The Peter Attia Drive - #138 - Lauren Miller Rogen and Richard Isaacson, M.D.: Alzheimer’s disease prevention—patient and doctor perspectives

Episode Date: November 23, 2020

Peter is joined by writer, director, actress, and founder of HFC, Lauren Miller Rogen, and previous podcast guest and director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian, Dr. Richard Isaacson. In this episode, Lauren tells the heartbreaking story of watching members of her family succumb to Alzheimer’s disease (AD) which motivated her to proactively address her own risk with Richard’s guidance. Richard discusses the various genetic and lifestyle factors that influence the risk of AD and uses Lauren’s unique situation to explain how he diagnoses patients and personalizes care. They go through Lauren’s protocol of preventative measures that have already produced marked results, and end with the uplifting message that one’s genetic predisposition does not seal one's fate. We discuss: Lauren’s deep family history of Alzheimer’s disease (3:10); The influence of genetics, epigenetics, and lifestyle on Alzheimer’s disease risk (13:45); Lauren’s mother’s disease progression and the enormous stress it causes for family members (24:30); The various manifestations of Alzheimer’s disease depending on the location of pathology (29:30); The three stages of Alzheimer's disease (34:45); Richard’s deep exploration into Lauren’s family history revealing clues about a diagnosis and a roadmap to successful disease mitigation (39:15); How exercise reduces Alzheimer’s disease risk, and the different risk between males and females (58:00); Why knowing your APOE status is important, and whether certain people should be wearier of head trauma (1:08:00); How Richard uses genetic testing to personalize care (1:14:45); The “ABCs” of Alzheimer’s prevention, lifestyle interventions, and Lauren’s personal protocol for reducing her risk (1:21:45); Unique treatment for people with the ApoE4 variant (1:36:30); Richard’s mixed opinion on CBD and THC as a tool for disease prevention (1:40:00); Cognitive testing procedures, and how Lauren’s tests furthered her commitment to her disease prevention protocol (1:41:45); The relevance of sense of smell and hearing in Alzheimer’s disease risk and prevention (1:50:00); The emotional benefit of knowing you have control over your mental and physical health (1:57:30); HFC—a charitable organization founded by Lauren and Seth (2:00:15); and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/laurenmillerrogen-richardisaacson/  Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

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

Now, without further delay, here's today's episode. My guests this week are Lauren Miller Rogan and Richard Isaacson. Lauren is an actress, screenwriter, director, but also a friend and patient. She's the co-founder of Hilarity for Charity or HFC, a national nonprofit organization whose mission is to care for the families facing the disease of Alzheimer's disease, educate them about living a healthy brain life, and activate the next generation of Alzheimer's advocates. Richard Isaacson should be a familiar name for some of you as he was a guest on a previous episode of The Drive in late 2018 when we did a deep dive into Alzheimer's disease. Many of you as he was a guest on a previous episode of The Drive in late 2018 when we did a

deep dive into Alzheimer's disease. Many of you have requested follow-up podcasts on this topic. Among them, this is one. Richard serves as the director of the Alzheimer's Prevention Clinic at Weill Cornell, New York Presbyterian Hospital, and is a assistant dean at the office of the faculty of Weill Cornell of Medicine. I've known Lauren for a couple of years. We actually met through Richard and the three of us been talking about doing this podcast for about a year. In fact, we were going to do it last fall and then we put it off until the spring and then COVID got in the way. So this one's been a long time coming. My intuition was that being able to talk about Alzheimer's disease with Richard and Lauren simultaneously would be a beautiful way to discuss the human tragedy of the disease and also to talk

about the science of prevention and the pathology of the disease. And honestly, by the end of this discussion, I felt we had really achieved that. I think Lauren's story is both heartbreaking and uplifting for reasons that will become clear as you listen to this. In this episode, we talk about her journey with her family history, what led her to Richard and ultimately what really changed the course of her life with respect to how she treats prevention. We talk a lot about what preventative measures look like today and how we look at the evolving body of literature to figure out how to modify risk. So if you have

even a slight interest in the prevention of Alzheimer's disease, I think you're going to find this episode both touching and enlightening. So without further delay, please enjoy my conversation with Lauren Miller-Ran and Richard Isaacson. Lauren and Richard, what a privilege to be sort of sitting down with you guys right now. We have been kicking around the idea of doing this for about a year now. COVID kind of got in our way. We were going to do this obviously in person last year. So while it's long overdue, I think this is just such an exciting opportunity both to kind of hear from you, Lauren, and kind of understand your personal journey,

which you've basically taken on as your life's mission. And then obviously Richard to, to, to have you back on, uh, and, and kind of, I don't know, I think bring people up to speed on what's, what's happened in the last couple of years. So thanks both of you for making time today. Thank you for having us. You know, I feel like long time listener, first time guest, very excited to be here. Long time listener as well. Yeah. I'm a, I hang on every word of most of the podcasts, especially, well, I had to listen to Tom Dayspring's podcast like 14 times. I'm still like need to listen to it on repeat. But Lauren, let's start with you. I mean, I want people to really get an understanding of your story. So I mean, when did you first become aware that there was something going on in your family that was robbing people of this precious thing called their mind?

Unfortunately, Alzheimer's has been a part of my life as long as I can have my own memory. My grandfather, my mom's dad, had Alzheimer's. My aunt has told me it seems like he showed symptoms maybe in his late 50s or early 60s. But he was in a nursing home, I think, from the time I was around 8 or 9, maybe 10. And he passed away when I was 12. But when you're young that age, to me, his memory issues were almost funny, right? Like he would take his teeth out of the table, and I thought was hysterical and he would, you know, repeat things. And again, like when you're little, that's funny. And I didn't have any concept of the fact that the reason he had to go into a

nursing home was because he was wandering and that my grandmother couldn't take care of him. And then after he passed away, my grandmother started showing signs of dementia. And, you know, she was struggling to take care of herself and clearly wasn't eating. But, you know, I was in high school. So, again, I wasn't really that aware of the situation and what was happening. But, you know, I was aware when they brought her from her home in South Florida up to where we were in Central Florida to put her in a facility. in South Florida up to where we were in Central Florida to put her in a facility, you know, and how she was curled over in the seat, sleeping and not aware when I was showing her how I could drive for the first time and how she eventually stopped being able to walk or talk or feed herself.

