaacson, M.D.： Alzheimer's disease prevention

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

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00:00:41.720 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. My guests this week are Lauren Miller Rogan and Richard Isaacson.

00:00:55.400 Lauren is an actress, screenwriter, director, but also a friend and patient. She's the co-founder

00:01:01.540 of Hilarity for Charity or HFC, a national nonprofit organization whose mission is to care for the

00:01:08.160 families facing disease of Alzheimer's disease, educate them about living a healthy brain life

00:01:13.440 and activate the next generation of Alzheimer's advocates. Richard Isaacson should be a familiar

00:01:19.560 name for some of you as he was a guest on a previous episode of The Drive in late 2018,

00:01:25.660 when we did a deep dive into Alzheimer's disease. Many of you have requested follow-up podcasts on

00:01:32.920 this topic. Among them, this is one. Richard serves as the director of the Alzheimer's Prevention

00:01:37.440 Clinic at Weill Cornell, New York Presbyterian Hospital, and is a assistant dean at the office

00:01:43.980 of the faculty of Weill Cornell of Medicine. I've known Lauren for a couple of years. We actually

00:01:50.340 met through Richard and the three of us been talking about doing this podcast for about a year. In fact,

00:01:55.600 we were going to do it last fall, and then we put it off until the spring, and then COVID got in the

00:02:02.060 way. So this one's been a long time coming. My intuition was that being able to talk about

00:02:06.600 Alzheimer's disease with Richard and Lauren simultaneously would be a beautiful way to discuss

00:02:12.160 the human tragedy of the disease, and also to talk about the science of prevention and the

00:02:17.780 pathology of the disease. And honestly, by the end of this discussion, I felt we had really achieved

00:02:22.800 that. I think Lauren's story is both heartbreaking and uplifting for reasons that will become clearer

00:02:28.060 as you listen to this. In this episode, we talk about her journey with her family history,

00:02:34.240 what led her to Richard, and ultimately what really changed the course of her life with respect to

00:02:39.000 how she treats prevention. We talk a lot about what preventative measures look like today and how

00:02:46.220 we look at the evolving body of literature to figure out how to modify risk. So if you have

00:02:53.480 even a slight interest in the prevention of Alzheimer's disease, I think you're going to find

00:02:57.680 this episode both touching and enlightening. So without further delay, please enjoy my conversation

00:03:03.740 with Lauren Miller Rogan and Richard Isaacson. Lauren and Richard, what a privilege to be

00:03:15.700 sort of sitting down with you guys right now. We have been kicking around the idea of doing this for

00:03:20.560 about a year now. COVID kind of got in our way. We were going to do this obviously in person last year.

00:03:26.960 So while it's long overdue, I think this is just such an exciting opportunity both to

00:03:32.720 kind of hear from you, Lauren, and kind of understand your personal journey,

00:03:38.700 which you've basically taken on as your life's mission. And then obviously Richard to have you

00:03:45.720 back on and kind of, I don't know, I think bring people up to speed on what's happened in the last

00:03:51.740 couple of years. So thanks both of you for making time today. Thank you for having us. You know, I feel

00:03:57.260 like long-time listener, first-time guest, very excited to be here. Long-time listener as well. Yeah,

00:04:05.500 I hang on every word of most of the podcasts, especially, well, I had to listen to Tom Dayspring's

00:04:10.900 podcast like 14 times. I'm still like need to listen to it on repeat, but. Lauren, let's start with you.

00:04:16.220 I mean, I want people to really get an understanding of your story. So I mean, when did you first become

00:04:23.240 aware that there was something going on in your family that was robbing people of this precious

00:04:30.900 thing called their mind? Unfortunately, Alzheimer's has been a part of my life as long as I can

00:04:37.740 have my own memory. My grandfather, my mom's dad had Alzheimer's. My aunt has told me it seems like he

00:04:44.540 showed symptoms maybe in his late fifties or early sixties, but he was in a nursing home. I think

00:04:49.800 from the time I was around eight or nine, maybe 10, and he passed away when I was 12. But when you're

00:04:56.920 young, that age, to me, his memory issues were almost funny, right? Like he would take his teeth

00:05:02.940 out of the table and I thought that was hysterical and he would, you know, repeat things. And again,

00:05:08.880 like when you're little, that's funny. And I didn't have any concept of the fact that the reason he had

00:05:14.920 to go into a nursing home was because he was wandering and that my grandmother couldn't take

00:05:18.380 care of him. And then after he passed away, my grandmother started showing signs of dementia and,

00:05:25.040 you know, she was struggling to take care of herself and was clearly wasn't eating. And, but,

00:05:30.020 you know, I was in high school. So again, I wasn't really that aware of the situation and what was

00:05:36.640 happening. But, you know, I was aware when they brought her from her home in South Florida up to

00:05:41.440 where we were in central Florida to put her in a facility, you know, and how she was curled over

00:05:47.320 in the seat, sleeping and not aware when I was showing her how I could drive for the first time

00:05:52.320 and how she eventually stopped being able to walk or talk or feed herself. And my senior year,

00:05:59.740 I would go visit her every Friday after school and, you know, a few other days during the week. But,

00:06:04.000 you know, when she spent the last year of her life curled up in a bed,

00:06:07.440 obviously not talking or being able to care for herself in any, any way at all. It was a lot at

00:06:14.000 18 and, but it was still, I was younger and it was my grandmother. You know, I think when you're young

00:06:18.160 and you envision your grandparents as like, well, they're grandparents, they're, you know, this happens

00:06:21.940 to them, even though, you know, my, I think my grandmother was 76 maybe. So then she passed away.

00:06:28.660 And then at my college graduation, when I was 22, my mom was 52. She repeated a story a few times.

00:06:35.640 And, you know, my mom, who was this incredibly smart, vibrant woman who was aggressive about the

00:06:45.660 things she wanted in her life. And she didn't take no for an answer type of woman. But throughout her

00:06:51.460 life, she would always say, when I get Alzheimer's, when I get Alzheimer's. And I would say, stop saying

00:06:54.980 that. Don't say that. Like, and then at my graduation, when she repeated the story a few

00:06:59.540 times, I thought, oh God, but I didn't say anything, of course. And then, you know, over the next year or

00:07:05.100 two, it became clear that this repetition was becoming a part of who she was. And she was losing

00:07:10.980 control of, you know, her ability to teach and to, you know, do any number of things that someone who

00:07:19.020 was fully functioning in a cognitive way could do. Eventually, we encouraged my dad to take her

00:07:25.620 to a doctor. And, you know, over the course of a year and a half or so, we got as, you know, as much

00:07:31.300 as a diagnosis as one could get at that time. You're just out of college. And you're being

00:07:38.180 confronted with the idea that your mom is not even in her mid-50s yet. And she's already in the early

00:07:43.700 stages of Alzheimer's disease, something that's already prematurely taken her parents. I'm guessing

00:07:50.660 it's now sort of setting in that there's something going on in your family, right?

00:07:55.120 Yeah. I mean, there was a lot of denial, I would say, a lot of fear, a lot of anger, and of course,

00:08:05.980 a lot of depression. And I think what was really hard about it at the time was my mom wouldn't let us

00:08:12.520 talk about it. And, you know, at this point, I can only imagine what her identity felt like as a

00:08:18.640 daughter of Alzheimer's herself, what was driving her at this point. But to me, things were really

00:08:26.260 starting to become clear in a really scary way at that point. I didn't talk to anyone about it,

00:08:32.420 because I didn't, I think, you know, when you talk about something, it seems real, all of a sudden,

00:08:35.440 it's really happening.

00:08:36.280 Even your father?

00:08:37.560 Oh, God, especially not my dad, because my dad was the most in denial about any of us.

00:08:41.440 You know, my dad, you know, my parents had, you know, an amazing marriage, and they were

00:08:46.980 best friends and partners. And he admired my mom for her brain, and for how smart she was,

00:08:54.640 and how passionate she was about what she did, and how hard she worked. And so, yeah,

00:08:59.740 he was the last one, I think, to come around. But eventually, a few months after Seth and I started

00:09:04.440 dating, actually, my parents came out to visit. This was in 2005, to meet him and came out for my

00:09:10.160 birthday. And when I dropped them off at the airport, and I came back to Seth's apartment,

00:09:14.640 it was the first time I'd said it out loud, that I was afraid my mom was developing Alzheimer's.

00:09:20.800 And it was the first time I cried about it. And he was like, no, no, she's fine. No, it's fine. And

00:09:25.980 I'm like, you don't know her. You don't know how the person you met this weekend is different

00:09:29.960 than who she was. And, you know, it was, I guess, around two years from that point

00:09:35.060 of going to visit, and she'd be worse. It was clear, you know, at some point, she shouldn't

00:09:41.260 be driving. Eventually, her school decided she shouldn't be in a traditional classroom anymore,

00:09:46.640 and took her out of that classroom. It was just who she was, was fading away and changing right in

00:09:52.100 front of her eyes. She couldn't have these long conversations anymore. She, again, would repeat

00:09:58.360 herself. She would call with the same thing over and over again. And it was devastating. I was in a

00:10:04.840 very dark place at the time. Do you have any sense that she was aware of some of these things? For

00:10:11.580 example, the idea that she could no longer teach her classes, and to have that taken away from her by

00:10:19.460 her peers, did that register with her what was happening and why? Yeah, you know, I never, I didn't

00:10:27.060 have that direct conversation with her about it. I'm sure my dad did. I think she took that stuff in

00:10:32.900 stride probably to act like a strong, independent person for us. But when she eventually had to retire,

00:10:40.620 I know she wasn't thrilled about it, but she was at a point where cognitively she wasn't at full

00:10:46.860 function anymore. And so it became a bit easier to change her life in a way where she didn't question

00:10:54.980 it, which is, you know, really sad to think about. But I think it was, I had one conversation with her

00:11:03.540 early, early on it, I read in teen magazine, if there's ever something difficult, you want to talk

00:11:08.700 to your parents about, do it in the car, because the drive will eventually end. And so the awkward

00:11:13.140 conversation will naturally end. So I remember one time I was home in Florida, and I was visiting them.

00:11:18.280 It might have been around the time she was forced to retire, and we were driving to Target.

00:11:22.040 And I asked her if she was scared about getting Alzheimer's. And she told me that she wasn't

00:11:28.520 scared for her. She was scared for me and my brother and my dad. Because I think she got that

00:11:34.500 at some point, she may not know what's happening, and that the weight would be on us. I think she knew

00:11:41.520 that because of what happened with her dad and her mom. And I can only imagine how terrifying that was

00:11:48.020 for her. But I, you know, I can't understand where she was at that point, cognitively or emotionally

00:11:54.460 even, to really know the fear there. So you mentioned that this is around the time when,

00:12:00.900 I mean, it's now hitting you with the full force. Yeah. And I assume it's much less, or I mean,

00:12:07.380 maybe somewhat, but probably less about what the implications are for you, and much more about the

00:12:12.560 loss of her. Yeah. Which, of course, you know, I was in my early 20s, so that was only about me.

00:12:18.540 I was at a point in my life where I was just starting to become friends with her.

00:12:23.000 She had, I'm getting a little emotional. She had come out to visit. I moved to LA in January of 2004,

00:12:28.660 and she came out to visit in March of 2004 during her spring break. And we had such a great time

00:12:35.080 being, you know, I was 22, but, you know, a grown-up. And we went to dinner, just the two of us,

00:12:42.240 like, as grown-ups, and, like, drank wine. And, like, she wasn't a big drinker. She would drink a

00:12:47.020 sea breeze, I remember. And, like, it felt like I was reaching that point where she was my friend,

00:12:52.600 which I think, you know, now I have so many girlfriends who their moms are their best friends.

00:12:56.840 And I instantly felt like that was being taken away from me and was so angry about it and so

00:13:07.200 jealous of all my friends who were having those relationships with their moms and felt so hopeless.

00:13:16.560 You know, I would go online and I would just search, like, cure for Alzheimer's, treatment for

00:13:20.660 Alzheimer's, got to be there. I know I can find it. Like, I'm the kind of person who's, like, if I'm

00:13:24.580 going to do something, I'm going to do it, you know? And, like, no, there's something out there.

00:13:27.580 I can find something for her. And there was nothing. Like, there was nothing. And so it was

00:13:36.080 a really scary, hard time where I felt like I could do nothing and that this train had left

00:13:43.560 the station for my mom and that was it. So I want to give you a chance to just sort of

00:13:49.940 catch your breath a bit. And Richard, I want to sort of ask you a couple of questions right now.

00:13:56.180 Not necessarily specifically about Lauren's mom, because I want to come to that in some detail

00:14:01.860 later when you actually, when we get to the part of the story where you and Lauren meet.

00:14:05.960 But I want to just ask you a broader question here, which is help a listener understand the

00:14:10.960 context of this type of Alzheimer's disease. And by this type, I mean one that is so clearly

00:14:19.320 familial and also so early in onset. How do you think about that as a neurologist? What's going

00:14:25.840 through your mind as you think about this type of a case in terms of genetic predisposition? Let's

00:14:31.720 just start with the genetics of this. Sure. So I first have to start with just,

00:14:36.280 I hate this disease. I just, like, hate it. I hate hearing these stories. Now you're going to

00:14:43.660 make me cry, Lauren. I'm on a podcast. Come on. I'm on record. I can't. Well, no one can see us,

00:14:48.640 so it's fine. Okay, good. Perfect. So I just hate this disease so much because it's so insidious. It's

00:14:53.980 so nasty. It's so just, it just, it robs not just the, I mean, it robs the person of who they are,

00:15:01.240 but it robs the whole family. I mean, just like you just said, it's like it robbed you of like

00:15:05.360 the good years, like the friendship years. And that's just, so I hate this disease.

00:15:10.180 Alzheimer's disease starts in the brain decades before the first symptom of memory loss begins.

00:15:17.440 And I didn't learn that in medical school. I hate to say it, but most doctors don't know that

00:15:22.620 still. You know, the new diagnostic criteria have been out now for about a decade.

00:15:28.300 But, you know, when I hear at 52, I say, oh my gosh, what was happening in her 30s? What was

00:15:35.320 happening in her 30s? Like, why? Why is this happening? And then I hear the family history and

00:15:40.120 I hear, wow, her mom and her dad, why? Why is this happening? And Lauren, we have some small

00:15:46.840 world coincidences, which we learned about later, but like my brother, he's a neurologist. He's older

00:15:52.040 than me. He took care of another one of your family members like on another. So like, why? Why is

00:15:58.600 this? And of course, the first thing you think about is genetic. And then you think about, well,

00:16:04.120 is this early onset? What is early onset? I think most people think about Alzheimer's disease and

00:16:08.120 older person's disease, greater than 70, 72, 74. What's the average age? But there's a small,

00:16:15.720 tiny sliver, a small, small group that I would qualify as having early onset Alzheimer's disease

00:16:21.840 due to a genetic reason where the person usually gets Alzheimer's in their, you know, 40s or 50s.

00:16:27.460 But, you know, Lauren, your family was different and we'll talk about this later. But when I hear a

00:16:32.060 family history like this, I say, well, why does certain people in one family get it later

00:16:37.340 and the other people in the family get it earlier? This is actually earlier onset Alzheimer's. And I

00:16:43.580 maybe made that up, but what is, what is it? This person should have been affected in the later years

00:16:49.660 and something is fast forwarding. Something is, there's like a one plus one equals three here.

00:16:54.540 There's like a mishmash of things that just, like the first thing I think about is why is this

00:16:59.240 happening? And number one, I say, okay, genetics is, there's gotta be some genetic something.

00:17:04.200 And then number two is, okay, then I think about, well, could it be lifestyle? Could it be an

00:17:08.280 exposure to something? Could it be head trauma? Could it be uncontrolled diabetes, high blood

00:17:14.240 pressure, cholesterol? These are all things that, you know, just synergize together to potentially make a

00:17:19.520 late onset Alzheimer's case start earlier. So, so these are the, some of the things like,

00:17:24.020 you know, detective work things that I think about, but no, it's not typical.

00:17:28.020 What genes do you think about Richard? What are the suite of genes? I mean, there's the obvious

00:17:31.860 ones, APOE4, but there are other genes that could be implicated in early cases. Can you

00:17:37.220 say a little bit about those? Sure. So there's a typical early onset genes. There's really only

00:17:42.180 three, presenilin one, presenilin two, and amyloid precursor protein gene mutation. I can count on my two

00:17:49.120 hands, how many patients I've seen with that. I've seen over 1500 patients easily, probably close to

00:17:55.360 2000 patients over the last 15 plus years, literally two hands. It's all I got. Lauren,

00:18:01.220 you actually introduced me to one, an amazing, amazing person, great individual, and someone that

00:18:06.160 I, she may have that gene, but I will not say that she will get Alzheimer's. So, so for the first time

00:18:17.120 in my career, I've, I'd not only, we not only figured out that someone has an early onset gene,

00:18:21.360 which means you're going to get Alzheimer's, but just wait, our field is making a lot of progress.

00:18:25.760 So, you know, these three genes are just so rare. That's number one. Most people that have earlier

00:18:32.160 onset Alzheimer's have a milieu of things. So I would call it polygenic risk. So APOE, APOE4,

00:18:40.460 the variant, APOE4 is the most common genetic risk factor for Alzheimer's disease. Now,

00:18:47.080 the difference between APOE4 having one variant or two, I'll explain that in a second,

00:18:53.160 means if you get the E4, it doesn't mean you're going to get Alzheimer's. It just increases your

00:18:56.960 risk. If you get presenilin one, presenilin two, or amyloid precursor protein gene mutation,

00:19:02.600 sorry for the long words there. If you get those genes, you get Alzheimer's. That's,

00:19:07.420 that's what the books say, except in that one person that you introduced me to, Lauren,

00:19:10.920 we're going to, we got time. She's in her twenties. We're going to, we're going to,

00:19:13.780 we're going to get this for her. And those Richard really represent far less than 1%

00:19:19.180 of the total cases are made up of APP, PSEN1, PSEN2. For what it's worth, I've never actually

00:19:25.880 seen one. I, for me, those only exist in the literature. The interesting aside, by the way,

00:19:30.980 is there's some people speculate that the index case of Alzheimer's disease was actually one of

00:19:37.640 those. And, and some of our understanding of this disease may be incorrect as a result of that,

00:19:42.440 but we'll, we'll kick that to another discussion. So when you meet a person like Lauren,

00:19:49.180 you're not necessarily thinking one of those three genes. You were just thinking some aggressive

00:19:54.180 combination of other things. Yep. And it's, um, epigenetics would be the word that I think about.

00:20:00.200 So the term epigenetics encompasses a person's genetics plus the environmental impact, the milieu

00:20:06.660 of what a person does in their lifestyle or behavior, or what they were exposed to, for example,

00:20:11.320 whether it was a virus or if it was a traumatic something, or if it was something that triggered

00:20:16.420 the gene to work in one way or another. And the term polygenic risk means that there are

00:20:21.060 multiple genes that work together. Now, some genes can increase risk and some people,

00:20:25.900 some genes actually decrease risk. So the future of Alzheimer's disease, well, I believe the future

00:20:30.720 of Alzheimer's disease is based in precision medicine, using these types of genetic underpinnings,

00:20:37.060 understanding all the individual genes that impact a person's risk, figuring out what they are,

00:20:42.940 figuring out what their biological function is, figuring out why it puts a person down the path

00:20:48.940 towards Alzheimer's, and then telling that person to do A, B, C, X, Y, and Z to get them off the path

00:20:55.180 towards Alzheimer's. That's the future of Alzheimer's. And I think in a lot of ways, the future is now,

00:20:59.600 but ApoE is by far the most well-understood, most well-researched. Every patient that walks

00:21:06.060 through our doors gets an ApoE test. You know, there are commercial, like anyone can basically

00:21:10.580 find out what their ApoE status is. Just for the listener out there, you get one from mom and one

00:21:15.920 from dad, either an ApoE 2, a 3, or a 4. It's called an allele or a variant. A lot of people call

00:21:22.580 it a mutation, but it's not a mutation. So you get a 2, a 3, or 4 from mom or dad,

00:21:27.100 and a 4 increases risk a little bit. A 3 is neutral, and a 2 actually is protective.

00:21:33.900 So if someone comes in as a ApoE 3, 3, that's a pretty, you know, neutral risk, kind of boring,

00:21:38.440 no big deal. ApoE 2, 3, okay, maybe they have some protection. And 1, 4, ApoE 3, 4, for example,

00:21:45.060 increases risk a little bit. And then 2, 4s, ApoE 4, 4s, increases risk more so, but again,

00:21:51.580 genes are not our destiny. We can absolutely win the tug of war against our genes. And

00:21:56.800 you know, 4, 4s, I have dozens of patients in my practice that I absolutely think that

00:22:01.920 they are not going to get Alzheimer's disease. They're going to be able to do some things to

00:22:05.780 delay it. They also have other genes to protect them. So without getting too detailed, ApoE 4 is

00:22:10.740 important. We personalize care. You know, if someone has a 4, we're going to tell them to do

00:22:14.840 certain things. If someone doesn't have a 4, we're going to do other things for them because

00:22:18.700 their other things are preferentially effective. But this polygenic risk is what I'm thinking.

00:22:23.960 So when I hear about Lauren's mom, like, what is it? What are her E4s? Sure. But what else?

00:22:29.720 There's got to be something else. The devil is in the details there.

00:22:33.660 Richard, I want to go back to Lauren to continue the story before I do. Can you explain for folks

00:22:38.280 that want a bit more of an understanding, what is it about having the E4 variant relative to

00:22:44.120 the E3 variant that increases risk? So the gene codes for a protein that differs in what way from

00:22:52.000 what we call the wild type or the E3 variant? So I guess how I would answer that is, starting by

00:22:57.820 basic, what does ApoE mean? Apo is apolipoprotein. That means something related to cholesterol, I guess.

00:23:05.220 People actually who get the gene tested in our practice actually get it through a cardiovascular

00:23:10.740 disease prevention panel. Peter, you and I have used the same labs. You maybe focus more on

00:23:16.740 cardiovascular disease prevention. I focus more on Alzheimer's disease risk reduction and

00:23:20.740 prevention, but it's really a cardiovascular risk gene just as much as it is an Alzheimer's

00:23:24.900 risk gene. So the way that I think about ApoE4 is it increases vascular risk. It increases

00:23:31.880 the likelihood of a bad pathologic protein called amyloid. It's a sticky stuff that builds up in the

00:23:38.180 brain of a person with Alzheimer's. And people with this gene are more likely to have accelerated

00:23:43.220 deposition or accelerated accumulation of this amyloid protein through a, what I would call just

00:23:50.600 in a basic sense, a cholesterol-like, vascular-like pathway. There's a ton more I can talk about it,

00:23:58.660 but once you've seen one person with Alzheimer's, you've seen one person with Alzheimer's. And

00:24:03.820 different people can take different roads to Alzheimer's disease. And the ApoE4 road is actually

00:24:10.420 something I kind of understand. I kind of get it. I feel good about it. I know that may sound callous

00:24:16.100 or strange, but I know what I'm up against. Like, okay, great. We can do lifestyle things. We can

00:24:21.580 manage cholesterol in a certain way. We can do all these different things. And I know certain things

00:24:25.780 that work. And I know what I'm up against. It's the person that actually doesn't have the E4

00:24:30.540 that I'm like, wow, they're either spared or they have another gene lurking. How do I find it? And what

00:24:37.540 the heck do I do about it? So E4 doesn't bother me. And I feel relieved sometimes when we find it in a

00:24:43.420 person. All right. Well, I think we'll talk a little bit more about this, but Lauren, I want to

00:24:48.780 kind of hear more from your story. So as you're now kind of coming to grips with the fact that your mom

00:24:54.360 is slowly slipping away and you're also realizing that unlike, oh, if my mom has premature heart disease

00:25:03.860 for which there's no shortage of treatments, you're realizing actually your ability to access the

00:25:10.840 best in medical care isn't really going to do much. What's the temporal course of her progression?

00:25:16.520 So as we get, let's say fast forward to when you and Seth get married, which is, you know, 10 years

00:25:20.760 ago, how is she at that point, which is still probably putting her in her late fifties, right?

00:25:25.960 She had just turned 60. So at that point she could still walk. She was

00:25:32.140 there were moments where she knew us. No, she knew us. She knew that we were her family and that

00:25:40.600 we were her loved ones, but she was, you know, at that point being fully cared for by my father at

00:25:48.560 that point, you know, but she could still dress herself and bathe herself and use the restroom.

00:25:53.120 But, you know, planning, I would say planning my wedding was, was a real emotional turning point

00:25:58.240 for me because it was, you know, I, I, I always was the kind of, you know, girl who like envisioned

00:26:04.380 my wedding and it was be this thing. And then my mom and I would do it together. And that is just not

00:26:08.820 what happened at all to the point where, you know, I couldn't even have her there when I was getting

00:26:15.080 ready because she would just be wandering. And my dad had to take her to a separate hair appointment

00:26:21.300 because it would just, would be too disruptive to get everything together to have her there. But,

00:26:28.580 you know, when she walked in, I remember that morning, I'll back up a bit to say we had a bit

00:26:34.340 of a weekend, our wedding. And Friday night was a small thing and Saturday and Saturday night there

00:26:39.780 was a dinner and it was not good. You know, we had taken my mom from her home, which for an

00:26:46.460 Alzheimer's patient, uh, for anyone with dementia is difficult to take someone out of their space,

00:26:51.580 their routine, where they know everything and they are familiar with their, their world.

00:26:56.860 So that of course had put her in a place where I think she was probably feeling very scared

00:27:01.480 because she didn't understand where she was or what was happening. And at our rehearsal dinner the

00:27:06.860 night before, I remember her telling me she just wanted to go home, which was, you know, really hard

00:27:11.800 to handle. But then miraculously the day of, like she walked in and she called me the bride and she

00:27:19.560 knew that I was the bride and that I think she knew that I was her daughter, but she knew she felt proud.

00:27:25.320 She knew she felt love. And I have an amazing photo of her, like looking at me and holding my hand.

00:27:30.680 And it's just, she knows, she knows that, you know, there's a connection there, but it wasn't,

00:27:35.940 you know, it wasn't the moment that I had certainly dreamed of. And I feel like it was my dad and I

00:27:40.440 that walked her down the aisle instead of him and her walking me down the aisle. And, you know,

00:27:45.680 normally in Jewish weddings, the family stands up next to the bride and groom and we didn't do that.

00:27:50.860 We had them sitting next to us because we knew my mom couldn't do that. So at that point she was,

00:27:56.380 you know, she hadn't, she wasn't teaching anymore. That was a few years earlier that had ended.

00:28:00.920 So it was, for me, it was a really hard thing, but luckily she rose to the occasion that day,

00:28:08.500 which, you know, it's interesting throughout this journey with her, you know, I think people

00:28:12.680 that don't understand the disease, trying to find some sort of lightness and hope would always be

00:28:16.920 like, but she must have good days sometimes. She must remember you sometimes. Does she,

00:28:20.640 does she remember you sometimes? And I would always be like, no, it's gone. Like that's gone.

00:28:26.600 It's not like, sometimes you remember like, oh, I use my legs for walking. Like once that's gone,

00:28:30.800 that's gone. But for whatever reason, the day of my actual wedding, I will say she was as there as

00:28:36.120 anyone could be in her state. And that was an amazing thing. But, but overall it was, it was

00:28:40.160 only a few months after that, that we encouraged my parents to move out to Los Angeles because,

00:28:44.040 you know, my dad, it was clear that it was killing, it was going to kill my dad before it

00:28:48.360 killed her. The stress of taking care of her. He always talks about the plane ride home from our

00:28:52.820 wedding was like the worst five hours of his life because she had had an accident in her seat

00:28:57.520 on the airplane and was acting out and was screaming. And they had to get help to get off the plane

00:29:04.240 when they landed back in Florida. And it was a, you know, a pretty horrific time.

00:29:09.260 I mean, these are some of the things that we're going to talk a lot about hilarity for charity

00:29:13.360 and why the focus is on the family, which I think is part of why I'm so excited about it. And

00:29:19.220 you can ask me a hundred times to do something for it and I'll always say yes. So you always

00:29:23.700 apologize when you ask me. Don't say that. Don't say that.

00:29:25.880 But, but, but I really, I'm really so fond of organizations that take that step and appreciate

00:29:33.400 what is being done for the family. Too often people think the only way to make a difference

00:29:40.100 is to fund research. And clearly that's important, but it's too easy to ignore that while we're

00:29:47.500 waiting for these things to happen, people need help in caring for this. And I suppose there's

00:29:53.020 no disease where that's more true than, than this one. Absolutely. Richard, can you just spend a

00:29:58.160 minute kind of explaining what it is about the deposition of these plaques, the accumulation of

00:30:07.340 the tau? Why does it lead to this largely predictable set of symptoms that don't just involve almost a

00:30:18.720 folksy, funny loss of memory, right? But also at some of this deeper level of this, what I suspect

00:30:25.800 is fear and confusion on some level, right? Like why would she be upset on the airplane? Well, I'm

00:30:32.100 guessing on some level, there's a sense of fear, right? There's something is wrong. Why is she not

00:30:38.480 able to control her bowel or bladder? Like how is this disease wreaking so much havoc on the central

00:30:45.740 nervous system, Richard? Yeah. So there's actually a couple who I believe were both pathologists,

00:30:52.880 Brock and Brock, B-R-A-A-K. And what they did was they kind of came up with the Brock staging of

00:30:58.800 pathology where the amyloid protein and then the pathology of Alzheimer's spreads over different parts

00:31:05.640 of the brain. And, you know, when I was in medical school, I was taught that Alzheimer's disease is a

00:31:11.340 progressive neurological disease characterized by changes in short-term memory. And then later on,

00:31:19.200 that includes changes in some behaviors, neuropsychiatric disease, changes in sleep.

00:31:25.340 And then the person, as the pathology spreads, they can no longer take care of themselves.

00:31:29.280 What we really now understand about Alzheimer's is it's a much more heterogeneous disease, meaning

00:31:34.920 wherever the pathology goes, those are the symptoms that manifest. So there are newer forms of

00:31:42.140 Alzheimer's and they're newer because they're now published in the literature, but we've seen this

00:31:47.280 for decades. There's one newer form that has something called a dis-executive syndrome. Well,

00:31:53.760 what does that mean? Executive function is higher order processing, judgment, planning. You know,

00:31:59.460 you find a wallet on the floor, what do you do with it, right? Peter would take the money out,

00:32:03.640 put the money in his pocket, throw the wallet back on the floor. You know, Lauren, she's very

00:32:07.740 empathetic and compassionate. She'd look at the license, you know, she'd say, oh, I'm going to go

00:32:11.540 find this guy. I'm going to go to the ends of the earth to find this person's wallet. So that's

00:32:16.000 executive function. Maybe. Depends. Depends on how much is in there. Exactly. That's one form of

00:32:22.760 Alzheimer's. You know, another form of Alzheimer's is PART, P-A-R-T, primary age-related tauopathy.

00:32:29.720 So we've talked about amyloid, but what about tau? Tau's another protein.

00:32:33.640 And there's tau and amyloid and neurofibrillary tangles. And then there's glucose hypometabolism,

00:32:40.420 meaning the glucose, the sugar in the brain. It's just not being efficiently able to be used

00:32:45.060 to power the brain cells. So depending on where the problem is, you have different manifestations,

00:32:51.440 cognitive symptoms, I guess. And PART, for example, is primary age-related tauopathy. Again,

00:32:57.640 one more time. It's related to age. So it's usually in older people, easily 70s,

00:33:02.160 more likely 80s and 90s. And it's specifically short-term memory. And it's specifically because

00:33:07.240 that pathology is localized to the memory centers in the brain, the hippocampus, for example.

00:33:13.580 But that person can still have good executive function. The frontal lobes, the front part of

00:33:17.580 the brain is working. So it just depends. It depends. You know, for example, there's when the

00:33:22.580 pathology, when the bad stuff goes to the back part of the brain, that's where the visual fibers are.