And my senior year, I would go visit her every Friday after school and, you know, a few other days during the week. But, you know, when she spent the last year of her life curled up in a bed, obviously not talking or being able to care for herself in any way at all. It was a lot at 18, but it was still, I was younger and it was my grandmother. You know, I think when you're young and you envision your grandparents as like, well, they're grandparents. They're, you know, this happens to them, even though, you know, I think my grandmother was 76 maybe. So then she passed away. And then at my college graduation, when I was 22, my mom was 52. She repeated a story a few times. And, you know, my mom, who was this incredibly

smart, vibrant woman who was aggressive about the things she wanted in her life. And she didn't take no for an answer type of woman. But throughout her life, she'd always say, when I get Alzheimer's, when I get Alzheimer's, and I would say, stop saying that. Don't say that. And then at my graduation, when she repeated the story a few times, I thought, oh God. But I didn't say anything, of course. And then over the next year or two, it became clear that this repetition was becoming a part of who she was. And she was losing control of, you know, her ability to teach and to, you know, do any number of things that someone who is fully functioning in a cognitive way could do.

Eventually, we encouraged my dad to take her to a doctor. And, you know, over the course of a year and a half or so, we got as, you know, as much as a diagnosis as one could get at that time. You're just out of college and you're being confronted with the idea that your mom is not even in her mid fifties yet. And she's already in the early stages of Alzheimer's disease, something that's already prematurely taken her parents. I'm guessing it's now sort of setting in that there's something going on in your family, right? Yeah. I mean, there was a lot of denial,

I would say, a lot of fear, a lot of anger, and of course, a lot of depression. And I think what was really hard about it at the time was my mom wouldn't let us talk about it. And, you know, at this point, I can only imagine what her identity felt like as a daughter of Alzheimer's herself, what was driving her at this point. But to me, things were really starting to become clear in a really scary way at that point. I didn't talk to anyone about it because I didn't, I think, you know, when you talk about something, it seems real all of a sudden it's really happening. Even your father? Oh God, especially not my dad. Cause my dad was the most in denial about any of us. You know,

my dad, you know, my parents had, my parents had an amazing marriage and they were best friends and partners. And he admired my mom for her brain and for how smart she was and how passionate she was about what she did and how hard she worked. And so, yeah, he was the last one I think to come around. But eventually a few months after Seth and I started dating, actually my parents came out to visit. This was in 2005 to meet him and came out for my birthday. And when I dropped them off at the airport and I came back to Seth's apartment, it was the first time I'd said it out loud that I was afraid my mom was developing Alzheimer's. And it was the first time I cried about it. And he was like, no, no, she's fine. No, it's fine. And I'm like, you don't know her. You don't know how the person you met this weekend is different than who she was. And, you know, it was, I guess, around two years from that point

of going to visit and she'd be worse. It was clear, you know, at some point she shouldn't be driving. Eventually her school decided she shouldn't be in a traditional classroom anymore and took her out of that classroom. It was just who she was, was fading away and changing right in front of her eyes. She couldn't have these long conversations anymore. She again would repeat herself. She would call with the same thing over and over again. And it was devastating. I was in a very dark place at the time. Do you have any sense that she was aware of some of these things? For example, the idea that she could no longer teach her classes and to have that taken away from her by her peers, did that register with her what was happening and why?

Did that register with her what was happening and why? Yeah, you know, I never, I didn't have that direct conversation with her about it. I'm sure my dad did. I think she took that stuff in stride probably to act like a strong independent person for us. But when she eventually had to retire, I know she wasn't thrilled about it, but she was at a point where cognitively she wasn't at full function anymore. And so it became a bit easier to change her life in a way where she didn't question it, which is, you know, really sad to think about. But I think it was, I had one conversation with her early on. I read in Teen Magazine, if there's ever something

difficult you want to talk to your parents about, do it in the car because the drive will eventually end. And so the awkward conversation will naturally end. So I remember one time I was home in Florida and I was visiting them. It might've been around the time she was forced to retire and we were driving to Target. And I asked her if she was scared about getting Alzheimer's and she told me that she wasn't scared for her she was scared for me and my brother and my dad because I think she got that at some point she may not know what's happening and that the weight would be on us I think she knew that because of what happened with her dad and her mom. And I can only imagine how terrifying that was for her. But I, you know, I can't understand where she was at that point, cognitively or emotionally even, to really know the fear there.

So you mentioned that this is around the time when, I mean, it's now hitting you with the full force. Yeah. And I assume it's much less, or maybe somewhat, but probably less about what the implications are for you and much more about the loss of her. Yeah, which of course, you know, I was in my early 20s, so that was only about me. I was at a point in my life where I was just starting to become friends with her.

She had, I'm getting a little emotional. She had come out to visit. I moved to LA in January of 2004 and she came out to visit in March of 2004 during her spring break. And we had such a great time being, you know, I was 22, but you know, a grownup. And we went to dinner, just the two of us,

like as grownups and like drank wine. And like, she wasn't a big drinker. She would drink a Seabreeze, I remember. And like it felt like I was reaching that point where she was my friend, which I think, you know, now I have so many girlfriends who their moms are their best friends. And I instantly felt like that was being taken away from me and was so angry about it and so jealous of all my friends who were having those relationships with their moms and felt so hopeless. You know, I would go online and I would just search like cure for Alzheimer's, treatment for 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 going to do something, I'm going to do it, you know? And like, no, there got to be there. I know I can find it. Like, I'm the kind of person who's like, if I'm going to do something, I'm going to do it, you know? And like, no, there's something out there. I can find something for her. And there was nothing. Like, there was nothing. And so it was a really scary, hard time where I felt like I could do nothing. And that this train had left the station for my mom and that was it.

So I want to give you a chance to just sort of catch your breath a bit. And Richard, I want to sort of ask you a couple of questions right now, not necessarily specifically about Lauren's mom, because I want to come to that in some detail later when you actually, when we get to the part of the story where you and Lauren meet. But I want to just ask you a broader question here, which is help a listener understand the context of this type of Alzheimer's disease. And by this type, I mean one that is so clearly familial and also so early in onset. How do you think about that as a neurologist? What's going through your mind as you think about this type of a case in terms of genetic predisposition? Let's just start

with the genetics of this. Sure. So I first have to start with just, I hate this disease. I just like hate it. I hate hearing stories. Now you're going to make me cry, Lauren. I'm on a podcast. Come on. I'm on record. Well, no one can see us, so it's fine. Okay, good. Perfect. So I just hate this disease so much because it's so insidious. It's so nasty. It's so just, it just, it robs not just the, I mean, it robs the person of who they are, but it robs the whole family. I mean, just like you just said, it's like it robbed you of like the good years, like the friendship years. And that's just, so I hate this disease. I hate to say it, but most doctors don't know that still. You know, the new diagnostic criteria have been out now for about a decade.