00:33:27.240 So the eyes are in the front, but they have visual projections that go to the back. You interpret

00:33:31.640 images. Well, when someone can't interpret images, they get confused. They act funny. They may be

00:33:38.500 weird. They may be, you know, confused. But it's not exactly a memory problem. It's a visual perception

00:33:44.920 problem. So, you know, I don't want to be cheeky, but like-

00:33:48.000 I mean, Richard, no, no, this is very interesting. And I've never really thought of it this way. But

00:33:52.140 as you probably are aware, we don't really think of cancer as one disease anymore, right? I mean,

00:33:58.240 I mean, that's, it's been a while that nobody's thought of cancer as one disease. So breast cancer

00:34:03.440 and colon cancer have very little in common. I mean, about the only thing they have in common

00:34:08.740 is unregulated cell growth. But thereafter, they're very different diseases, not just in the ability to

00:34:14.640 impact a different organ. And it sounds like what you're saying is Alzheimer's is not really one

00:34:19.780 disease. It's kind of an umbrella term that encompasses many different diseases of the brain

00:34:26.320 that have some common features in the way that cancers, all cancers have some common features

00:34:31.420 that, you know, cells don't respond to normal signaling. But this notion that someone could

00:34:37.200 have a form of Alzheimer's that largely spares the frontal cortex and therefore preserves some higher

00:34:44.140 order functioning versus another person that has something that's not, I mean, listening to the story

00:34:49.700 of Lauren's mom, just hearing what we've heard so far, how would you think about the etiology

00:34:58.820 or the insult? Well, I'll try not to bias my answer because I know a lot about Lauren's mom

00:35:07.720 and Lauren's whole family. But if I just took for face value, what Lauren said, that symptoms began

00:35:14.160 with little repeating of stories and memory glitches around 52 to 54, to where she had to have then a

00:35:20.760 modified work schedule to then six years later, she's having trouble caring for herself, maybe not

00:35:26.460 recognizing her daughter, and then having emotional, behavioral, psychiatric components. I mean, that

00:35:32.480 sounds like Alzheimer's disease. That sounds like progressive short-term memory loss, plus behavior

00:35:41.320 changes, plus, you know, other things. So it sounds like she started in the mild cognitive impairment

00:35:46.760 phase with the symptoms. So there's just three phases of Alzheimer's, three stages. Maybe we should take a

00:35:52.640 step back for listeners. The first stage is actually the preclinical phase, the pre-symptomatic phase, where

00:35:58.820 Alzheimer's disease has started in the brain, but there are no symptoms yet, no clinically apparent symptoms.

00:36:04.520 Believe it or not, there are 46 million Americans with Alzheimer's disease in their brain right now,

00:36:12.500 but no symptoms. That's crazy. I've never heard that before, that number. That's, wow. Yeah, I try to

00:36:18.560 keep that close to my vest because- And how do we know that, Richard?

00:36:22.580 That's what the studies say, you know. I don't know, you're the critical appraiser of studies. I'll have to

00:36:27.300 send you the study and you can tear it apart, Peter. You're going to bring this one to Journal Club next

00:36:31.420 month. What a great, what a great idea. I love those Journal Clubs. That sounds like the nerdiest

00:36:35.980 club of all time. Oh my. And we've discussed you and we've discussed- It is nerdy. It is pretty

00:36:43.160 freaking nerdy. And we record it and then we watch it and we- Oh my God. Yeah. I was captain of my math

00:36:49.360 team at Comac High School. Well, there you go. Nevermind. It sounds really cool then. Thank you.

00:36:55.140 Thank you. Also the alma mater of Lauren's mom, high five, go Comac, and Lauren's uncle and some

00:37:02.980 others. Anyway, so this preclinical pre-symptomatic phase is by far the most important phase, I think,

00:37:11.760 well, maybe to focus on because that would be prevention of Alzheimer's. You can call it either

00:37:18.060 treating preclinical Alzheimer's or secondary prevention of Alzheimer's because you're trying

00:37:23.620 to prevent the dementia from happening. So stage one is preclinical Alzheimer's. Stage two is mild

00:37:29.520 cognitive impairment due to Alzheimer's where there are enough memory glitches and other changes to

00:37:34.980 where it's noticeable. It's greater than a standard deviation and a half below the norm, but the person

00:37:41.440 can still take care of themselves. So I think, Lauren, when your mom started having symptoms, she was

00:37:45.520 easily in the borderline preclinical to MCI stage. And then people have roughly between a 12% and 16%

00:37:53.500 per year, depending on what study you read, chance of converting from MCI, mild cognitive impairment,

00:37:59.120 due to Alzheimer's to dementia due to Alzheimer's. And the only difference is, is they still have the

00:38:04.600 symptoms. They're just worse and they can no longer take care of themselves. So, you know, Lauren,

00:38:08.720 many people would be very pleased and thankful that if symptoms started at 52 and she was able to

00:38:17.280 attend your wedding at 60, I mean, that's horrible, but better than it could have been in the grand

00:38:23.000 scheme of things. At least she was there. You know, I have friends who, who unfortunately lost,

00:38:27.440 had weddings without parents there. So, because they had lost them already. So. Yeah, absolutely. So,

00:38:32.500 so these are the stages. Okay. It's a staggering number and whether it's 46 million or 36 million or

00:38:38.360 whatever the number is, you know, it's not surprising in the sense that if, when you look at how many

00:38:43.120 people are pre-diabetic and you think about how that is one of the pathways to Alzheimer's disease,

00:38:52.180 sort of the energy dependent pathway, it's very plausible, especially when you consider the other

00:38:56.260 pathways. Richard, one thing I want to park with you to come back to is some thinking around how many

00:39:02.680 different variants of the disease there are, right? Sort of the lipid variant of the disease,

00:39:07.940 the toxin variant, the potentially an infectious variant, if such, if one such exists. So maybe we'll,

00:39:12.860 I'll let you think about that for a minute. So Lauren, I want to talk about how you made your

00:39:19.020 way to, to Richard, because that's how you and I met, you and I met through Richard, but I want to

00:39:24.560 know how you and Richard met. Sure. So, okay. I'll try to keep this somewhat brief. I feel like it

00:39:30.120 might be long. This is a hilarious story. I'm sorry. I remember this like a video in my mind,

00:39:35.040 but anyway, I don't want to interrupt. So in 2011, it was the year that I got married. It was the year

00:39:41.080 I shot for a good time call and it was the first year that we planned the first Hilarity for Charity

00:39:45.620 event, which was January of 2012. So 2011 was a pivotal year for me. And up until that point,

00:39:51.200 like I said, I had been really dark and depressed and I had been trying to work and I, you know,

00:39:55.640 I'm a screenwriter and I was writing, but like, I just spent a lot of time just being pretty dark

00:40:01.060 and pretty upset. And then a friend came to me and was like, let's throw an event and raise money

00:40:04.580 for Alzheimer's. And I was like, no, but then he wore me down. Thank God. And we did. And so in

00:40:11.460 January of 2012, we threw our first variety show to raise money for the Alzheimer's Association.

00:40:16.840 And that was, you know, an incredible event. We raised a few hundred thousand dollars, but was

00:40:21.080 the most incredible part of that was that we were contacted by young people who felt seen for the

00:40:31.060 first time because they were seeing me in my, you know, late twenties and my husband in his late

00:40:36.260 twenties talk about Alzheimer's, which, you know, even for me up until that point, every image of

00:40:42.800 Alzheimer's I had seen was of someone who was old and gray and not at all related to me in any way

00:40:51.960 that I could understand. So we felt like we had an opportunity to continue talking and to continue

00:41:00.740 hopefully gathering people and helping them feel like they too had a place in this disease,

00:41:06.880 which is considered a disease for old people. And so that's when we kind of decided to form our own

00:41:11.280 little organization, which was a fund within the Alzheimer's Association for many years in 2017,

00:41:15.580 became our own 501c3. But during that time, of course, we became Alzheimer's advocates and I met

00:41:24.840 many smart people and doctors and scientists and other advocates who were doing all sorts of

00:41:31.480 incredible work. We became friendly with Maria Shriver, who of course has always used her platform

00:41:37.500 to raise awareness about Alzheimer's and is so, so incredible and had really sort of gotten to know

00:41:44.240 the Alzheimer's community a bit. So then my uncle, who is my mom's brother, who was five years older

00:41:51.720 than her, was starting to show symptoms. Now, my uncle, who was an athlete his whole life, he was,

00:42:01.060 and his later life started when he was, I don't know, I guess maybe in his 40s, riding a bike and was

00:42:05.660 a obsessive bike rider. And he was in great shape and he's a big, strong, muscular guy. And we'll get

00:42:12.640 into some of the other things why Alzheimer's happened in my mom earlier than it did with him, but he

00:42:16.640 started showing symptoms. And I wasn't allowed to talk about that publicly at the time. Unfortunately,

00:42:21.920 he passed away in March this year, only a month after my mom and his family, my aunt and my cousins

00:42:27.900 have fortunately now given permission to tell his story so it can potentially help. So he was starting

00:42:34.200 to show symptoms and they were on the East Coast. So they came to me and said, what do we do? How do we,

00:42:39.120 what do we do at this point? And at this point, by the way, my mom was very advanced at this point.

00:42:43.160 They were out here. This was, I don't know what Richard, it was 2014, 15, 16, even? 17?

00:42:51.180 And basically I'd reach out to a doctor that I knew and was like, you know, my uncle's on the

00:42:55.120 East Coast. I want to get him into the best of the best. Who is it? And this person recommended

00:43:00.900 Richard. The best looking, I hope? The best looking Alzheimer's doctor there could, yes, exactly.

00:43:07.140 Thankfully, this is a podcast. That's what my uncle was hoping for,

00:43:10.040 it was the best looking Alzheimer's doctor. The one with the best phones, I think is what

00:43:15.600 it was really about. Definitely the best phone. Well, I mean,

00:43:17.620 certainly I've listened to that episode where we talk about, where you guys talked about Richard's

00:43:21.380 phones. Oh God, he's showing one. Everyone's missing it. There's rhinestones. There's a horse

00:43:26.000 on the back at the top. Are those not rhinestones? Diamonds. Hello? Oh, diamonds. Excuse me. Those are

00:43:31.060 diamonds. It's a diamond pillow. Come on. Anyway, so gave me Richard's name and I went on his

00:43:38.340 website and I found his email. It's direct email. Because of course I was, again, I'm not the kind

00:43:42.760 of person who's like, I'm going to be polite and keep my mouth shut and follow the rules to get to

00:43:46.420 where I need to go. Like, I'm going to do what I got to do. So I found his like direct email address

00:43:51.180 and was like, hi, here's who I am. This is what I've done. My uncle has Alzheimer's and needs your

00:43:58.160 help. And so he wrote me back right away. And then of course, then we connected that he was from

00:44:03.460 Comac and that my mom and my uncle had gone to the same high school as Richard, which is, you know,

00:44:09.380 what a small world. He of course got my uncle in there right away and they went on the journey that

00:44:15.060 they went on. So then I was in LA and then I, once I connected them, I came to New York, you know,

00:44:20.440 a few months later or something. And I, you know, said, I'm coming to New York. I want to come see the

00:44:24.140 clinic, come meet you. And then of course, you know, I'm seeing the clinic and talking to him. And I was

00:44:28.160 like, I want in, I want to be a patient. I want to prevent Alzheimer's. Let me in, help my brain.

00:44:34.680 You literally like, I don't know how to do this, but like, like shot out your arm and said, like,

00:44:40.020 take my blood now, let's do it. And like, literally you walked into the clinic. We like

00:44:45.840 literally stuck a needle. You signed a consent form. And then like, it was the quickest, most rapid

00:44:51.020 Alzheimer's prevention consult in the history of our program. So lucky for me, lucky for me.

00:44:56.180 And what kind of shape was your uncle in at that point in time? I'd actually didn't realize this

00:45:00.880 part of the story that, that the initial connection with Richard was actually a consultation for your

00:45:06.660 uncle. Is that presumably because at that point you felt your mom was just advanced enough that it.

00:45:14.240 Yeah, no, at that point, my mom was, she was fully bedridden. I'm pretty sure at that point,

00:45:19.520 getting everything fed to her, fully cared for. There was, her train had long left the station.

00:45:24.440 So your mom at that point would have been in her early sixties, I guess. And your uncle is a

00:45:31.700 little older, did you say? Yeah. So he's five years older than her. And he was, you know,

00:45:35.900 I would say in that, that MCI, in that mild cognitive impairment space, right, Richard? Or

00:45:40.380 even almost a little before that, it was, he was a very functional guy. I, you know, with both my mom

00:45:46.280 and my uncle and, you know, and you guys can speak to this more about other people, they could both

00:45:52.520 like rise to the, the occasion in a way. And so, you know, I knew that what my aunt was seeing with my

00:45:58.480 uncle was different than what I saw, that he could somehow dig deep and put on a show, if you will,

00:46:03.960 and act like he was still in control. But there were little things, little hints that that wasn't

00:46:08.580 happening. Whereas my mom, we were far past that point. Richard, let's talk a little bit about now

00:46:15.560 the beginning, you go down this path of kind of being a detective. So you're never going to get

00:46:22.440 to meet the parents, the grandparents in this case, but the parents of the, your first patient,

00:46:27.320 but you know enough about their story. You're meeting Lauren's uncle, you know about Lauren's mom,

00:46:35.660 though you haven't met her. How are you now starting to piece together this family first

00:46:42.820 for the standpoint of trying to understand if anything can be done to help Lauren's uncle,

00:46:47.940 but ultimately to really figure out what to do to help Lauren and her brother.

00:46:54.520 Yeah, this is detective work. This is a spelunking mission down the deepest, darkest cave with no light.

00:46:59.780 And, um, you know, instead of a, a pickaxe, I don't know, maybe with a plastic fork and knife,

00:47:05.660 let me take a step back. Lauren, before I met your mom, I saw a video of your mom,

00:47:10.840 which kind of changed things for me. This was a video of a movie actually that you can maybe talk

00:47:17.980 about you'd worked on. And I had actually watched, I don't know if it was a clip online or maybe it was

00:47:24.120 something you sent me and seeing the video of your mom from the, I don't know, you can tell me eight

00:47:31.640 something years before the present that was so instructive. I mean, I, I don't know how to explain

00:47:41.440 this, but like, I'm not psychic or anything like that, but I trust my gut. And when I see people,

00:47:47.920 sometimes this is going to sound weird, but I think it's true. I see genes. I see, I don't know,

00:47:53.820 my gut just feels something and I can, I don't know if it's just because I've seen the pattern so

00:47:58.680 many times there's genotype meaning the genes and the phenotype, which is the, you know, the physical

00:48:03.940 real world manifestations of genes. But there was something about your mom, her behavior, her

00:48:09.840 mannerisms, her, I don't know her, her shape or her face. I mean, I don't want to get too like kooky

00:48:15.860 and weird, but like there was something that my gut or my subconscious just saw. And your mom was a

00:48:22.480 little confusing to me because I saw something consistent with Alzheimer's, but there was,

00:48:29.100 you know, my gut said that there's something else. This is, this is just strange. This is not

00:48:34.020 clearly Alzheimer's. This, this could be something else. And then when I talked to you, Lauren, about,

00:48:41.100 and really I talked to, you know, your aunt and your uncle, and I learned all the intricate details.