But, you know, when I hear at 52, I say, oh my gosh, what was happening in her 30s? What was happening in her 30s? Like, why? Why is this happening? And then I hear the family history and I hear, wow, her mom and her dad. Why? Why is this happening? And Lauren, we have some small world coincidences, which we learned about later, but like my brother, he's a neurologist, he's

older than me. He took care of another one of your family members like on another. So like, why? Why is this? And of course, the first thing you think about is genetic. And then you think about, well, is this early onset? What is early onset? I think most people think about Alzheimer's disease as an older person's disease, greater than 70, 72, 74. What's the average age? But there's a small, tiny sliver, a small, small group that I would qualify as having early onset Alzheimer's disease due to a genetic reason where the person usually gets Alzheimer's in their 40s or 50s.

But Lauren, your family was different and we'll talk about this later. But when I hear a family history like this, I say, well, why do certain people in one family get it later and the other people in the family get it earlier? This is actually earlier onset Alzheimer's and I maybe made that up, but what is it?

This person should have been affected in the later years, and something is fast-forwarding. Something is, there's like a one plus one equals three here. There's like a mishmash of things that just, like, the first thing I think about is why is this happening? And number one, I say, okay, genetics. There's got to be some genetic something. And then number two is, okay, then I think about, well, could it be lifestyle? Could it be an exposure to something?

Could it be head trauma? Could it be uncontrolled diabetes, high blood pressure, cholesterol? These are all things that just synergize together to potentially make a late onset Alzheimer's case start earlier. So these are some of the things like detective work things that I think about. But no, it's not typical. What genes do you think about, Richard? What are the suite of genes? I mean, there's the obvious ones, ApoE4, but there are other genes that could be implicated in early cases. Can you say a little bit about those? Sure. So there's a typical early onset genes. There's really only three, presenilin 1,

presenilin 2, and amyloid precursor protein gene mutation. I can count on my two hands how many patients I've seen with that. I've seen over 1,500 patients easily, probably close to 2,000 patients over the last 15 plus years. Literally two hands, it's all I got. Lauren, you actually introduced me to one, an amazing, amazing person, great individual and someone that I, she may have that gene, but I will not say that she will get Alzheimer's. So, so for the first time in my career, I've, I'd not only, we not only figured out that someone has an early onset gene, which means you're going to get Alzheimer's, but just wait, our field is making a lot of progress. So, you know, these three genes are just so rare. That's number one. Most people that have earlier onset Alzheimer's have a milieu of things. So I would

call it polygenic risk. So APOE, APOE4, the variant APO4, is the most common genetic risk factor for Alzheimer's disease. Now, the difference between ApoE4, having one variant or two, I'll explain that in a second, means if you get the E4, it doesn't mean you're going to get Alzheimer's. It just increases your risk. If you get presenilin 1, presenilin 2, or amyloid precursor protein gene mutation, sorry for the long words there. If you get those genes, you get Alzheimer's. That's what the books say, except in that one person that you introduced me to, Lauren. We got time. She's in her 20s. We're going to get this up for her. And those, Richard, really represent far less than 1% of the total cases are made up of APP,

PSEN1, PSEN2. For what it's worth, I've never actually seen one. For me, those only exist in the literature. The interesting aside, by the way, is there's some people speculate that the index case of Alzheimer's disease was actually one of those. And some of our understanding of this disease may be incorrect as a result of that, but we'll kick that to another discussion. So when you meet a person like Lauren, you're not necessarily thinking one of those three genes. You were just thinking some aggressive combination of other things. Yep. And it's epigenetics would be the word that I think about. So the term epigenetics encompasses a person's genetics plus the environmental impact, the milieu of what a person does in their lifestyle or behavior or what they were exposed to, for example, whether it was a virus or if it was a traumatic something or if it was something that triggered the gene to work in one way or another. And the term polygenic risk means that there are multiple genes that work together.

Now, some genes can increase risk and some genes actually decrease risk. So the future of Alzheimer's disease, well, I believe the future of Alzheimer's disease is based in precision medicine, using these types of genetic underpinnings, understanding all the individual genes that impact a person's risk, figuring out what they are, figuring out what their biological function is, figuring out why it puts a person's risk, figuring out what they are, figuring out what their biological function is, figuring out why it puts a person down the path towards Alzheimer's, and then telling that person to do A, B, C, X, Y, and Z to get them off the path towards Alzheimer's. That's the future of Alzheimer's. And I think in a lot of ways, the future is now. But APOE is by far the most well

understood, most well-researched. Every patient that walks through our doors gets an ApoE test. You know, there are commercial, like anyone can basically find out what their ApoE status is. Just for the listener out there, you get one from mom and one from dad, either an ApoE 2, a 3, or a 4. It's called an allele or a variant. A lot of people call it a mutation, but it's not a mutation. an allele or a variant. A lot of people call it a mutation, but it's not a mutation.

So you get a two, a three, or four from mom or dad, and a four increases risk a little bit. A three is neutral, and a two actually is protective. So if someone comes in as a APOE33, that's a pretty neutral risk, kind of boring, no big deal. APOE23, okay, maybe they have some protection. And one four, APOE three four, for example, increases risk a little bit. And then two fours, APOE four fours, increases risk more so. But again, genes are not our destiny. We can absolutely win the tug of war against our genes. And, you know, four fours, I have dozens of patients in my practice that I absolutely think that they are not going to get Alzheimer's disease. They're going to be able to do some things to delay it. They also have other genes to protect them. So without getting too detailed, APOE4 is important. We personalize care. If someone has a four, we're going to tell them to do certain things. Someone doesn't have a four, we're going to do

other things for them because their other things are preferentially effective. But this polygenic risk is what I'm thinking. So when I hear about Lauren's mom, like, what is it? What are her E4s? Sure. But what else? There's got to be something else. The devil is in the details there. Richard, I want to go back to Lauren to continue the story. Before I do, can you explain for folks that want a bit more of an understanding, what is it about having the E4 variant relative to the E3 variant that increases risk? So the gene codes for a protein that differs in what way from what we call the wild type or the E3 variant. So I guess how I would answer that is starting by basic, what does ApoE mean? Apo is

apolipoprotein. That means something related to cholesterol, I guess. People actually who get the gene tested in our practice actually get it through a cardiovascular disease prevention panel. Peter, you and I have used the same labs. You maybe focus more on cardiovascular disease prevention. I focus more on Alzheimer's disease risk reduction and prevention. But it's really a cardiovascular risk gene just as much as it is an Alzheimer's risk gene. So the way that I think about APOE4 is it increases vascular risk. It increases the likelihood of a bad pathologic protein called amyloid. It's a sticky stuff that builds up in the brain of a person with Alzheimer's. And people with this gene are more likely to have accelerated deposition or accelerated

accumulation of this amyloid protein through a, what I would call just in a basic sense, a cholesterol-like, vascular-like pathway. There's a ton more I can talk about it. But once you've seen one person with Alzheimer's, you've seen one person with Alzheimer's. And different people can take different roads to Alzheimer's disease. And the APOE4 road is actually something I kind of understand. I kind of get it. I feel good about it.