00:48:45.320 I just learned that this was, this was more complicated than Alzheimer's. Maybe there's

00:48:49.400 Alzheimer's on one side, but there's Alzheimer's plus something else on another. And I don't know

00:48:53.720 if, I don't know if I ever told you this story, but your uncle brought in his Comac High School

00:48:58.240 yearbook. I don't know if we ever talked about that. Yeah. And then, I don't know. And then when

00:49:02.440 I was actually at your place in LA, your, I think your dad found your mom's Comac High School

00:49:07.900 graduation yearbook. And this is going to sound even kookier, but you can tell in the handwriting,

00:49:13.800 your grandparents signed your mom's yearbook and your uncle's yearbook, and they were five years

00:49:20.440 apart. And I could tell in the handwriting, there's like research to support this, but you know, you

00:49:26.540 could just tell by the change in the handwriting over the years and just the, you know, like Alzheimer's

00:49:32.720 is a neurological disease. There's other neurological conditions like Parkinson's disease, dementia with

00:49:37.520 Lewy bodies. And in Parkinson's disease, when you, when you start writing, as you write more and

00:49:42.640 more, the writing gets smaller and there's like a shaky nature to the writing. This is really hard

00:49:47.680 to explain. I don't know. Something about the handwriting was just different. And about the

00:49:52.880 word choice, like, you know, there was a study that looked at nuns and the nuns wrote their

00:49:57.040 autobiographical sketches in like their late teens. And then depending on analysis of, of their

00:50:02.640 autobiographies that they wrote, you could predict which nuns were going to get dementia 60 years

00:50:08.520 later. So there's a lot, you know, I believe Alzheimer's is a life course disease. It literally

00:50:13.300 people with the 8.4 variant, one or two copies have smaller brains when they're born. So I know

00:50:19.200 we say Alzheimer's, you know, starts 20 to 30 years before in the brain. Well, that may be because of

00:50:24.100 the biomarkers of Alzheimer's that we can detect are noticeable then. But I believe Alzheimer's is a

00:50:29.780 life course disease. And sorry for the long story here, but I learned a lot about your family from the

00:50:35.460 clues that I got from those videos and the handwriting samples of your grandparents. So I guess I would

00:50:40.840 start with that. And then I think I just said earlier, but my brother ran, completely randomly

00:50:46.620 cared for another one of your family. My great uncle. Your great uncle. I mean, like just completely

00:50:52.060 strange and bizarre, but you know, I actually talked to my brother about him and we just start to put the

00:50:58.120 clues together. So, so first we do the detective work and kind of the investigative part. And then we just

00:51:03.360 do a clinical history. We ask about all sorts of things from medical history to what are the risk

00:51:09.600 factors for a parent. We did some genetic testing, which was critical. So we just try to put together

00:51:16.060 lots of different pieces to the puzzle and do as best as we can with the information we have to

00:51:21.820 personalize or individualize a person's care. So Richard and Lauren, I don't know if you, and if you

00:51:28.180 don't, if you don't have permission to talk about Lauren's uncle's case, then we don't need to talk

00:51:32.500 about it at all. But if we do, so I'm curious, Richard, you have this clinical history that is

00:51:39.060 at least for me would be very overwhelming. I realized that a lot of people walk into your

00:51:44.400 clinic with stories as tragic and as complicated as this, but what are the things you most want to

00:51:52.900 see come back out of that blood work? Once you have a very detailed clinical history, at this point,

00:51:57.940 you've probably established that brother and sister are on the same pathway, though sister is moving

00:52:03.760 much quicker in Lauren's mom versus uncle, the ApoE genotype comes back. What does it show? And what

00:52:11.180 does that tell you? All I can say is my brain kept asking why, why, why, why, why? Like why did Lauren's

00:52:17.840 mom have symptoms at 52? But Lauren's uncle, five years older, start having symptoms in his late

00:52:26.060 60s? Or maybe it was early 70s. Why, why, why, why, why? Why was there this 15 something year old?

00:52:32.980 What is going on here? So the first thing I think about is, and this is also because of a genotype

00:52:37.960 phenotype thing. I felt or smelled or whatever it was that there was some E4 something, ApoE4 something.

00:52:45.280 Lauren, when I saw that video, your mom, I don't know, again, this is weird, but your mom

00:52:51.140 was E4. I actually thought she was E4-4. I'll just be frank.

00:52:55.360 She was 4-4.

00:52:56.200 Yeah, I know. Well, I, I, exactly.

00:52:58.160 I mean, from the video.

00:52:58.860 Yeah, from the video. Yeah. And again, I, this is weird talking about when it's being recorded,

00:53:03.280 but like, I don't know, I've seen a lot of patients, so I can just, you know, I can,

00:53:06.640 I don't know, something subconscious. When your uncle walked in, 4-4.

00:53:10.240 But just to be clear, Richard, did you think that Lauren's mom was 4-4 because of how early

00:53:16.740 it affected her or because of the fact that she had such a clear history of disease on both sides

00:53:23.820 of the family? Honestly, I guess what I'm saying now is I saw her on video and the phenotype that

00:53:30.200 I saw, the, the, the, her body makeup, her habitus, her structure, again, sounds weird,

00:53:36.940 but I, I saw 4-4. I felt 4-4. Plus, of course, in my subconscious mind, I knew she got it early.

00:53:43.980 I knew the parents, I knew her parents, Lauren's grandparents got it later. So it just fit. And

00:53:49.900 also big, big, big, you heard it here first. No, this is common knowledge, I hope, or it should be

00:53:54.020 common knowledge. Women with the E4 variant, much higher risk. I mean, women with E4 are very different

00:54:02.220 than men with E4. And I think most people just completely are not aware of that. And then

00:54:06.280 Lauren, I forget when this came up, but I don't know if I asked you this, but I said,

00:54:10.660 when did your mom go through menopause? And then you told me about the hysterectomy and they took

00:54:14.760 the ovaries out. And I said, oh my goodness, my goodness. I said, wow, E4-4, even though I don't

00:54:21.700 think we had the genetics at the time, or maybe we did, plus the, you know, surgical menopause,

00:54:27.960 taking out, you know, immediate withdrawal of estrogen and taking out the ovaries. Back then we had

00:54:32.240 no idea relationship to Alzheimer's or anything else. Plus she's a woman and there's a synergistic,

00:54:37.200 you know, impact on risk. So it kind of was the perfect storm, but, but still a 4-4 plus a woman

00:54:44.060 plus a, plus a hysterectomy, there had to have been something else. And then we went on a spelunking

00:54:50.780 mission to find the something else. Lauren, how old was your mom when she had a hysterectomy? Was

00:54:55.180 she in her forties, late forties? I want to say she was 46, maybe 47, but I'm pretty sure it's 46.

00:55:01.420 All right. You've alluded to this just in passing a moment ago. I want you to expand on it a little

00:55:07.100 bit. You basically created a little bit of a contrast between your uncle and your mom in terms

00:55:11.680 of lifestyle, your uncle being exercising constantly. Tell us a little bit about your mom.

00:55:17.480 Obviously you've spoken about her intellectually and you mentioned she didn't consume much alcohol.

00:55:22.740 What other lifestyle factors do you know about her? Did she sleep well? Was she under a lot

00:55:27.540 of stress? What was her diet like? How much did she exercise? Did she smoke? Any other things that

00:55:32.000 you, you can tell us? I mean, she never, she never smoked. She told me once she tried to smoke a

00:55:36.560 cigarette in high school and threw up and never did again. So that's why I never smoked a cigarette.

00:55:41.460 But, um, she did not exercise. We were a big sugar house who had dessert every night.

00:55:47.240 She probably had cookies most nights after dinner. She used her brain every single day.

00:55:56.720 But was she constantly learning new things? A little. She taught first grade for 15 years. And

00:56:05.800 so, you know, sure. Could she have been learning things? Yes. But was she recycling information that

00:56:09.960 she'd already learned potentially, but I think, you know, knowing what I know now, she got almost no

00:56:17.440 cardio exercise and she ate a lot of sugar and combining those things with, you know, her family

00:56:25.300 history, of course. And then of course the hormonal issues that arose from her hysterectomy, you know,

00:56:33.160 seemed to really put her on the path that she eventually went down. Do you know if she had any

00:56:39.840 difficulty sleeping prior to that hysterectomy? I can only imagine afterwards it was devastating, but.

00:56:45.400 Yeah. I mean, it's funny. She and my uncle and my grandfather were similar sleepers, I would say,

00:56:53.240 and that they would fall asleep on the couch every night and then wake up super early. That's as much

00:57:00.300 information that I got from her. But like, you know, of course less as I get older, but like I'm

00:57:04.260 the kind of person who loves to sleep and is very happy to sleep. Whereas like she wasn't a big

00:57:09.900 sleeper. She definitely did herself no favors with her sleep habits, especially again, knowing what we

00:57:15.660 know now. She did not use her sleep to help her brain at all. I just want to comment one thing.

00:57:21.420 And I talked to your dad about this at some point. Your mom was not, you know, when you looked at

00:57:25.960 your mom when she was, you know, in the 80s and 90s, your mom was not unhealthy by any means.

00:57:29.720 No, no. I don't want to paint the picture of her as being this like disgustingly, you know,

00:57:33.920 unhealthy person who didn't care about herself. It wasn't that. It just, she didn't make the effort

00:57:39.060 that is needed that we know now to, you know, as Richard said, to take control of the genes that

00:57:45.220 she had been given. In prevention, in the prevention space and preventative medicine or

00:57:49.480 preventative health, at least the way I think about it is there's normal and then there's optimal.

00:57:55.480 You know, your mom for the time, that was kind of the typical, you know, what I would call your mom

00:58:00.920 now is, you know, maybe, maybe, you know, they've heard the term skinny fat, right? Skinny on the

00:58:06.460 outside. I would say that. Fat on the inside. You know, and you're, maybe, I don't know what your

00:58:10.360 mom's waist circumference was in high school versus her waist circumference in her, you know,

00:58:14.040 40s and 50s. But I, yeah, I can guarantee you it was larger based on, you know, my understanding

00:58:19.160 of the pathology of this disease. And, but back then that wasn't really talked about or thought

00:58:23.900 about, you know, you know, in the eighties, it was like, you know, that was like when 10,000 steps

00:58:28.360 came about, you know, like who came up with 10,000 steps? Well, sorry, I know who came up with it,

00:58:32.040 but I understand that there's some better than nothing and calculating, but 10,000 steps is like

00:58:37.140 so antiquated. It's like, it's like, you know, literally the eighties compared to now we truly

00:58:41.180 understand physical fitness and how to optimize physical performance. Your mom was not unlike most

00:58:47.040 middle-aged women at the time. You know, and the difference between her and my uncle,

00:58:51.000 or even, you know, me and my brother is like, my mom was never an athlete. Like I was a gymnast

00:58:55.660 growing up. My brother was a baseball player. My uncle ran track and then he got into cycling and was

00:59:01.600 always a physically active person. Whereas my mom was an intellectually active person. She read,

00:59:08.320 she, you know, like I said, she was a great student. She loved to learn and then to teach,

00:59:13.700 but she didn't use her body in a way that perhaps could have at least delayed what, you know, her

00:59:23.720 genes were leading her toward. When someone meets me at a cocktail party or I think you asked me that

00:59:29.560 question, Peter, what are the three things that you tell someone when they- Yes, that wasn't your

00:59:33.820 podcast. That was, yeah. And I, I would, I refuse to answer it. I was like out walking the dogs the

00:59:37.660 other day and someone, someone asked me the same question. I'm like, well, but, but the number one

00:59:41.700 thing by far is exercise and physical activity, but it's not just like, you know, going for

00:59:45.700 a walk. It's, there's physical activity and then there's physical exercise. And the difference

00:59:50.140 is key. Cardiovascular and strength training. There's just so many degrees, high intensity

00:59:53.840 interval training, specifically for this case, you know, high intensity interval training is

00:59:57.860 probably the only thing that can move the needle in terms of certain aspects of cognitive

01:00:02.220 function and people with the APOE4 variant. And like no one knew any of that even a few years

01:00:06.840 ago, let alone a decade ago. So optimization of physical activity is key. And, and your

01:00:11.240 uncle, just so we can paint the picture, your uncle was like, he was a machine.

01:00:16.780 I was like, he was a beast. Yeah.

01:00:18.200 He was ripped. I mean, I'm, I'm, you know, he could put Pete, I don't know him and Peter

01:00:21.720 next to each other be close. Um, you know, I'm, I'm scrawny or whatever compared, but he

01:00:25.720 was ripped. He just looked great. He, he, his leg muscles were like, Oh my word. Yeah.

01:00:30.420 My goodness. And because of that, your metabolism is better. All these different things.

01:00:33.480 Richard, was he three, four or four, four? Uh, he was four, four also.

01:00:38.200 I see. Okay. So this is very interesting, right? Because until you have that information,

01:00:44.080 you could say, well, maybe the reason everything came to him so much later is he was the three,

01:00:49.080 four, his sister's the four, four, and that explains the 15 year gap. But to have them both

01:00:55.880 before four, you're basically looking at gender inclusive of the removal of hormones, lifestyle

01:01:05.000 factors. It's some, probably some combination of those things that's explaining it. Can you

01:01:10.740 explain a little bit the gender issue? Again, most people who follow the research will be very

01:01:16.620 well aware that Alzheimer's disease disproportionately affects women. The answer that used to be thrown

01:01:24.720 about was, well, that's because women live longer. Anybody who understands even first order mathematics

01:01:30.940 will realize that the increase in expected lifespan of women does not fully explain that. So there

01:01:37.020 must be something else. Do you think that it's the loss of hormones that explains the remainder

01:01:42.760 of that gap? Or do you think it's even something beyond that? Yeah. So I would have answered that

01:01:47.800 question just like you did with the age thing, even five, six, seven years ago. And then it was one day

01:01:53.880 on some television, something where someone kept elbowing me, someone named Maria, our friend, Maria

01:01:59.100 Shriver. It's like, no, no, you got to figure it out. Why do women? No, no, no. Two out of every three

01:02:03.940 brains of Alzheimer's are women's brains. And we don't know why. Isaacson, go figure it out. And I said,

01:02:08.780 yes, ma'am, I'll go do it. I think I understand much better now. And in the category of likelihood

01:02:14.480 is during the perimenopause transition, there are bioenergetic shifts in the brain that absolutely

01:02:23.620 can predispose a woman to accelerated Alzheimer's pathology. And we call it the window of opportunity

01:02:31.840 during the perimenopause transition. If we can intervene the right way at the right time in the

01:02:40.020 right woman, I believe that we can negate a reasonable amount, if not much of, careful with

01:02:49.480 my words, of the negative impact of this precipitous drop of estrogen, which I believe is neuroprotective,

01:02:57.460 again, the right type of estrogen, the right whatever, the natural estrogen, I believe is

01:03:02.400 protective. Whether we get into hormone replacement, that could be a different part of the conversation

01:03:07.060 and which types and what this and what that. But the bioenergetic shifts during the perimenopause

01:03:12.160 transition, you know, why do people have perimenopause? What are the symptoms? They get

01:03:15.700 hot flashes, right? Night sweats. Talk about that. Oh boy, night sweats. I don't know what you're

01:03:20.640 talking about. No, not at all. Irritability, never. Never. So all of these different things. It's a brain

01:03:27.400 disease. Perimenopause is a brain condition. Those are manifestations of the hormone withdrawal in

01:03:34.040 the brain. And those are the symptoms that, you know, brain fog. Like I used to think, I'll just

01:03:38.040 be very frank. I was completely dead wrong. Like women that had perimenopause and they had this

01:03:42.820 brain fog thing, maybe they're just not sleeping right. Maybe, well, no, they're not sleeping right.

01:03:47.680 And their sleep is interrupted because of this bioenergetic shift. And heck yeah, you're going

01:03:52.380 to have brain fog. And now we know what it looks like. I hate that term brain fog. It's so

01:03:56.320 nonspecific, you know, it's problems with processing speed and attention. And that's how I think of it.

01:04:02.060 But perimenopause is a brain disease. So I think that's really important. And this bioenergetic

01:04:07.500 shift is like, it's like, if you want to fast forward brain aging, like in a woman, sorry,

01:04:13.100 in a susceptible woman, because not all women are created equal, an E4 for a woman, a surgical

01:04:19.260 menopause, meaning taking out the ovaries with the uterus. Wow, that could do it. Now, I don't want

01:04:26.400 to say this in all cases. It again, depends on the individual person, but perimenopause transition

01:04:31.580 is a huge unrealized risk factor for progression to dementia in an Alzheimer's susceptible woman.

01:04:41.720 And just be careful and listen to those words because just because you're going through

01:04:45.240 perimenopause does not mean you're going to get Alzheimer's, but in susceptible people,

01:04:48.960 it is. And I really believe that from a precision medicine perspective, we can intervene

01:04:54.220 with specific hormones in specific ways. Is it a patch? Is it a gel? Is it a, you know,

01:05:00.020 all these different things. Do you need estrogen? What type of estrogen? From horses, from, you know,

01:05:04.100 from natural, from what about progesterone? When do we add it? And these are things that I talk,

01:05:08.960 I talk to an OBGYN every other week now. I'm a neurologist, what the heck? So I could talk about

01:05:16.180 this for a long time, but just know that this hormone thing is real.

01:05:20.640 That's where you think the bulk of it is then, Richard, is it's less about the age gap or the

01:05:26.480 age advantage, like, you know, the sort of lifespan advantage women have. And you think it's

01:05:30.760 the elephant in the room is this enormous hormonal shift.