I know that may sound callous or strange. But I know what I'm up against. Like, okay, great. We can do lifestyle things. We can manage cholesterol in a certain way. We can do all these different things. And I know certain things that work. and I know what I'm up against. It's the person that actually doesn't have the E4 that I'm like, wow, they're either spared

or they have another gene lurking. How do I find it? And what the heck do I do about it? So E4 doesn't bother me. And I, I'm, I feel relieved sometimes when we find it in a person. All right. Well, I think we'll, we'll talk a little bit more about this, but Lauren, I want to kind of hear more from your story. So as you're now kind of coming to grips with the fact that your mom is slowly slipping away and you're also realizing that unlike, oh, if my mom has premature heart disease for which there's no shortage of treatments, you're realizing actually your ability to access the best in medical care isn't really going to do much. What's the temporal course of her progression? So as we get, let's say, fast forward to when you and Seth get married, which is 10 years ago, how is she at that point,

which is still probably putting her in her late 50s, right? She had just turned 60. So at that point, she could still walk. There were moments where she knew us. No, she knew us. She knew that we were her family and that we were her loved ones. But she was, at that point, being fully cared for by my father. But she was, you know, at that point being fully cared for by my father at that point, you know, but she could still dress herself and bathe herself and use the restroom. But, you know, planning, I would say planning my wedding was, was a real emotional turning point for me because it was, you know, I, I, I always was the kind of, you know, girl who like envisioned my wedding and it would be this thing

and then my mom and I would do it together. And that is just not what happened at all to the point where, you know, I couldn't even have her there when I was getting ready because she would just be wandering. And my dad had to take her to a separate hair appointment because it would just, would be too disruptive to get everything together to have her there. But, you know, when she walked in, I remember that morning, I'll back up a bit to say we had a bit of a weekend, our wedding, and Friday night was a small thing and Saturday and Saturday night there was a dinner and it was not good. You know, we had taken my mom from her home, which for an Alzheimer's

patient, for anyone with dementia is difficult to take someone out of their space, their routine, where they know everything and they are familiar with their world. So that of course had put her in a place where I think she was probably feeling very scared because she didn't understand where she was or what was happening. And at our rehearsal dinner the night before, I remember her telling me she just wanted to go home, which was, you know, really hard to handle. But then miraculously, the day of, like she walked in and she called me the bride and she knew that I was the bride and that I think she knew that I was her daughter. But she knew she felt proud. She knew she felt love. And I have an amazing photo of her like looking at me and

holding my hand. And it's just, she knows that, you know, there's a connection there, but it wasn't, you know, it wasn't the moment that I had certainly dreamed of. And I feel like it was my dad and I that walked her down the aisle instead of him and her walking me down the aisle. And, you know, normally in Jewish weddings, the family stands up next to the bride and groom, and we didn't do that. We had them sitting next to us because we knew my mom couldn't do that. So at that point, she was, you know, she wasn't teaching anymore. That was a few years earlier that had ended. So it was, for me, it was a really hard thing. But luckily, she rose to the occasion that day, which, you know, it's interesting throughout this journey with her. You know, I think people

that don't understand the disease, trying to find some sort of lightness and hope would always be like, but she must have good days sometimes. She must remember you sometimes. Does she remember you sometimes? And I would always be like, no, it's gone. Like, that's gone. It's not like sometimes you remember like, oh, I use my legs for walking. Like, once that's gone, that's gone. But for whatever reason, the day of my actual wedding, I will say she was as there as anyone could be in her state. And that was an amazing thing. But overall, it was only a few months after that that we encouraged my parents to move out to Los Angeles because, you know, my dad, it was clear that it was killing, it was going to kill my dad

before it killed her. The stress of taking care of her. He always talks about the plane ride home from our wedding was like the worst five hours of his life because she had had an accident in her seat on the airplane and was acting out and was screaming and they had to get help to get off the plane when they landed back in Florida. And it was a, you know, a pretty horrific time. acting out and was screaming and they had to get help to get off the plane when they landed back in Florida. And it was a, you know, a pretty horrific time. I mean, these are some of the things that we're going to talk a lot about hilarity for charity and why the focus is on

the family, which I think is part of why I'm so excited about it. And you can ask me a hundred times to do something for it and I'll always say yes. So you always apologize when you ask me. Don't say that. Don't say that. But, but, but I really, I'm really so fond of organizations that take that step and appreciate what is being done for the family. Too often people think the only way to make a difference is to fund research. And clearly that's important, but it's too easy to ignore that while we're waiting for these things to happen, people need help in caring for this. And I suppose there's no disease where that's more true than this one. Absolutely. Richard, can you just spend a minute kind of explaining what it is about the deposition of these plaques, the accumulation of the tau,

why does it lead to this largely predictable set of symptoms that don't just involve almost a folksy, funny loss of memory, right? But also at some of this deeper level of this, what I suspect is fear and confusion on some level, right? Like why would she be upset on the airplane? Well, I'm guessing on some level, there's a sense of fear, right? There's something is wrong. Why is she not able to control her bowel or bladder? Like how is this disease wreaking so much havoc on the central nervous system, Richard? Yeah. So there's actually a couple who I believe were both pathologists, Brock and Brock, B-R-A-K. And what they did was they kind of came up with the Brock staging of pathology where the amyloid protein and then the pathology of Alzheimer's spreads over different parts of the

brain. And when I was in medical school, I was taught that Alzheimer's disease is a progressive neurological disease characterized by changes in short-term memory. And then later on, that includes changes in some behaviors, neuropsychiatric disease, changes in sleep. And then the person, as the pathology spreads, they can no longer take care of themselves. What we really now understand about Alzheimer's is it's a much more heterogeneous disease, meaning wherever the pathology goes, those are the symptoms that manifest. So there are newer forms of Alzheimer's, and they're newer because they're now published in the literature, but we've seen this for decades. There's one newer form that has something called a disexecutive syndrome. Well, what does that mean? Executive function is higher order processing, judgment, planning. You find a wallet on the floor, what do you do with it? wallet on the floor, what do you do with it? Peter would take the money out, put the money in his pocket, throw the wallet back on the floor. Lauren, she's very empathetic and compassionate.

She'd look at the license. She'd say, oh, I'm going to go find this guy. I'm going to go to the ends of the earth to find this person's wallet. So that's executive function. Maybe. Depends. Depends on how much is in there. Exactly. That's one form of Alzheimer's. Another form of Alzheimer's is part, P-A-R-T, primary age-related tauopathy. So we've talked about amyloid, but what about tau? Tau's another protein. And there's tau and amyloid and neurofibrillary tangles. And then there's glucose hypometabolism, meaning the glucose, the sugar in the brain, it's just not being efficiently able to be used to power the brain cells. So depending on where the problem is, you have different manifestations, cognitive symptoms, I guess. And part, for example, is primary age-related telepathy. Again, one more time, it's related to age. So it's usually in older people, easily

70s, more likely 80s and 90s. And it's specifically short-term memory. And it's specifically because that pathology is localized to the memory centers in the brain, the hippocampus, for example. But that person can still have good executive function. The frontal lobes, the front part of the brain is working. So it just depends. It depends. For example, when the pathology, when the bad stuff goes to the back part of the brain, that's where the visual fibers are. So the eyes are in the front, but they have visual projections that go to the back. You interpret images. Well, when someone can't interpret images, they get confused. They act funny. They may be weird. They may be, you know, confused, but it's not exactly a memory problem. It's a visual perception problem.

So I don't want to be cheeky, but like- I mean, Richard, no, no, this is very interesting. And I've never really thought of it this way, but as you probably are aware, we don't really think of cancer as one disease anymore, right? I mean, it's been a while that nobody's thought of cancer as one disease. So breast cancer and colon cancer have very little in common. I mean, about the only thing they have in common is unregulated cell growth, but thereafter they're very different diseases, not just in the ability to impact a different organ. And it sounds like what you're saying is Alzheimer's is not really one disease. It's kind of an umbrella term that encompasses many different diseases of the brain

that have some common features in the way that cancers all cancers have some common features that you know cells don't respond to normal signaling but this notion that someone could have a form of alzheimer's that largely spares the frontal cortex and therefore preserves some higher order functioning versus another person that has something that's not. I mean, listening to the story of Lauren's mom, just hearing what we've heard so far, how would you think about the etiology or the insult? Well, I'll try not to bias my answer because I know a lot about Lauren's mom and Lauren's whole family. But if I just took for face value what Lauren said, that symptoms began with little repeating of stories and memory glitches around 52 to 54, to where she had to

have then a modified work schedule to then six years later, she's having trouble caring for herself, maybe not recognizing her daughter, and then having emotional, behavioral, psychiatric components. I mean, that sounds like Alzheimer's disease. That sounds like progressive short-term memory loss plus behavior changes plus other things. So it sounds like she started in the mild cognitive impairment phase with the symptoms. So there's three phases of Alzheimer's, three stages. Maybe we should take a step back for listeners. The first stage is actually the preclinical phase, the pre-symptomatic phase where Alzheimer's disease has started in the brain, but there

are no symptoms yet, no clinically apparent symptoms. Believe it or not, there are 46 million Americans with Alzheimer's disease in their brain right now, but no symptoms. That's crazy. I've never heard that before, that number. That's wow. Yeah. I try to keep that close to my vest because- And how do we know that, Richard? That's what the studies say. I don't know. You're the critical appraiser of studies. I'll have to send you the study and you can tear it apart, Peter. You're going to bring this one to Journal Club next month. What a great idea.

I love those journal clubs. That sounds like the nerdiest club of all time. Oh, my. And we've discussed you. It is nerdy. It is pretty freaking nerdy. And we record it and then we watch it and we... Oh my God. Yeah. I was captain of my math team at Comac High School. Well, there you go. Nevermind. It sounds really cool then.

Thank you. Thank you. Also the alma mater of Lauren's mom, high five, go Comac, and Lauren's uncle and some others. Anyway, so this preclinical pre-symptomatic phase is by far the most important phase, I think, well, maybe to focus on because that would be prevention of Alzheimer's. You can call it either treating preclinical Alzheimer's or secondary prevention of Alzheimer's because you're trying to prevent the dementia from happening. So stage one is preclinical Alzheimer's. Stage two is mild cognitive impairment due to Alzheimer's where there are enough memory glitches and other changes to where it's noticeable. It's greater than a standard deviation and a half below the norm, but the person can still

take care of themselves. So I think Lauren, when your mom started having symptoms, she was easily in the borderline preclinical to MCI stage. And then people have, you know, roughly between a 12 and 16% per year, depending on what study you read, chance of converting from MCI, mild cognitive impairment due to Alzheimer's to dementia due to Alzheimer's. And the only difference is, is they still have the symptoms, they're just worse, and they can no longer take care of themselves. So, you know, Lauren, many people would be very pleased and thankful that if symptoms started at 52, and she was able to attend your wedding at 60. I mean, that's horrible, but better than it could have been in the grand scheme of things. At least she was there, you know? I have friends who unfortunately had weddings without parents there because they had lost them already. Yeah, absolutely. So these are the stages.

Okay. It's a staggering number. And whether it's 46 million or 36 million or whatever the number is, you know, it's not surprising in the sense that if, when you look at how many people are pre-diabetic and you think about how that is one of the pathways to Alzheimer's disease, sort of the energy dependent pathway, it's very plausible, especially when you consider the other pathways. Richard, one thing I want to park with you to come back to is some thinking around how many different variants of the disease there are, right? Sort of the lipid variant of the disease, the toxin variant, the potentially an infectious variant, if one such exists. So maybe we'll, I'll let you think about that for a minute. So Lauren, I want to talk about how you made your way to Richard, because that's how you and I met. You

and I met through Richard, but I want to know how you and Richard met. Sure. So, okay, I'll try to keep this somewhat brief. I feel like it might be long. This is a hilarious story. I'm sorry. I remember this like a video in my mind, but anyway, I don't want to interrupt. So in 2011, it was the year that I got married. It was the year I shot for a good time call. And it was the first year that we planned the first Hilarity for Charity event, which was January of 2012. So 2011 was a pivotal year for me. Up until that point, like I said, I had been really dark and depressed and I had been trying to work and I'm a screenwriter and I was writing, but I just spent a lot of time just being pretty dark and pretty upset. And then a friend came to me and was like, let's throw an event and raise money for Alzheimer's. And I was like, no. But then he wore me down, thank God. And

we did. And so in January of 2012, we threw our first variety show to raise money for the Alzheimer's Association. And that was an incredible event. We raised a few hundred thousand dollars, but the most incredible part of that was that we were contacted by young people who felt seen for the first time because they were seeing me in my, you know, late twenties and my husband in his late twenties talk about Alzheimer's, which, you know, even for me up until that point, every image of Alzheimer's I had seen was of someone who was old and gray and not at all related to me in any way that I could understand. So we felt like we had an opportunity to continue talking and to continue hopefully gathering people and helping them feel like they too had a place in this disease, which is considered a disease for old people.