01:05:35.240 I think that's the most under-recognized slash largest impact in a lot of women, but I have to take

01:05:42.400 a step back in age is the number one risk factor for Alzheimer's. Women plus age. So a 65 year old

01:05:49.020 woman with the APOE4, with at least one or two APOE4 variants, that's like the perfect storm. Plus

01:05:55.040 you add in this, you know, the perimenopause transition, but you know, there's individual

01:05:59.340 things when it comes to a woman's life. So for example, there's more widows than widowers and

01:06:07.480 widowhood is a astronomically important risk factor for cognitive decline and dementia. Also women

01:06:15.940 specifically with abdominal obesity, sorry, enlarged waist circumference, visceral fat, as the belly

01:06:22.800 size gets larger, the memory center of the brain gets smaller. And we now know that in women

01:06:29.040 specifically, women have a 39% increased risk of dementia when they have, you know, enlarged waist

01:06:37.760 circumferences over a certain degree. And they're impacted more so than men. When I think of a woman,

01:06:43.120 and I think of body composition, I'm really paying attention to body fat. And I'm not just paying

01:06:47.800 attention, like weight, I don't care about. For women, I care about what's percent body fat and

01:06:52.900 where is the fat? Is it visceral or is it otherwise? Cellulite on the thighs, I don't care.

01:06:57.740 Oh, thank God.

01:06:58.400 Belly fat. Thank you. Thank you. Great. You don't have cellulite on your thighs.

01:07:04.540 You're on the Atiyah Isaacson program.

01:07:06.800 Thank goodness this is a podcast.

01:07:08.100 You beat me in the spin class. You were a hoss in there.

01:07:12.900 I did.

01:07:13.760 That was impressive. I was dying. So where the fat is is key. Like in men, I really believe,

01:07:19.040 and I think evidence is coming around to support this, but muscle mass in men is more important

01:07:23.580 as opposed to body fat, especially visceral fat in women as a specific individual sex-specific

01:07:29.400 risk factor to Alzheimer's.

01:07:30.560 So I was going to ask you about that, Richard. Do you think that part of the sex difference is that

01:07:34.320 men have more lean mass than women? So it's that they have greater capacity for glucose disposal

01:07:39.880 and that that could be an independent predictor beyond the loss of hormones?

01:07:45.860 I don't know. I think we need to tease this out. You know, we're honestly doing one of the,

01:07:50.560 if not the only, one of the very few studies where we're looking at, you know, pretty comprehensive

01:07:54.700 brain imaging on women and men between the ages of 40 to 65. Lauren, you don't qualify yet because

01:08:01.320 you're still a baby, but one day you'll, you'll jump in. We're going to be able to answer this

01:08:07.500 question. I hope in the next five to seven to 10 years or sooner, but I don't know the answer to

01:08:13.320 that question. So Lauren, you finally decide you also now want to be a part of this prevention

01:08:19.860 program. You're watching your uncle hopefully have his disease course slowed. You're watching your mom

01:08:27.700 in the final stages of her life. What is the hardest thing for you to hear from Richard? Once you get

01:08:36.140 through that initial diagnostic workup and battery of tests, what are, what are the things you're now

01:08:42.440 starting to confront about yourself? What do you learn first of all? Oh God, where do I begin? I mean,

01:08:47.440 I, I learned a lot. Well, I mean, first we, I learned my APOE status, which is that I'm a three,

01:08:53.660 four. Okay. So that means you got a four from mom and obviously a three from dad.

01:08:58.760 Right. And you know, I felt okay. I didn't throw it. You know, it's funny. My, my brother had done

01:09:06.380 23 and me a couple of years before, before we knew Richard, before anything. And he got it back and

01:09:11.380 it was like, you know, and this is early on in 23 and me. So I don't even know if it said APOE four.

01:09:16.140 It said like Alzheimer's risk. Yes. And he freaked out. But then by a few years later, I think it was like,

01:09:23.200 you know, and it even could have been the information that came with that along with

01:09:27.500 Richard, which is, this is not the genes that he had been talking about before, which are,

01:09:32.860 you're going to get Alzheimer's. This is even a four, four. This is a three, four. And there are

01:09:38.120 things that we can do to modify my risk. And so I, again, as I touched on as someone who's like,

01:09:43.840 if I'm going to do it, I want to do it and dive in on it. So I don't get me wrong. I wasn't like,

01:09:49.460 yes, I have a three, four. Let's celebrate. But like, I felt, you know, okay, I have this

01:09:55.720 information. Science is telling me there's something I can do. Why don't I do it? But it

01:10:01.600 was easier in the beginning. I kind of, have I been a patient at the clinic for five years, five,

01:10:07.760 five, six years? At least four or five years. Yeah. At least. You know, when I kind of like half

01:10:11.200 started, I was like, you know, a little better at my diet and a little less sugar. And you know,

01:10:15.580 when I were, I exercised, but not, not what I needed to be doing. And then certainly then,

01:10:22.340 and in the year leading up to when I met you, Peter was, you know, I was directing a movie that

01:10:26.720 year. And that is certainly not the time where you have all the space in your life to take control of

01:10:32.480 your health. So that it certainly, I fell off the wagon during like sitting on my ass in an editing

01:10:36.800 room for eight or nine hours a day was, I didn't exercise before that. You know what I mean?

01:10:42.260 It felt like power in a way. And it took me a while to figure out how to harness that power

01:10:50.580 and what lifestyle changes I needed to adopt and to change. And certainly took both of you at

01:10:56.920 different points in my journey to help me and guide me. And I'm lucky for that. But to me,

01:11:02.800 it felt exciting. You know, people often are like, aren't you scared? How do you, why would you want

01:11:07.400 to know? Blah, blah, blah. And I'm just like, why don't you want to know? Science gives us tools.

01:11:12.720 I don't want to live in the dark and not use the few tools that I've been given at this point.

01:11:17.040 That seems way worse to me. So I felt very lucky that I was, you know, getting to access your smart

01:11:26.140 brains. And of course, other people that I've met and take some control over my genes.

01:11:31.560 It is an interesting point you raise, Lauren, because, and I may have even told this story on a

01:11:35.340 podcast before, but I remember maybe 2014 or so, I had a husband and wife that were both in the

01:11:42.000 practice and simultaneously coming in and did blood tests on both of them. And we always do screen for

01:11:46.760 APOE on the way in. And each of them came back 3-4, 3-4. They have three children. So one, I'm

01:11:53.560 explaining to them what the E4, E4 means for them. And I'm also saying, look, you know, your kids are

01:11:57.220 young now, but at some point it's going to make sense, probably in their twenties to do a screen on them

01:12:03.160 because there's a 25% chance that each of them will be a 4-4, a 50% chance that there'll be 3-4 and

01:12:09.020 a 25% chance there'll be three threes. And I think because their kids were girls, I wasn't so worried

01:12:16.740 about head trauma. If their kids were boys, I probably would have said I would even test sooner

01:12:21.200 to really revisit, you know, if they, if, if, if they're thinking about playing football, I would

01:12:25.480 probably reconsider that in the case of an E4. Richard, I'd like to hear your thoughts on that,

01:12:29.600 by the way. Anyway, the point of the story is I got a real heated call from their PCP a couple of

01:12:37.780 weeks later saying, how dare you test them for this gene? I mean, what are you trying to do?

01:12:44.460 We can't do anything about this. So what on earth, what good comes of scaring them with the fact that

01:12:51.360 they have an E4 gene? And obviously that led to a discussion. I actually think that person has since

01:12:57.400 then changed, changed their tune a little bit on that front in large part, thanks to the work that

01:13:02.320 Richard's done. But Richard, just a quick digression there. Is there, what's the evidence on people with

01:13:08.460 an E4 gene being better off without head trauma? Not that anybody does well with more head trauma,

01:13:13.460 but are E4 is more susceptible to head trauma? Well, just to take one step back. I mean, Peter,

01:13:19.580 you, you did the right thing. I mean, this, this is when the conversations need to start. I mean,

01:13:24.480 for example, eating fatty fish, people with APOE4s just don't absorb for just as one example,

01:13:33.440 and I can just soak so many things, but eating fatty fish from early in life. Again, I'm not a

01:13:38.560 pediatrician, so I'm not recommending little kids and 12 and I don't know. I don't even know what or

01:13:43.420 when to start, but omega-3 fatty acids in E4 brain should be started as early as possible and at

01:13:49.820 reasonable doses to really protect the brain. Head trauma is something that's a little confusing.

01:13:55.560 My opinion on this has shifted a little bit. You know, my nephew, Bobby, my sister asked me about

01:14:01.700 this. You know, should he be playing football? And you know, of course I have some adjutant in my

01:14:05.500 stomach, but you know, you know, if you have the four genes, sure, you may be at higher risk and head

01:14:11.960 trauma may certainly intermingle. Again, epigenetic risk, head trauma plus E4 potentially can

01:14:18.000 increase risk. These are really difficult conversations to have, but knowledge is power.

01:14:24.340 Lauren, you felt empowered, you know, our patients like, okay, I'm ready. Let's do it. And if I,

01:14:29.720 at least I tried, you know, I mean, it's better to try than not. When it comes to E4, I don't know

01:14:34.860 when the best age is to learn. I guess that's a tricky question, but you know, the reveal study

01:14:41.120 showed that people that find out their APOE4 status in the initial six months, maybe there's a little bit

01:14:47.020 more anxiety initially, but at the end, there's no negative psychiatric psychological outcomes. And

01:14:53.020 you know, the studies that we've published, you know, I wrote our first paper on this in 2011.

01:14:58.200 So like a decade ago, and like just the fact that you could use genetics to personalize Alzheimer's

01:15:03.220 care, that paper fell on its face. I don't even think it's been cited. Like it's one of those papers,

01:15:08.440 you know, it just kind of sat. I mean, now we write papers that like specifically the entire paper is

01:15:12.940 about if you're E4 versus not E4, do this versus that. And, and I don't know one day,

01:15:18.520 I hope it's soon. We're going to know all these genes and people, when they get their preventative

01:15:23.100 health screenings, we're going to, it's not just E4, we're going to get a whole bunch of genes

01:15:26.920 and primary care doctors, I hope one day soon, five years, 10 years, who knows, are going to

01:15:32.340 basically do these genetic screens on multiple genes and give people targeted personalized plans

01:15:37.780 for disease risk reduction as early as possible. So anyway, I support you doing the E4. I would say

01:15:43.880 though, that most doctors are not aware of this. So it's not exactly the doctor's fault,

01:15:48.220 but understanding genetic type to personalized care is the future of medicine.

01:15:54.480 What other genes are there? We've talked about obviously the three that are of greatest concern,

01:16:00.520 but fortunately the, the three that virtually nobody's ever going to have to hear about or deal

01:16:05.700 with the PSE and one, two and APP. APOE4 sucks all the air out of the room. There are a couple of

01:16:12.920 other genes, Richard, in this space that we're just starting to become aware of. Can you speak

01:16:19.120 to a couple of those? And did any of those figure into the detective work you did in Lauren's family?

01:16:25.440 I learned a lot about Lauren's family and it was in part because of my brother. It was in part

01:16:30.240 because of actually you and your brother learn. And I just met so many different people. I mean,

01:16:35.340 I really got to know your family tree pretty well between videos and talking and all this sort

01:16:40.780 of thing. And your family is one of the first, I would say first 12 to 15 families that we ever

01:16:46.040 really, you know, did some super deep, deep dives on. I mean, I looked at all sorts of different

01:16:51.280 things in your family. And I guess what I would say is, huh, do I really want to call out one gene

01:16:56.500 or another? Or even just generally, like even independent of, of Lauren's family, Richard,

01:17:01.760 when we think about some of these other genes that are now kind of starting to become of interest to

01:17:08.100 us, Tom 40, TNF, what can you say about these and how they impact our understanding of this disease?

01:17:17.400 I hesitate to call out any one specific gene because this is a complicated topic, but, you know,

01:17:25.000 there are around 30 or so Alzheimer's risk genes that have been found that I think are very

01:17:31.000 important. But aside from just those risk genes and, you know, you could say CLU and PICLAM or

01:17:38.240 whatever you call it and BIN1 and, you know, I could just name a whole bunch. And Tom 40 is really

01:17:42.500 important because not all APOE4s are created equal. I believe this is confusing and it's even been

01:17:48.920 confusing for me, but the Tom 40 that's next to the E4 is really can influence, in my opinion,

01:17:55.600 I believe, I'm not certain, but I believe that the different Tom 40 chain length or whatever it is,

01:18:02.060 one E4 can behave one way and another E4 can have a lower or higher risk depending on the gene next to

01:18:07.920 it. So there's, there's a lot of confusion here with this polygenic risk thing, but Tom 40 is

01:18:12.840 important. But, you know, when we take a step back and I look at Alzheimer's as a medical condition,

01:18:18.240 it's a medical condition that causes neurologic manifestations. I think Alzheimer's is a medical

01:18:23.160 disease. I love being a neurologist. It's fun. The brain is interesting. I possibly could have,

01:18:29.400 should have been an internal medicine specialist. I am really intrigued by all the lower organs as

01:18:34.460 the neurologist would say below the neck. No, no disrespect to the lungs and the liver and

01:18:38.700 everything else, but no, it's a medical condition. And whether you're on the lipid path or the

01:18:43.240 inflammation path or the potentially infectious path or the head trauma path, there's so many

01:18:49.920 different things that can trigger brain related pathology. So I'm very interested in the vascular

01:18:56.580 genes, vascular, like FTO and, and other cholesterol LDL and PCSK9 related genes. Like I, I'm interested in

01:19:05.440 those things because that, then that can have an increase in or decrease depending on polygenic risk.

01:19:11.300 Longevity genes. What about like FOXO and CLOTHO? Like there's gotta be, there's, I know that there

01:19:16.560 are genes that kind of protect you against the Alzheimer's risk of the other genes. So I really

01:19:22.220 look at the metabolism genes. I look at the vascular risk genes in Lauren specifically. Lauren was,

01:19:27.860 was one of the first people that we found another gene that kind of co-interacts with APOE

01:19:34.880 to even be even more interesting because maybe this gene related to TNF, TNF alpha, which we can talk

01:19:43.200 about when someone has that TNF alpha gene and also has an APOE4 gene, well, they're also at higher

01:19:50.340 risk than someone with E4 without the TNF. So, so again, we're trying to put the pieces of the puzzle

01:19:55.380 together of why the heck did your mom get this? And we can pin it on exercise and we can pin it on

01:20:00.660 one thing, but, but it's not just one thing. It's not like your mom didn't get Alzheimer's

01:20:05.220 because she didn't exercise. Your mom would have gotten Alzheimer's anyway, if she would have

01:20:08.840 exercised rigorously, which no one knew back then. Sure. Would she have delayed it? I firmly believe

01:20:15.000 so. But your mom was different than your uncle in other ways too. Cause you know, your uncle did not

01:20:19.720 have that TNF alpha related gene. And now because we found this gene, I mean, this is like imprecise

01:20:26.520 science. This is like, I would call it better than back of a napkin, but not perfect science.

01:20:30.880 We're doing things with you, Lauren, now that are trying to get ahead of the curve and trying to

01:20:36.200 make that TNF alpha gene have a less of a negative impact on your trajectory. So between Peter and I,

01:20:42.440 we've really kind of hit you with certain things that can potentially help that. So I guess what I

01:20:47.880 would say is polygenic risk is probably the answer. And I think there's something else you've said

01:20:53.360 that the other analogy is not all E4s are created equal. I don't think that can be overstated enough.

01:20:58.780 And the analogy for in the cardiovascular world is LP little a. I've seen so many patients with

01:21:06.080 elevated LP little a's and in some of them, it absolutely tears through the family with premature

01:21:13.460 heart disease that you can spot a mile away. So just in the same way you look at Lauren's family

01:21:19.420 history and a mile away, you say it's APOE4, you'll look at people having heart attacks in their

01:21:25.500 forties and dying in their fifties from heart disease. And you say that's LP little a until

01:21:30.520 proven otherwise. And then there's other patients that show up with elevated LP little a, even very

01:21:36.000 elevated LP little a, normal, apparently normal risk of cardiovascular disease. So even though this

01:21:43.060 is technically not the correct term, it's almost like there's variable penetration of the gene as

01:21:47.900 well. So let's go back to kind of the, what can you do, Lauren? So let's go back in time. It's now

01:21:54.740 a couple of years ago, you finished, you're off the, uh, the, the editing floor.

01:22:00.880 You're off the cruise ship. Weren't you living on a cruise ship for a while?

01:22:03.980 I mean, too long, too many days. Yes.

01:22:08.220 It's been about two, three years that you really switched this into overdrive.

01:22:12.840 Yeah. I mean, you've, you've really become the poster child for, I'm going to do every single

01:22:20.600 thing in my power every day to reduce the risk of this beast. I guess I just get the sense from you,

01:22:28.080 like you don't seem to push back on this. Like you've, I guess it's in part because it's come

01:22:34.240 from within you and not, it's not been thrust upon you. Is that, do you think that's the reason

01:22:38.640 that it's been so, I want to use the word easy because I don't think it's easy, but.

01:22:42.660 Yeah. I think when you see what I have seen over the last 15 years,

01:22:48.540 you know, why wouldn't I do anything I possibly can to avoid what I saw over the last 15 years?

01:22:57.060 I want to do everything I possibly can to not go through that myself, to not put that on my husband

01:23:02.120 or my family. And I feel like I've been given an opportunity to at least try.

01:23:09.880 So why wouldn't I?

01:23:11.700 Well, it is really amazing to watch how Seth basically acts the same way, right? It's sort

01:23:18.520 of like, he's sort of in it with you, right? It's kind of like, well, okay, you're both on the

01:23:24.220 complete risk reduction pathway.

01:23:25.900 Well, I mean, only since this pandemic have I really gotten him into exercise in a way and

01:23:31.220 he's still not where I am. And of course, obviously all of us, I'm not, you know, exercising the way

01:23:36.660 I was before all of this, but yeah, we eat, we eat, you know, we eat every meal together. So we eat

01:23:43.680 the same things and he has certainly changed his eating habits, which has been wonderful. And he

01:23:51.640 supports me and yeah, he goes along with it. We don't have the same genes, but like, why wouldn't

01:23:55.940 he also care about his brain? He's still got one, you know, as, as Richard said, just because he

01:24:00.860 doesn't have a four doesn't mean he's not at some risk. And so I'm very lucky that I have someone who

01:24:06.860 is supporting me most of the time. That doesn't mean he's not always like orders too much at dinner

01:24:11.640 or orders extra things. And I'm like, I have to have a bite of that or, you know, but exercise is

01:24:16.360 always very supportive of. But it also speaks to, I think the difference between having a spouse or

01:24:22.920 a family member that can kind of go through the journey with you, whether it's cancer, Alzheimer's

01:24:28.640 disease, heart disease, whatever it is that, that a person is really trying to make these lifestyle

01:24:32.640 changes to, to work against. And, and so we've spoken a lot about exercise, certainly on other

01:24:38.560 podcasts, we've spoken a lot about nutrition. How does one improve glycemic control? How does one

01:24:45.960 ensure maximum insulin sensitivity and glucose disposal? Richard, can we talk about some of the

01:24:53.020 other tools in the toolkit that we have with, with Lauren and, and frankly, a number of the other

01:24:58.540 patients that we take care of that are high risk in some way? I mean, in our practice, Richard, as you

01:25:03.980 know, we define patients as high risk, meaning you come into their care, basically, if their family

01:25:12.600 history is notable, they have at least one copy of the four gene or they're over 60. You check one of

01:25:19.200 those boxes, Richard is a part of your care. And then we kind of have a protocol that obviously

01:25:24.760 you're the poster child for Lauren. What are some of the other things that we're doing on that

01:25:29.420 protocol, Richard? Sure. So to give you an evidence-based answer, let's, let's start with that

01:25:34.580 first and then we'll go to a, you know, a case study of Lauren. So within the last year, we published

01:25:38.920 the results of our, of our clinical trial that Lauren, thank you. You're a part of you. Thank

01:25:43.680 you for participating. You forced your arm upon me, but we said, okay, I have to sign the consent.

01:25:48.660 But, and I think you, you guys win the prize for the most family members in the, I think you guys

01:25:52.760 may be tied for the most family members in the study, but we have a study that we published in

01:25:57.080 the journal Alzheimer's and dementia, the journal of the Alzheimer's association. And Peter, thank you.

01:26:01.220 You are a co-author in that study. You're, you really fundamentally helped me understand and

01:26:08.340 developed the approach towards maximizing human performance from both, not, not just physical

01:26:13.940 activity, but nutrition. And just, you got me to understand, quick shout out for Peter. I give you

01:26:18.060 all these shout outs, Lauren, because you're the best, but Peter, quick shout out. You got me to

01:26:21.800 understand the difference between lifespan, longevity, health span, which is kind of quality and brain

01:26:27.440 lifespan. And really that's what, that's what we mostly focus on, but there's a lot of overlap.

01:26:31.460 But what we did is we did a study because we had to prove whether or not this individualization of

01:26:36.860 care could work. And in this study we found that on average people got 21 different interventions.

01:26:44.320 You know, again, that's average. Lauren, how many things did we tell you to do? Probably around

01:26:47.800 there. I have, I can count. I have, I have your list right here. Definitely around there. I mean,

01:26:51.620 I'm on a lot of supplements. And then of course there's the lifestyle stuff, the sleep and the

01:26:56.900 food and all this stuff. I'm just, we're loading up one of your things from December, 2019. So a

01:27:03.240 major important part of this is also regular follow-up. So every six months we repeat body

01:27:08.120 composition measures, which is, we use the term ABCs of Alzheimer's prevention management. So the

01:27:13.160 A is for anthropometrics or body composition, body fat, muscle mass, stuff like that. The B is the

01:27:19.380 blood-based biomarkers. We look at your cholesterol markers. We look at your inflammation, your metabolism,

01:27:23.840 your nutrition, genetics are in there too. And then C is cognitive function. So we assess

01:27:29.500 and track all of these things. And at each, every six months, depending on what the repeat is,

01:27:34.260 depending on what your memory function is and what your cholesterol is and all this, we'll keep

01:27:38.260 refining or fine tuning so that we can, you know, this is really an iterative process.

01:27:43.000 So basically we, we keep tracking. And then in your case, because of your APOE4 and because of your,

01:27:50.660 and I have permission to talk about this, I guess. Okay, great. Because of your APOE4,

01:27:55.520 we really honed in on exercise and also more high intensity interval training, really,

01:28:01.040 really focusing on that. In terms of nutrition, we, we, and we checked your omega-3 levels in your

01:28:06.000 blood, red blood cell, DHA levels and EPA and whatnot. We had you eat fish, but also omega-3 fatty

01:28:11.700 acids via capsules, a very specific type and brand that we often recommend. I have nothing to disclose.

01:28:16.600 I wish I did. I could pay my student loans, but nothing to disclose from any supplement or

01:28:21.080 vitamin companies, but omega-3 fatty acids are key, pretty reasonable dose, omega-3s, DHA and EPA.

01:28:27.360 Based on studies that thankfully this was proven this past year, but we've had you on this for the

01:28:31.840 last several years that people with the APOE4 gene require higher doses of omega-3s. So even eating

01:28:37.540 fish just wasn't enough. So we also have you on roughly 2000 milligrams or so of DHA and

01:28:43.460 something or other of EPA. We also put you on a very purified form of cocoflavanols that have been

01:28:50.220 studied in multiple randomized trials. We gave you a very specific type of curcumin, a type of more

01:28:56.840 nanoparticle version. Again, nothing to disclose, but that may have anti-TNF alpha effects,

01:29:03.060 may help with inflammation. So we put you on a reasonable dose of that. We put you on specific

01:29:08.600 types of B-complex vitamins. This was to address your homocysteine. Homocysteine is an amino acid

01:29:13.980 in the blood that is an independent risk factor. So if you have high homocysteine, you are more

01:29:19.160 likely to have brain shrinkage over time and impaired memory function. But only in people with

01:29:24.340 high homocysteine, we can give B-complex vitamins, B12, B6 in tiny amounts, and then a folic acid. If we

01:29:31.280 can control that and the person has sufficient levels of omega-3s, then you can slow brain shrinkage,

01:29:36.820 brain atrophy, and improve memory. So we've modified that risk factor, homocysteine. We

01:29:42.260 optimized your vitamin D. I think your vitamin D wasn't terrible, but it was lower than it could

01:29:47.000 be. I think 60% of people, for example, in Florida are vitamin D deficient. That makes no sense.

01:29:52.200 The first time I saw you, my vitamin D was not good. I can remember that.

01:29:56.200 It was like 19 or 17.

01:29:57.760 I remember it was definitely not good. And I remember being like, I got to sit outside

01:30:00.720 more and not wear as much sunscreen because I'm obviously, I'm the palest human ever.

01:30:06.660 And so I wear a lot of sunscreen, but like we've helped that.

01:30:11.880 Is there a level, Richard, that you try to, do you want to see vitamin D within a certain range?

01:30:17.060 Yeah, great question. So in a study in neurology, I think it was Little John and other studies,

01:30:21.860 I can name several. Cedric Anweiler also has some great, great work on this. But

01:30:25.800 the best that I can do in across the board and in a general answer is, you know, 30 is kind of

01:30:32.040 normal, but what is optimal? I'm thinking closer to 40 to 50, maybe more likely 50.

01:30:37.040 In someone that has two ApoE4 variants, so an ApoE4-4, based on a study in the European Journal of

01:30:43.540 Nutrition a couple of years back, E4-4s are probably preferentially protected or E4-4s better have good

01:30:51.480 vitamin D levels. I'll put it that way. At 50 or more, maybe it's 50 to 70.

01:30:55.260 I don't think we know the exact answers, but a level of 17 to 19 when Lauren first came in to

01:31:00.260 see me was definitely not sufficient. Aside from taking vitamin D, we recommend how to take it.

01:31:05.760 It's a fat-soluble vitamin, so take it with a meal with a little bit of fat in it. That's key.

01:31:09.500 Otherwise, it doesn't help with absorption. Getting some sun, from my perspective, you know,

01:31:13.700 10 to 15 minutes between the hours of 11 to 1 when the sun is, when the UV or whatever it is is

01:31:18.600 strongest. There's lots of devil in the details here, but, you know, Lauren, we've been able to

01:31:23.120 completely modify that risk factor, so that's been pretty good.

01:31:26.460 And going back to the EPA-DHA issue, do you give whatever amount is needed to reach a certain

01:31:34.700 level in the red blood cell membrane, or do you just say, look, we know that E4s are going to have

01:31:42.240 a harder time assimilating. We're just going to give a higher dose. Again, our patients, we use this

01:31:47.480 stuff like very liberally. I think Lauren is on at least two grams combined EPA-DHA. So do you just

01:31:54.920 leave it at the dose, or do you like to rely on the omega quant type assay?

01:31:59.160 I don't know that I have the perfect answer for this, but I titrate it up based on the person's

01:32:04.700 red blood cell level. I try to get an index of at least 12 to 14, and higher is probably better.

01:32:09.740 I think Lauren's is like 14+, which is awesome. I also look at the cholesterol. So ApoB, and Peter

01:32:16.300 and I, I hate disagreeing with Peter on anything, but I still like LDL-P, but I know I've been a

01:32:22.060 convert to ApoB. If someone has high ApoB and LDL cholesterol, I really believe that we can even be

01:32:28.080 more liberal, and people need it even more. But, you know, the study by Hussein Yassin that was just

01:32:33.760 published recently just showed that you really need to get at least to two grams of DHA alone to even

01:32:39.720 get enough. They did a spinal fluid study. Thankfully, these people volunteered to get

01:32:43.720 spinal taps. And I mean, Lauren, we're really hitting you with this stuff, and I'm really glad

01:32:48.860 because, you know, the cumulative effect of ApoE4 plus DHA and EPA over time, there's a cumulative

01:32:56.720 effect, and we really started right with you. So we hedged our bets a little because it was safe,

01:33:01.660 and then it was proven, you know, five years later. So that was cool. But I don't know that I have a

01:33:05.940 great answer. I also look at omega-6 to 3 ratio, and I know, Peter, I know you and I may not look

01:33:12.080 at the same that way. I also look at trans fats in the blood, and I know that that's maybe an

01:33:17.440 imperfect assay or science, but trans fats are no bueno when it comes to Alzheimer's risk. So I don't

01:33:23.320 know. I think there's a lot of important aspects to omega-3s and fat assays, but I don't know that I

01:33:29.980 know the perfect answer on how to do it. You spoke briefly about theracumin. We tend to reserve

01:33:36.200 theracumin for those higher risk patients versus curcumin for most people. What's our belief for

01:33:42.700 why theracumin? There's been some reasonable data suggesting that despite the enormous increase in

01:33:48.780 cost, when you switch to theracumin, it's worth the cost. This is based on an important study from

01:33:54.200 Small, Gary Small at UCLA. And they showed that when people randomized to this, it sounds kitschy,

01:34:01.940 but like nanoparticles, ooh, that sounds cool. Nanoparticles can get through the blood-brain

01:34:05.720 barrier. Well, that sounds like in some ways marketing, but then they did a study and they

01:34:09.820 had less amyloid accumulation. So like, okay, sign me up. It's safe. Yes, it has a cost to it,

01:34:16.880 but it's not astronomically expensive. I don't know what the exact effect is, but the effect size was

01:34:23.060 large enough, even though it was a small study to, you know, when we talk about evidence-based and

01:34:28.720 safe, I think there's enough evidence. It's not perfect, but it's safe and it's not super,

01:34:33.860 super, super costly. So, and especially with TNF, should Lauren be on both curcumin longa plus

01:34:41.540 theracumin? Like who knows? Like I have no idea because of the TNF, but she's doing so much exercise

01:34:46.800 that maybe we don't need to do it, but I'm babbling, but basically I don't know the answer.

01:34:52.220 I just think it's, it's a reasonable option, even though it's not perfect.

01:34:55.940 Okay. Well, another supplement that I'm a huge fan of is magnesium L3 and 8. What are your thoughts on

01:35:03.140 that? And, and I'll explain to folks what it is. L3 and 8 is a transporter that gets magnesium into the

01:35:10.000 brain much more easily. So normally if you take magnesium, it's not, you know, going to get too much

01:35:15.320 in the brain. There is actually some interesting clinical data in humans suggesting that magnesium

01:35:20.780 L3 and 8 in patients with MCI improves symptoms. So again, one has to take a leap of faith to say,

01:35:28.500 well, if you give it to people prior to MCI, it would even delay progression from phase one to phase

01:35:34.140 two and potentially from phase two to phase three. So what are your thoughts on that, Richard?

01:35:38.760 Yeah. So I actually learned a little bit about this from you. I've been a magnesium glycinate kind of guy

01:35:43.080 for a while because just kind of from the headache community as a neurologist, it's very well tolerated

01:35:48.640 and, and, and that kind of thing. But I think the data on, on 3 and 8 is compelling. I think it may

01:35:53.680 also help with sleep if I'm not mistaken. And I've, I've had some success with that. And then some pretty,

01:35:58.380 shall we say, stressed out type A people. So it's not at the very top of my list, but it's somewhere in

01:36:05.260 the middle-ish, you know, middle to, it's not, not super low, but it's, it's, it's,

01:36:09.320 again, evidence-based enough and completely safe. So when it comes to Alzheimer's prevention,

01:36:14.800 we don't want to give anything to anyone that has any degree of, you know, risk, because what if

01:36:20.040 they're not going to get Alzheimer's anyway, then we've done our patients harm and we take the oath,

01:36:23.280 do no harm. So I'm pro Mag 3 and 8, but I don't have as much evidence that's lower on the evidence

01:36:29.380 list. How do you think about, you've already kind of alluded to this, but I want to make sure we round

01:36:34.260 it out around what we would call E4 specific maneuvers, right? So let's assume you have two

01:36:41.520 theoretical patients in front of you that you believe are both at higher risk than you'd like.

01:36:48.460 One of them is an E4 patient. Another one is not. Given what we know about E4, how does that change

01:36:55.340 your thinking? You've already made several points in reference to this. One of them, for example, is,

01:37:00.380 boy, there's no ambiguity around the benefits of exercise in E4 people. People with E4 tend to

01:37:07.140 require higher doses of EPA and DHA. They tend to benefit disproportionately from vitamin D. Are there

01:37:12.960 any other things that are unique to patients with E4? Yeah. So we wrote a paper on this that's open

01:37:17.860 access. It's in the Journal of Prevention of Alzheimer's Disease. It's called Clinical Application

01:37:22.300 of ApoE and Alzheimer's Prevention, a Precision Medicine Approach. Kara Berkowitz is the first author.