And so that's when we kind of decided to form our own little organization, which was a fund within the Alzheimer's Association for many years in 2017, became our own 501c3. But during that time, of course, we became Alzheimer's advocates. And I met many smart people and doctors and scientists and other advocates who were doing all sorts of incredible work. We became friendly with Maria Shriver, who of course has always used her platform to raise awareness about Alzheimer's and is so incredible. And I had really sort of gotten to know the Alzheimer's community a bit. So then my uncle, who is my mom's brother, who was five years older than her, was starting to

show symptoms. Now, my uncle, who was an athlete his whole life, he was, and his later life started when he was, I don't know, I guess maybe in his 40s, riding a bike and was a obsessive bike rider. And he was in great shape and he's a big, strong, muscular guy. And we'll get into some of the other things why Alzheimer's happened in my mom earlier than it did with him, but he started showing symptoms. And I wasn't allowed to talk about that publicly at the time. Unfortunately, he passed away in March this year, only a month after my mom and his family, my aunt and my cousins, have fortunately now given permission to tell his story so it can potentially help. So he was starting to show symptoms and they were on

the East Coast. So they came to me and said, what do we do? How do we, what do we do at this point? And at this point, by the way, my mom was very advanced at this point. They were out here. This was, I don't know what Richard, it was 2014, 15, 16, even 17. And basically I'd reach out to a doctor that I knew and was like, you know, my uncle's on the East coast. I want to get him into the best of the best. Who is it? And this person recommended Richard. The best of the best looking, I hope. The best looking Alzheimer's doctor there could, yes, exactly. Thankfully, this is a podcast. That's what my uncle was hoping for, was the best looking Alzheimer's doctor. The one with the best phones, I think is what it was.

Definitely the best phone. Well, I mean, certainly I've listened to that episode where we talk about, where you guys talked about Richard's phones. Oh God, he's showing one. Everyone's missing it. There's rhinestones. There's a horse on the back at the top. Are those not rhinestones? Diamonds. Hello. Oh, diamonds. Excuse me. Those are diamonds. It's a diamond pillow. Come on. Anyway, so gave me Richard's name and I went on his website and I found his email. It's direct email. Because of course, again, I'm not the kind of person who's like, I'm going to be polite and

keep my mouth shut and follow the rules to get to where I need to go. Like I'm going to do what I got to do. So, so I found his like direct email address and was like, hi, here's who I am. This is what I've done. My uncle has Alzheimer's and needs your help. And so he wrote me back right away. And then of course, then we connected that he was from Comac and that my mom and my uncle had gone to the same high school as Richard which is you know what a small world he of course got my my uncle in there right away and they went on the journey that they went on so then I was in LA and then I once I connected them I came to New York you know a few months later or something and I you know said I'm coming to New York I want to come see the clinic come meet you and And then of course, I'm seeing the clinic and talking to him. And I was like,

I want in. I want to be a patient. I want to prevent Alzheimer's. Let me in, help my brain. You literally, I don't know how to do this, but shot out your arm and said, take my blood now, let's do it. And literally, literally you walked into the clinic. We like literally stuck a needle, you signed a consent form. And then like, it was the quickest, most rapid Alzheimer's prevention consult in the history of our program. So lucky for me. Lucky for me. What kind of shape was your uncle in at that point in time? I'd actually didn't realize this part of the story that, that the initial connection with Richard was actually a consultation for your uncle. Is that presumably because at that point you felt your mom was just

advanced enough that it... Yeah. No, at that point my mom was, she was fully bedridden. I'm pretty sure at that point getting everything fed to her, fully cared for. There was, her train had long left the station. So your mom at that point would have been in her early 60s, I guess. And your uncle is a little older, did you say? Yeah. So he's five years older than her. And he was, you know, I would say in that, that MCI, in that mild cognitive impairment space, right, Richard? Or even almost a little before that, it was, he was a very functional guy. I, you know, with both my mom and my uncle, and, you know, and you guys can speak to this more about other people, they could both like rise to the occasion in a way. And so, you know, I knew that what my aunt was seeing with my uncle

was different than what I saw. That he could somehow dig deep and put on a show, if you will, and act like he was still in control. But there were little things, little hints that that wasn't happening. Whereas my mom, we were far past that point. Richard, let's talk a little bit about now the beginning you go down this path of kind of being a detective. So you're never going to get to meet the parents, the grandparents in this case, but the parents of your first patient. But you know enough about their story.

You're meeting Lauren's uncle. You know about Lauren's mom, though you haven't met her. How are you now starting to piece together this family? First, for the standpoint of trying to understand if anything can be done to help Lauren's uncle, but ultimately to really figure out what to do to help Lauren and her brother. Yeah, this is detective work. This is a spelunking mission down the deepest, darkest cave with no light. And instead of a pickaxe, I don't know, maybe with a plastic fork and knife. Let me take a step back.

Lauren, before I met your mom, I saw a video of your mom, which kind of changed things for me. This was a video of a movie, actually, that you can maybe talk about you'd worked on. And I had actually watched, I don't know if it was a clip online or maybe it was something you sent me. And I had actually watched, I don't know if it was a clip online or maybe it was something you sent me. And seeing the video of your mom from the, I don't know, you can tell me eight something years before the present, that was so instructive. I mean, I don't know how to explain this, but like I'm not psychic or anything like that, but I trust my gut. And when I see people, sometimes this is going to sound weird, but I think it's true. I

see genes. I see, I don't know, my gut just feels something. And I can, I don't know if it's just because I've seen the pattern so many times there's genotype, meaning the genes and the phenotype, which is the, you know, the physical real world manifestations of genes. But there was something about your mom, her behavior, her mannerisms, her, I don't know, her, her shape of her face. I mean, I don't want to get too like kooky and weird. But like, there was something that my gut or my subconscious just saw. And your mom was a little confusing to me, because I saw something consistent with Alzheimer's, but there was, you know, my gut said that there's something else. This is just strange. This is not clearly Alzheimer's. This could be something else. And then when I talked to you, Lauren, about,

and really I talked to, you know, your aunt and your uncle, and I learned all the intricate details, Lauren, about, and really I talked to your aunt and your uncle, and I learned all the intricate details. I just learned that this was more complicated than Alzheimer's. Maybe there's Alzheimer's on one side, but there's Alzheimer's plus something else on another. And I don't know if I ever told you this story, but your uncle brought in his Comac High School yearbook. I don't know if we ever talked about that. Yeah. And then I don't know. And then when I was actually at your place in LA, I think your dad found your mom's Comac High School graduation yearbook. And this is going to sound even kookier, but you can tell in the handwriting.