01:37:27.480 She's awesome. She was a med student at Cornell. Peter, we lost her to surgery. I don't know how

01:37:31.920 that happened. You surgeons. But she wrote this terrific paper and did several other papers with

01:37:36.440 us too. So I mentioned this paper first because this is a complicated topic. Let's just start by

01:37:42.200 saying physical exercise is, I believe, likely preferentially effective in people with the E4

01:37:49.780 variant or more. Brain imaging studies show that E4 carriers exacerbates the effect of having a

01:37:56.300 sedentary lifestyle and Alzheimer's pathology. So someone with E4, really, really, really better

01:38:01.740 exercise. And it's like, no joke. It's got to be really important. And the intensity of the exercise

01:38:07.340 is key. Tobacco use, just worse in E4s. Like, I'm not telling you that a non-carrier can smoke,

01:38:14.180 but I think it's worse. Alcohol use. Alcohol is really confusing. And the data on alcohol kind of

01:38:20.740 darts all over the place. But a few drinks a week is kind of where I'm at now. Men and women may be a

01:38:26.460 little bit different. This is really confusing. But there's probably an E4 impact. But what I would

01:38:32.020 say that while light to moderate alcohol consumption, I mean, more on the light side,

01:38:36.600 like four to seven drinks may be beneficial for non-carriers of E4, decreasing alcohol intake or

01:38:43.180 even abstaining, maybe even more so helpful for carriers. But this is tricky. And I don't really

01:38:50.080 know the answer to that. Cognitive engagement, if you don't use it, you lose it. Staying cognitively

01:38:54.720 engaged is like critical. There's some difference with E4s and cognitive engagement strategies.

01:39:00.100 But I think the jury's out a little bit. The dietary stuff is, you know, just specific dietary types is

01:39:06.060 key. Omega-3 fatty acids we talked about are probably preferentially effective, but you need to be at

01:39:10.760 higher dose. You know, there's a randomized trial underway now to try to understand, you know,

01:39:16.180 the impact of high saturated fats and a high glycemic index diet on cognitive function for E4

01:39:21.540 carriers, but that's not published yet. I guess I want to be cautious in saying this, but I think

01:39:25.940 people with E4s are probably, you have to be more cautious and careful in terms of high saturated fat,

01:39:31.140 you know, MCTs. I'm pro-MCTs if they're the right MCTs, and this is a topic for another discussion.

01:39:37.140 And I'm pro-MCTs if it's not specifically more so likely in people without the E4 variant.

01:39:45.060 There's more window or more leeway to be able to use them. But MCTs is a really tricky topic,

01:39:51.120 but I personalize MCT use based on this, but this is a whole thing. So I don't know how much down the

01:39:57.080 rabbit hole to go. I have another question about, this is one we've all spoken about, and yet I'm still

01:40:02.520 very much unclear. And I'm curious as to where your thinking is evolving, which is THC in any form,

01:40:10.300 be it edible, be it inhaled. I mean, what do we know? And acknowledging that it's probably

01:40:15.560 complicated, right? Because there are probably benefits that come in terms of stress reduction,

01:40:19.620 certainly if it facilitates sleep. But what do we know on that front? And are we ever going to get

01:40:25.840 good answers? Because the epidemiology is obviously heavily negatively biased based on the cohort that

01:40:32.920 studied.

01:40:33.720 This is a hard one. I'm not negative on THC specifically. I think there's something with

01:40:41.140 the CBD and THC connection. I think it depends on the amount of CBD versus THC. If I had to choose,

01:40:49.260 if someone's going to use THC or CBD, edible to me makes more sense because of less smoking is better.

01:40:55.600 But I don't know. That's just what I believe. But I don't think that's grounded in perfect science.

01:41:00.140 But I guess I would say I don't know. If every one study you read where it helps Alzheimer's

01:41:04.560 pathology, you can read another study where it causes greater pathology. So I'm not anti-CBD, THC.

01:41:11.640 I'm not pro. I'm kind of in the middle. I think it's an individualized decision. And I think if

01:41:16.620 someone's going to use CBD or THC because, for example, hey, when I take it, my sleep is better.

01:41:21.720 I feel better. Okay. But that's subjective. I want to know objectively. Let me see your fitness

01:41:28.120 tracker. Let me see your ring. Let me see your whatever you do to track things. And all these

01:41:33.920 gadgets may or may not work great in different people. But I think one has to really – the term

01:41:38.140 here would be an N of one study where you make one specific change and then you compare what

01:41:43.900 happens to that person over the three months, say, or six months of only taking that one thing.

01:41:48.720 And does cognitive function improve or does sleep metrics improve? I think the THC-CBD story is a

01:41:54.920 precision medicine answer. Well, speaking of cognitive testing, Lauren, how many times now

01:41:59.160 have you been through the battery of cognitive tests that Richard puts people through?

01:42:04.820 I don't know. Is that a cognitive test to see if I even know that number?

01:42:09.540 Maybe, but six, seven times? I don't know if you know that right off the information in front of

01:42:16.380 you. But something like that, enough that I'm starting to learn the tests.

01:42:21.040 Is it intimidating when you sit down and do it? Because I've had some patients that don't want to

01:42:25.620 do it. Well, okay. Because I had a bad time, I visited Richard the day that Like Father came out,

01:42:33.940 which was because of a number of reasons. Perhaps the most stressful day and emotion,

01:42:40.040 one of the most emotional days I'd had in a while. And it was not good. And my brain was a million

01:42:45.040 different places. And of course, my body was not in the best of shape leading up to that. And it was

01:42:51.060 bad news. And Richard was so unhappy and so mad at me. But it was a good kick in the behind to get

01:42:59.660 myself back on track because I had been making progress. Then I lost that progress. So of course,

01:43:05.380 the tests that I think now I've come in twice since then?

01:43:08.540 Twice, yeah. Yeah. I psych myself up a bit. And I'm like, I'm nervous. And I'm like, you know,

01:43:14.280 get all into it. But fortunately, I've done well. But is that true, Richard? I mean, do we really

01:43:20.060 think, like, I guess, do we know that the cognitive test reflected her change in effort around the

01:43:30.200 preventative measures? Or is it confounded by the fact that she was having a very, very stressful,

01:43:35.360 distracted day? Even though both of those are true, is the test really able to distinguish those

01:43:40.580 things? And I mean, my blood work wasn't great that day either. But I'll let Richard answer.

01:43:45.540 Yeah, you know, it's really interesting. And I have the whole trajectory here. I mean,

01:43:49.600 this is worth its weight in gold, like all these, all this, these tests. Now, let me take a step back

01:43:54.160 and talk about cognitive assessments. Now, when we do a cognitive battery related to Alzheimer's

01:43:59.620 prevention, we use something, it's a modified form of the Alzheimer's prevention cognitive composite.

01:44:04.340 These are mostly computer-based tests, the NIH toolbox, as well as other kind of traditional

01:44:09.060 tests that people with mild cognitive complaints kind of come in and take. But we use a battery that

01:44:15.120 is sensitive to detect changes in brain function before symptoms. And different cognitive domains or

01:44:23.700 different cognitive areas are related to Alzheimer's disease pathology, as well as other things like

01:44:31.320 vascular pathology, vascular cognitive decline, or age-related cognitive decline. So I'm not going

01:44:37.540 to portend that our cognitive assessment battery is anywhere close to perfect. It is as good as

01:44:43.160 cognitive testing can be because people can have good days and bad days. But it's funny, Lauren,

01:44:47.420 like you, I remember you that day. That was a whole day. Didn't we do a video shoot that day?

01:44:52.500 Well, that was the day you filmed Seth, and I went for other blood work, and then I just was in such

01:44:57.400 a state I couldn't even stay. Oh, my. That's right. That's right. I remember that day.

01:45:01.980 And my in-laws were with us. Yeah.

01:45:05.020 That was a lot. Yeah, that was a whole day. So I guess what I would say is there are certain,

01:45:11.640 when someone doesn't sleep well, then the thing that I would expect to have a bad effect on cognitive

01:45:18.840 testing that day would be related to processing speed and attention. When someone has, let's just

01:45:25.320 say, early Alzheimer's before symptoms, I'm more paying attention to certain types of memory tasks,

01:45:32.560 certain types of naming tasks. When someone has vascular risk factors, I'm more concerned with

01:45:39.140 how are they doing in executive function measures. So when I see homocysteine and vitamin D and the

01:45:45.960 cholesterol, I correlate that or I associate that in my brain with different cognitive domains. So

01:45:53.780 this is hard to explain, but like, Lauren, you felt like you did bad that day, because maybe

01:46:00.920 emotionally you were whatever. But looking back on it, if you take that into consideration,

01:46:06.640 it made sense that you were having a stressful day. However, in the next couple of years, when I think I

01:46:13.720 may have scared you, because I got upset. I mean, I was concerned. I think you saw the concern. I

01:46:19.040 think Seth was there. We all did. Yeah. I mean-

01:46:21.540 My in-laws were there. They were concerned. Yeah. I mean, I didn't know I was going to call your

01:46:25.920 brother. Like, what do I do? Like, I was, you know, I don't want to involve other people with

01:46:29.240 HIPAA and all that kind of stuff. But I was like, how do I address this? And I just said,

01:46:32.720 I'm sorry you're having a crappy day, but here's the deal. Like, this is what's going on. And

01:46:37.120 I'll be frank, I was getting worried. Things weren't going in the right direction. You were doing good and

01:46:42.520 then bad and then good and then bad. And then, you know, cruise ship situation and then the stress.

01:46:46.060 And I said, Lauren, I'm sorry. It's got to change now. And I think maybe that's when we got Peter

01:46:51.240 involved or maybe a little before that. We hadn't sat down with Peter. We'd been talking about Peter.

01:46:56.680 Yeah, that's right. So all I can say is in the two plus years, whatever, since that time,

01:47:03.200 Peter, I know you've been cautious about cognitive tests because of the variability,

01:47:07.240 the imprecise nature. And I agree with that. But you can't fake, Lauren, your last set of cognitive

01:47:13.800 tests, you can't fake this. You have optimized your cognitive function, in my opinion, period,

01:47:21.320 like no discussion. You said there's an element of practice effects. Now, I totally agree with that.

01:47:26.460 There are certain tests.

01:47:27.360 But because I have a four, that doesn't help me.

01:47:31.280 Wow. Look at you, little encyclist.

01:47:33.420 See, I can learn.

01:47:34.360 That's higher order processing. There you go.

01:47:36.980 Wow. Dr. Miller-Rogan, you're learning. Good job. Correct. EPOE4s are more resistant to practice

01:47:42.480 effects. And also men's brains and women's brains have different strengths and weaknesses,

01:47:46.800 for example, verbal memory. So when we really digest your trajectory of cognitive function over

01:47:52.840 the last several years, I'm going to be honest. I don't know that I've really talked about this too

01:47:57.920 much in public or on a recording, but your brain is functioning. And again, you can take all the

01:48:03.420 practice effects you want. There are certain tests here that I believe are resistant enough. And it's

01:48:08.260 not like you're taking these every day. You're taking these like every six to 12 months. And we

01:48:13.020 change it up. We change the versions and stuff like that. So you have a plateau at some point

01:48:17.200 with the practice effects. But your brain is absolutely, without a doubt, hands down, I have

01:48:23.340 visual proof. Your brain and biomarkers, your blood-based biomarkers, you're optimized. You're

01:48:31.040 different. Your brain is firing on more cylinders. Like you can even just, let's just say we'll average

01:48:36.300 out the first three sessions, right? I mean, there's just no comparison. You're more than a

01:48:41.160 standard deviation above normal. Like you've improved, like your processing speed.

01:48:46.940 My brain is above normal. I know.

01:48:49.200 Yeah. Well, no, I mean, it's interesting because I really want to see if you feel anything,

01:48:53.720 but just can you tell the difference? But the most important test that we do for age-related

01:48:58.280 cognitive decline, you're several years older. And I know you're, oh, I'm 30-something to 30-something,

01:49:02.900 big deal. Well, no, the brain ages in that timeframe. Your brain is younger now than it was

01:49:08.520 five years ago. Like you're greater than 90th percentile on all these different tests. Your memory

01:49:15.380 function is a standard deviation above the mean. And when you started out, it like was 0.87 standard

01:49:21.560 deviations below the mean. Yeah.

01:49:23.780 I mean, I remember this, Lauren, because our very first meeting was at Cornell and we were going over

01:49:30.400 your results. And I remember we were kind of looking for an explanation for how it could have been so

01:49:36.460 poor. And the best explanation that you came up with, which frankly I thought was a viable one,

01:49:42.400 was you said, look, I did well in school, but I did poorly on standardized tests. And is it possible

01:49:49.280 that my cognitive score is low because I'm not a good standardized test taker? So it's been very

01:49:58.700 exciting to watch this progression. One element of the standardized test I want to ask you about,

01:50:04.580 Richard, is odor. You put another one of our patients through this test recently. And I was very

01:50:13.740 surprised to learn. So he came back, is it 10? Nine, nine item test. Nine. And in this case, the patient

01:50:22.120 correctly identified eight. And I remember thinking, oh, that's awesome. And you were like, if it had been

01:50:29.500 seven, I would have been really concerned. And with eight, it was, we're going to do a retest.

01:50:35.300 Why is odor identification so important in this disease?

01:50:39.720 Yeah. I mean, there's so much subjectivity to cognitive assessments. You could be sleep deprived.

01:50:45.060 You could be like, you know, distracted by, I don't know, you forgot to silence your cell phone. You

01:50:49.660 could, I don't know, it's warm in the room or cold in the room and Lauren's always freezing. So,

01:50:54.360 you know, we got to get the temperature just right for Lauren. Lauren's coming, you know,

01:50:57.560 regulate the temperature. You don't do that.

01:50:59.880 No, I'm kidding. And then Seth's coming. Oh, change the temperature, change the thermostat.

01:51:05.480 No, as we get older, we change. Now he's the cold one and I'm the hot one. I know I've been

01:51:10.020 huddling during this because the air is low. But no, it's, that's, honestly, it's the funniest thing.

01:51:14.380 The older he gets, the colder he is and the hotter I am. And of course it used to be different.

01:51:18.840 Anyway. Fascinating. So odor is more objective rather than subjective. And odor identification,

01:51:26.560 like, what is that? Well, it's your ability to recognize a smell and name what it is.

01:51:31.940 And again, in med school, decreased odor identification. The first thing I thought

01:51:36.160 of was Parkinson's disease. That's something that's, that's common in preclinical Parkinson's.

01:51:40.740 So before someone gets the tremor and the slow movements and the shuffling gait, meaning the

01:51:45.520 walking is slow and, and, and the rigidity, odor identification, loss of smell is something that

01:51:51.380 can, you know, be a harbinger of badness for a neurodegenerative disease to come. Well,

01:51:55.780 the studies have shown that loss of smell or lack of the ability to precisely identify certain smells

01:52:01.220 can be a harbinger of Alzheimer's disease as well. My mom had a very poor sense of smell

01:52:06.040 and, and not an amazing sense of taste either, but sense of smell was, she never had a good sense of

01:52:12.520 smell. That's impactful. With COVID, I mean, it's a different thing. Like, you know, and Peter,

01:52:17.220 you know, you and I talked about this, but I lost my smell for five, six weeks, which is a little

01:52:21.940 bit longer than, than, than some people. And we can talk about. Has your smell returned back to

01:52:25.900 normal? So I'm seven months out now. And you know, just for folks know what we're talking about. You,

01:52:32.320 you had a pretty good case of COVID. I did. Yeah. I had one of these cases where, oh, I'm fine. Three,

01:52:37.240 four, five days later. I'm like, you know, okay, cool. I'm going to, I'll exercise tomorrow. And then

01:52:41.340 on day nine, 10, I went with my O2 sat dropping and all that stuff. And I'm Peter help and Paul help.

01:52:47.880 And what the heck I called every doctor in my Rolodex, did an EKG on myself in my office at

01:52:52.780 midnight. Cause I wanted to stay the heck out of the ER. My O2 sat was 94 PTSD time, but they

01:52:58.520 wouldn't have admitted me cause it was above 90. But anyway, I had a pretty reasonable case of COVID

01:53:02.440 and my smell after five weeks started to come back. I mean, like ahead of a thing of bleach and I

01:53:09.220 smelled nothing. I mean like zero, I'm like real smell sensitive. Then I had phantom smells for a while.