Your grandparents signed your mom's yearbook and your uncle's yearbook. And they were five years apart. And I could tell in the handwriting. There's research to support this, but you could just tell by the change in the handwriting over the years and just the, you know, like Alzheimer's is a neurological disease. There's other neurological conditions like Parkinson's disease, dementia with Lewy bodies. And in Parkinson's disease, when you start writing, as you write more and more, the writing gets smaller and there's like

a shaky nature to the writing. This is really hard to explain. I don't know, something about the handwriting was just different. And about the word choice, like, you know, there was a study that looked at nuns and the nuns wrote their autobiographical sketches in like their late teens. And then depending on analysis of their autobiographies that they wrote, you could predict which nuns were going to get dementia 60 years later. So there's a lot. I believe Alzheimer's is a life course disease. Literally, people with the 8.4 variant, one or two copies, have smaller brains when they're

born. So I know we say Alzheimer's starts 20 to 30 years before in the brain. Well, that may be because of the biomarkers of Alzheimer's that we can detect are noticeable then. But I believe Alzheimer's is a life course disease. And sorry for the long story here, but I learned a lot about your family from the clues that I got from those videos and the handwriting samples of your grandparents. So I guess I would start with that. And then I think I just said earlier, but my brother completely randomly cared for another one of your family.

My great uncle. Your great uncle. I mean, just completely strange and bizarre. But I actually talked to my brother about him. And we just start to put the clues together. So first we do the detective work and kind of the investigative part. And then we just do a clinical history. We ask about all sorts of things from medical history to what are the risk factors for a parent. We did some genetic testing, which was critical. So we just try to put together lots of different pieces to the puzzle and do as best as we can with the information we have to personalize or individualize a person's care.

So Richard and Lauren, I don't know if you, and if you don't, if you don't have permission to talk about Lauren's uncle's case, then we don't need to talk about it at all. But if we do, so I'm curious, Richard, you have this clinical history that is, at least for me, would be very overwhelming. I realized that a lot of people walk into your clinic with stories as tragic and as complicated as this, but what are the things you most want to see come back out of that blood work? Once you have a very detailed clinical history, at this point, you've probably established that brother and sister are on the same pathway, though sister is moving much quicker in Lauren's mom versus uncle, the APOE genotype comes back. What does it show and what does that tell you? All I can say is my brain kept asking why, why, why, why, why? Why did Lauren's mom have symptoms

at 52, but Lauren's uncle, five years older, started having symptoms in his late 60s. Or maybe it was early 70s. Why, why, why, why, why? Why was there this 15-something-year-old? What is going on here? So the first thing I think about is, and this is also because of a genotype, phenotype thing. I felt or smelled or whatever it was that there was some E4 something, ApoE4 something. Lauren, when I saw that video, your mom, I don't know, again, this is weird, but your mom was E4.

I actually thought she was E44. I'll just be frank. She was 44. Yeah. Well, I... Yeah. Exactly. I mean, from the video. Yeah. And again, this is weird talking about when it's being recorded, but like, I don't know. I've seen a lot of patients.

So I can just, you know, I can, I don't know, something subconscious. When your uncle walked in, 4-4. But just to be clear, Richard, did you think that Lauren's mom was 4-4 because of how early it affected her or because of the fact that she had such a clear history of disease on both sides of the family? of the fact that she had such a clear history of disease on both sides of the family? Honestly, I guess what I'm saying now is I saw her on video and the phenotype that I saw, her body makeup, her habitus, her structure, again, sounds weird, but I saw 4-4. I felt 4-4.

Plus, of course, in my subconscious mind, I knew she got it early. I knew the parents, I knew her parents, Lauren's grandparents got it later. So it just fit. And also big, big, big, you heard it here first. No, this is common knowledge, I hope, or it should be common knowledge. Women with the E4 variant, much higher risk. I mean, women with E4 are very different than men with E4. And I think most people just completely are not aware of that. And then Lauren, I forget when this came up, but I don't know if I asked you this, but I said, when did your mom go through menopause?

And then you told me about the hysterectomy and they took the ovaries out. And I said, oh my goodness, my goodness. I said, wow, E4-4, even though I don't think we had the genetics at the time, or maybe we did, plus the, you know, surgical menopause, taking out, you know, immediate withdrawal of estrogen and taking out the ovaries. Back then we had no idea relationship to Alzheimer's or anything else. Plus she's a woman and there's a synergistic, you know, impact on risk. So it kind of was the perfect storm, but still a 4-4 plus a woman, plus a hysterectomy, there had to have been something else. And then we went on a spelunking mission to find

something else. Lauren, how old was your mom when she had a hysterectomy? Was she in her forties, late forties? I want to say she was 46, maybe 47, but I'm pretty sure it was 46. All right. You've alluded to this just in passing a moment ago. I want you to expand on it a little bit. You basically created a little bit of a contrast between your uncle and your mom in terms of lifestyle, your uncle being exercising constantly. Tell us a little bit about your mom. Obviously you've spoken about her intellectually and you mentioned she didn't consume much alcohol. What other lifestyle factors do you know about her? Did she sleep well? Was she under a lot of stress? What was her diet like? How much did she

exercise? Did she smoke? Any other things that you can tell us? I mean, she never smoked. She told me once she tried to smoke a cigarette in high school and threw up and never did again. So that's why I never smoked a cigarette. But she did not exercise. We were a big sugar house who had dessert every night. She probably had cookies most nights after dinner. She used her brain every single day, but was she constantly learning new things? A little. She taught first grade for 15 years. And so, you know, sure, could she have been learning things? Yes. But was she recycling information that she'd already learned? Potentially. But I think, you know, knowing what I know now, she got almost no cardio exercise and she ate a lot of sugar. And combining those things with, you know, her family history, of course, and then,

of course, the hormonal issues that arose from her hysterectomy, you know, seemed to really put her on the path that she eventually went down. Do you know if she had any difficulty sleeping prior to that hysterectomy? I can only imagine afterwards it was devastating. Yeah. I mean, it's funny. She and my uncle and my grandfather were similar sleepers, I would say, in that they would fall asleep on the couch every night and then wake up super early. That's as much information that I got from her, but of course, less as I get older, but I'm the kind of person who loves to sleep and is very happy to sleep. Whereas like, she wasn't a big sleeper. She definitely, she definitely did herself no favors with her sleep habits, especially again, knowing what we know now, she did not use her sleep to help her brain

at all. I just want to comment one thing. So, and I talked to your dad about this at some point, your mom was not, you know, when you saw, when you looked at your mom in the 80s and 90s, your mom was not unhealthy by any means. She didn't- No, no. I don't want to paint the picture of her as being this disgustingly unhealthy person who didn't care about herself. It wasn't that. It's just she didn't make the effort that is needed that we know now to, as Richard said, to take control of the genes that she had been given. In prevention, in the prevention space in preventative medicine or preventative health, at least the way I think about it is there's normal and then there's optimal. You know,