01:53:14.760 I was like, oh, the dog peed. Oh, Bon Bon, Kitty. My dog's name is Kitty. How's Zelda doing by the

01:53:21.140 way? Well, honestly, I've been worried a few times. I don't know if you saw me. I was checking to see

01:53:25.100 if my microphone has picked up her snoring because she's right across from me and she has been snoring

01:53:30.420 so loud this whole time. So if anyone has heard that, it's, it's just Zelda. Oh no, it's golden.

01:53:36.300 Yeah. Bon Bon had his second snoring surgery, but he's great now. He's awesome. King Charles

01:53:41.300 Cavalier fan club of America. We're talking to you right here. Anyway, so I had phantom smells and

01:53:45.900 then my smell is basically back, but I'm like a little smell sensitive. Can't, can't explain it.

01:53:50.120 So that this COVID may change our ability to use smell sensitivity for Alzheimer's related

01:53:55.120 testing. But anyway, we'll cross that bridge later. Sorry for the tangent.

01:53:58.260 What about, what about hearing? Because you see these reports from time to time that say,

01:54:03.560 we've got to get more aggressive with hearing aids in people. The moment a person has even the

01:54:09.280 slightest amount of hearing deterioration. We've got to correct it. The implication being that

01:54:14.780 hearing loss will have a causative role in Alzheimer's disease, such that correction of it

01:54:22.000 can delay or prevent versus just the obvious correlation between hearing loss and dementia,

01:54:28.500 given the obvious age association. What's your thought on that?

01:54:31.700 Yeah, I don't, I don't know that I have a perfect answer, but hearing loss, when they've done the studies,

01:54:35.360 the Lancet Commission 2020 report came out and basically showed that hearing loss is like

01:54:40.380 the most impactful modifiable risk factor that they found in their study, which is like striking,

01:54:47.900 like a huge number of cases of dementia could be potentially reduced if a person gets early

01:54:54.640 recognition of hearing impairment and gets it addressed. Now-

01:54:57.780 Why, sorry, why is that?

01:54:59.200 Yeah, this is confusing. And this is a quote unquote new risk factor. I mean, it's been around for,

01:55:03.860 you know, the evidence has been emerging for years now, but I don't know, is it because you're,

01:55:09.100 and I hate to say, I'm not an expert in this at all, but you're just, you disengage, you can't hear,

01:55:14.000 you kind of, you're in your own little world, you miss social cues, you have different interaction

01:55:18.460 levels. I actually don't know the answer to this. And this, the classic line, we need more research to

01:55:23.980 truly be able to figure this out.

01:55:25.500 I mean, I feel like it's one of those things, Richard, that we, because we're constantly updating

01:55:30.380 our protocol. And I've been thinking for about the past three months, do we need to now take those

01:55:38.320 high risk patients that we described and say, everyone's got to go to an audiologist. And

01:55:44.060 of course the implication is you're going to get people in their thirties and forties that have

01:55:49.020 low, low, low grade hearing loss. Are they actually going to want to wear hearing aids or is it just

01:55:53.780 going to be, Hey, we're going to use more noise cancellation stuff and sort of try to protect

01:55:58.260 hearing longer. But I, I'm curious as to this. It also strikes me that from the precautionary

01:56:04.440 principle, there's no downside to protecting your hearing. And as much as one can do that, I don't

01:56:10.320 see a downside to it.

01:56:11.780 I think we, meaning doctors need to do a little bit of, I say a better job. Doctors have it really

01:56:17.100 hard. So it's, this is not doctor's fault. It's like our medical system is in disarray and broken

01:56:22.900 beyond. I have no idea how to fix it with 10 minutes or 15 minutes per patient. I have lots of

01:56:27.720 empathy for tremendous empathy for, for physicians working out there, but in the trenches, but hearing

01:56:33.260 screening, I think is something that should be part of at some age, at some point, an evaluation.

01:56:38.400 Real briefly though, I want to go back to Lauren's odor identification. So this is a weird comment.

01:56:43.020 And I, I've never really also said this on a recording, but Lauren, this is not the first time

01:56:48.120 that I've seen patients that have really firing on all cylinders, done 23 of the 25 things we told you

01:56:54.340 to do like compliance out to wazoo, 10 out of 10, your odor identification. This is weird. And this

01:57:00.260 may be a red herring, completely random or whatever. Your odor identification has improved.

01:57:06.780 I think it's because, and, and maybe this goes again, goes against my four. It's because now I

01:57:12.680 know the difference in the cards between the coffee and the gasoline smell, which used to really throw me

01:57:17.180 off.

01:57:17.640 Gotcha. Okay. So even with an objective test, we still have subjectivity with learning effects and stuff.

01:57:23.340 Now I, now when I smell it, I'm like, okay, really be sure. Is this the coffee or the gas? All the

01:57:28.660 other ones are easy, but between those two, those always trip me up.

01:57:32.840 Gotcha. Interesting. You know, just to get back to one thing, Lauren, yes, I have objective data,

01:57:36.700 but you know, data is only as good as data is. And all of our tests are imprecise. And Peter and I

01:57:40.720 talk about this a lot. Sure. Your calculated cardiovascular risk, when we put all your numbers in a

01:57:45.720 calculator, much lower. Your calculated Alzheimer's risk based on the different scales,

01:57:50.220 much lower. Like we're doing a great job. Like in terms of living longer, yeah, knock on wood.

01:57:56.080 Yeah. We're, we're, we're really, we're really doing well. Do you feel anything different in your

01:58:01.780 brain or, or not so much? And just be honest. No, no. And you know, and I don't, I don't know how much

01:58:09.040 we want to get into any of this, but I'm on my own hormonal journey and often wonder, you know,

01:58:15.080 if that plays a part in it. I, I've always been someone who's enjoyed sleep. We kind of talked

01:58:19.280 about that and like, you know, I, I like sleep and I, I can, I love a nap as I get older and my

01:58:26.300 hormones become bigger players in my health. I sometimes think that has to do with it, but

01:58:33.360 overall, do I feel cognitively better? It's hard to say, but physically I feel better. My overall

01:58:42.140 health is, I can tell that it's better from a total body energy, the way I can approach a situation.

01:58:52.420 I feel like I have a different type of body energy, if that makes any sense. Cognitively,

01:59:01.140 you know, knock on wood, I fortunately feel like someone who is pretty in control of their cognition

01:59:06.840 most of the time. So, you know, do I have moments? Yes. Where I'm like, I feel tired or weird,

01:59:13.960 or even that, you know, like you said, that brain fog, which I don't think I understand at this

01:59:18.460 point, but the black and white answer is yes, I feel better. Do I feel greatly better? I'm not sure.

01:59:24.280 I mean, to me, I think there's an emotional piece here too, right? Which is we go back to 10 years ago,

01:59:28.940 there's this depression that basically feels like there's something inevitable that's going to happen

01:59:36.360 to you. And I think, you know, by now, Richard and I are very much in the camp of saying there's no

01:59:44.940 reason to believe you're going to get Alzheimer's disease. Yeah. Like there's really no reason to

01:59:50.020 believe that. If you stay this course that you're on, you get to be like normal people in their 80s.

01:59:56.740 So maybe that's the greatest single benefit of all this is that it changes the way you feel.

02:00:02.920 I wasn't physically in such rough shape that I could really pinpoint a difference, but emotionally,

02:00:09.660 yes, so much of the fear has dissipated because I have control in a way that I didn't before. I see,

02:00:17.960 I see my blood work, you know, I see numbers going from red to green and that gives me a hope that,

02:00:25.920 you know, I think translates into my physical being, but also into my, into my cognitive health

02:00:30.240 as well. I don't want us to close without talking a little bit about Hilarity for Charity, which we

02:00:35.980 started talking about a little bit, but bring us up to speed on the, on specifically what the mission

02:00:40.900 is, how you decided to pick the lane that you guys are going to be in. You know, we touched on this a

02:00:46.380 little bit before, but I have been so fortunate in my terrible journey. I think I've had the best

02:00:53.580 situation of a horror show that could happen with Alzheimer's and that one, my family was able to

02:00:59.320 afford care for my mom. And that too, I have, because of my relationships and the advocate that I've

02:01:06.820 become, I have met smart people like you guys who have helped me take control of my brain health. And so

02:01:13.360 HFC, what we've done with that is try to help other people be at least a part of that situation.

02:01:22.160 And so I like to think of HFC as sort of like, this is our non-official, you know, mission statement,

02:01:28.180 which is like, we're here for your, for your brain today and tomorrow. Meaning that, you know, we're here

02:01:33.860 for people today through care, through our numerous support groups, which are personalized and which we

02:01:40.780 really take the time to connect people to people who would understand their situation. Early on, I went to a

02:01:47.120 support group where, you know, I was like 26 and upset about my mom. And there was a guy there who

02:01:51.960 was like 56 and who was upset about his mom. And not that I didn't feel bad for this person, but also

02:01:57.060 like, I did not feel bad for this person, you know, because I was like, you're 56. You have your mom at

02:02:03.000 56. Like I'm 26. And so, you know, we really try to recognize that in our care, we put people together

02:02:11.820 who would understand a situation. And of course, then there is the other aspect of it, which is,

02:02:16.880 I think what makes the greatest impact in people's lives today, which is our care program. You know,

02:02:21.240 like I said, my family could afford care for my mom so that my dad could catch his breath and take a

02:02:26.680 break and go to the grocery store if he needed, or, you know, come have dinner with me if he wanted.

02:02:32.060 And so many people are with their loved one 24-7, without a break, without relief. And that is a

02:02:42.120 completely thankless job. And so we provide care for people and provide caregivers

02:02:48.880 to go into people's homes and give the primary caregiver respite, give them a break. And then

02:02:56.620 there's, of course, how we invest our dollars in research, which is in brain health. HFC really

02:03:02.880 focuses on activating young people in the fight against Alzheimer's. We don't think that people

02:03:08.780 should wait till they're older to start talking about their stories or losing loved ones to

02:03:13.720 Alzheimer's. And they certainly shouldn't wait, as we've talked about today, to start taking care of

02:03:17.720 their brains. And so we really do our best to share what we've learned from you guys and educate

02:03:25.040 people that it is never too early to start taking care of your brain and how important that is.

02:03:32.600 That's really our focus. I wish that we raised the kind of money that would research a medication

02:03:39.720 that could cure Alzheimer's, but no one has yet given us $5 billion. I'm out here ready to receive

02:03:46.120 it if someone is listening and wants to send it our way. But for now, I'm going to do what is

02:03:51.080 practical, which is help people today with support and care and teach people how to take care of their

02:03:59.180 brains for tomorrow. So that's who we are. So people can go to the website. They can obviously

02:04:05.480 donate directly. Is there any other way people can get involved or be a part? I mean, there are all

02:04:10.400 sorts of events. Yeah. What else can people do? Yeah. I mean, obviously this year, the event thing has

02:04:16.280 sort of taken a turn for all of us and all nonprofits, I think are feeling the strain of

02:04:22.060 not being able to host our normal fundraising events and, you know, and the strain of that a

02:04:26.880 lot of philanthropists who normally would donate our way feel that they can't this year because they

02:04:32.800 are donating towards COVID-related organizations or even racial organizations, which please keep

02:04:40.140 donating. These things are very important. I'm not saying you shouldn't. But at the same time,

02:04:43.840 people still have brains. And unfortunately, there are still millions of people in this country with

02:04:48.680 Alzheimer's and their caregivers are in even worse situations now. So what we do is even more important

02:04:55.680 these days. So yeah, you can go to our website and of course, give us your hard earned dollars. We're

02:05:02.000 happy to do something good with them. But we also give people a space to share their story if they have

02:05:07.920 one. We provide infrastructure if you want to throw your own Alzheimer's fundraiser. We've had so many

02:05:13.660 amazing individuals over the years who have done their own fundraisers for whatever speaks to them.

02:05:20.180 One of my favorites is a guy like drove, do you say a tuk-tuk? Do you say drove a tuk-tuk? I guess

02:05:25.420 so. Rode one? Whatever. Pulled one across India and raised money for HFC? Like how cool. But like

02:05:30.820 that's what spoke to him. That was organic to him. And Seth and I always say when it comes to fundraising

02:05:35.340 or philanthropy, like do what's organic to you, what makes sense for your life. So we provide an

02:05:40.600 infrastructure. If you want to raise money for us, we're happy to help you do it. You know, again,

02:05:44.820 if you need support, you can come to us. We have so many different options. We have an amazing

02:05:48.840 partnership with the Rosalind Carter Institute in which we train caregivers. We give them one-on-one

02:05:54.440 caregiving training, which is really, I think, so invaluable. I mean, the truth is there's no

02:05:59.560 training to be a caregiver. Every day is a surprise and who knows, but there are certain tools that we can

02:06:05.620 give people. And, you know, and I think we try to do it all in a way that is approachable. Certainly,

02:06:11.020 you know, our original name is Hilarity for Charity. Now we're HFC because we want to seem

02:06:14.600 like grownups and we want people to take us seriously. But we approach everything through a

02:06:18.780 way that, you know, has some comedy that is certainly our work. But we often say Alzheimer's

02:06:25.840 is so devastating and it is so sad and people don't want to hear about it. So we'll tell them some jokes

02:06:31.480 and trick them into laughing. And then all of a sudden we hit them with the facts and tell them

02:06:35.840 how important it is. And we rope them in that way. I think overall, we're just trying to provide

02:06:41.300 people the hope that I have found over the years. You know, we started this podcast talking about

02:06:48.300 my dark, devastating times and like, that's not who I am anymore. And that's not my vision about all

02:06:54.700 of this anymore. And I think there is so much control that can be had that we did not have even just a

02:07:00.680 few years ago. And, you know, we through HFC are just trying to teach people that they have that

02:07:05.420 control too. Well, Lauren, Richard, it has been such a pleasure to sit down with you guys today.

02:07:12.240 And it has been worth every bit of the wait from almost a year ago when we wanted to first do this.

02:07:19.280 And no one would have imagined a year ago, all that was going to happen in the next 12 months.

02:07:23.320 But it's also given us a chance to see one more year of your incredible progress, Lauren. So thanks

02:07:31.580 for being the poster child for what Alzheimer's prevention looks like.

02:07:35.620 Well, we're trying. It's a journey, right? I don't know if I can be the poster child yet,

02:07:39.240 but maybe in some time we'll see if... I think, you know, we'll keep going.

02:07:43.340 No pressure.

02:07:44.000 There's a poster child for the journey.

02:07:45.760 There you go.

02:07:46.720 Well, hey, if we would have done this podcast a year ago, I could have only said one out of every

02:07:51.060 three cases of Alzheimer's is preventable. But now, based on the latest data, four out of 10

02:07:56.320 cases of Alzheimer's may be preventable if that person does everything right.

02:08:01.360 So I'm going to have to change the signature in my email.

02:08:04.440 I'm sorry.

02:08:04.780 Is what you're saying to me?

02:08:05.880 Who wrote that signature? Jeez.

02:08:07.860 Someone wrote that signature. I don't know who it was.

02:08:10.340 Unbelievable. Typos everywhere. Fired. Peter, thanks for sharing our story. And Lauren,

02:08:16.360 thank you for being courageous. And you're the one that puts... I mean, I get to sit here at this

02:08:20.960 desk and hang out and like, you know, whatever. And you actually have to go home and do all the

02:08:24.880 27 things that Peter and I tell you to do. So thanks for being...

02:08:27.720 You do things too.

02:08:28.600 A good sport.

02:08:29.580 You do your own things.

02:08:30.900 Yeah. Got to do what you got to do.

02:08:32.020 I know you do.

02:08:32.600 Yeah. And we're really grateful to your family for also feeling that it's been okay for you to

02:08:37.240 talk about this because I know that these are things people don't want to talk about. And yet,

02:08:41.300 I think the understanding that, hey, we talk about these things that suck because it makes a

02:08:47.220 difference. Because there's a lot of people that are listening to this right now that can relate to

02:08:50.800 what you're saying.

02:08:51.880 Yeah. I hope so. Well, there's so much that can be done. So I appreciate the chance to talk about it.

02:08:58.700 All right, guys. Thanks so much.

02:09:00.220 Thanks for that.

02:09:01.120 Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

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The Peter Attia Drive - November 23, 2020

#138 - Lauren Miller Rogen and Richard Isaacson, M.D.： Alzheimer's disease prevention—patient and doctor perspectives

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