your mom for the time, that was kind of the typical, you know, what I would call your mom now is, you know, maybe, maybe, you know, they heard of the term skinny fat, right. Skinny on the outside, fat on the inside, you know, and you're maybe, I don't know what your mom's waist circumference was in high school versus her waist circumference in her forties and fifties. But I, yeah, I can guarantee you it was larger based on, you know, my understanding of the pathology of this disease. And, but back then, that wasn't really talked about or thought about, you know, you know, in the eighties, it was like, you know, that was like when 10,000 steps came about,

you know, like who came up with 10,000, well, sorry, I know who came up with it, but I understand that there's some better than nothing and calculating, but 10,000 steps is like so antiquated. It's like, it's like, you know, literally the eighties compared to now we truly understand physical fitness and how to optimize physical performance. Your mom was not unlike most middle-aged women at the time. You know, and the difference between her and my uncle or even, you know, me and my brother is like, my mom was never an athlete. Like I was a gymnast growing up. My brother was a baseball player. My uncle ran track and then he got into cycling and was always a physically active person, whereas my mom was an intellectually active person. She read. Like I said, she was a great student. She loved to learn and then to

teach, but she didn't use her body in a way that perhaps could have at least delayed what her genes were leading her toward. When someone meets me at a cocktail party, or I think you asked me that question, Peter, what are the three things that you tell someone when they- Yes, that wasn't your podcast. That was. Yeah, and I refuse to answer it. I was out walking the dogs the other day and someone asked me the same question.

I'm like, well, but the number one thing by far is exercise and physical activity. But it's not just like, you know, going for a walk. It's, there's physical activity and then there's physical exercise. And the difference is key, cardiovascular and strength training. There's just so many degrees, high intensity interval training, specifically for this case, you know, high intensity interval training is probably the only thing that can move the needle in terms of certain aspects of cognitive function in people with the APOE4 variant. And no one knew any of that, even a few years ago, let alone a decade ago. So optimization of physical activity is key. And your uncle, just so we can paint the picture, your uncle was like, he was a machine. He was a beast, yeah.

He was ripped. I mean, he could put, I don't know, him and Peter next to each other, be close. I'm scrawny or whatever compared, but he was ripped. He just looked great. His leg muscles were like, oh my word. My goodness. And because of that, your metabolism is better, all these different things. Richard, was he 3-4 or 4-4? He was 4-4 also.

I see. Okay. So this is very interesting, right? Because until you have that information, you could say, well, maybe the reason everything came to him so much later is he was the three, four, his sister's the four, four, and that explains the 15 year gap. But to have them both be four, four, you're basically looking at gender inclusive of the removal of hormones, lifestyle factors. It's some, probably some combination of those things that's explaining it. Can you explain a little bit the gender issue?

Again, most people who follow the research will be very well aware that Alzheimer's disease disproportionately affects women. The answer that used to be thrown about was, well, that's because women live longer. Anybody who understands even first order mathematics will realize that the increase in expected lifespan of women does not fully explain that. So there must be something else. Do you think that it's the loss of hormones that explains the remainder of that gap? Or do you think it's even something beyond that? Yeah. So I would have answered that question just like you did, but the age thing, you know, even five, six, seven years ago. And then it was one day on some television, something where someone kept elbowing me, someone named Maria, our friend, Maria Shriver. It's like,

no, no, you got to figure it out. Why do women, no, no, no. Two out of every three brains of Alzheimer's are women's brains. And we don't know why. Isaacson got to figure it out. Why do women, no, no, no. Two out of every three brains of Alzheimer's are women's brains. And we don't know why. Isaacson, go figure it out. And I said, yes, ma'am, I'll go do it. I think I understand much better now. And in that category of likelihood is during the perimenopause transition, there are bioenergetic shifts in the brain that absolutely can predispose a woman to accelerated Alzheimer's pathology.

And we call it the window of opportunity. During the perimenopause transition, if we can intervene the right way at the right time in the right woman, I believe that we can negate a reasonable amount, if not much of, careful with my words, of the negative impact of this precipitous drop of estrogen, which I believe is neuroprotective. Again, the right type of estrogen, the right whatever. The natural estrogen, I believe, is protective. Whether we get into hormone replacement, that could be a different part of the conversation and which types and what this and what that. But the bioenergetic shifts during the perimenopause transition, why do people have perimenopause? What are the symptoms? They get hot flashes, right? Night sweats.

We can talk about that. Oh boy, night sweats. I don't know what you're talking about. No, not at all. Irritability, never. Never. So all of these different things. It's a brain disease. Perimenopause is a brain condition. Those are manifestations of the hormone withdrawal in the brain. And those are the symptoms that, you know, brain fog. Like I used to think, I'll just be very frank.

I was completely dead wrong. Like women that had perimenopause and they had this brain fog thing, maybe they're just not sleeping right. Maybe, well, no, they're not sleeping right. And their sleep is interrupted because of this bioenergetic shift. And heck yeah, you're going to have brain fog. And now we know what it looks like. I hate that term brain fog. It's so nonspecific. It's problems with processing speed and attention. And that's how I think of it. But perimenopause is a brain disease. So I think that's really important. And this bioenergetic I think of it. But perimenopause is a brain disease. So I think that's really important. And this bioenergetic shift is like, it's like, if you want to fast

forward brain aging, like in a woman, sorry, in a susceptible woman, because not all women are created equal, an E4 for a woman, a surgical menopause, meaning taking out the ovaries with the uterus, wow, that could do it. Now, I don't want to say this in all cases. It, again, depends on the individual person, but perimenopause transition is a huge, unrealized risk factor for progression to dementia in an Alzheimer's susceptible woman. And just be careful and listen to those words because just because you're going through perimenopause does not mean you're going to get Alzheimer's, but in susceptible people, it is. And I really believe that from a precision medicine perspective, we can intervene

with specific hormones in specific ways. Is it a patch? Is it a gel? Is it a, you know, all these different things. Do you need estrogen? What type of estrogen? From horses? From, you know, from natural? What about progesterone? When do we add it? And these are things. Do you need estrogen? What type of estrogen? From horses, from natural, what about progesterone? When do we add it? And these are things that I talk to an OBGYN every other week now. I'm a neurologist, what the heck? So I could talk about this for a long time, but just know that this hormone thing is real. That's where you think the bulk of it is then, Richard, is it's less about the age gap or the age advantage, like, you know, the sort of lifespan advantage women have. And you think it's the elephant in the room is this enormous hormonal shift. I think that's the most under-recognized

slash largest impact in a lot of women, but I have to take a step back and age is the number one risk factor for Alzheimer's. Women plus age. So a 65 year old woman with the APOE4, with at least one or two APOE4 variants, that's like the perfect storm. Plus you add in this, you know, the perimenopause transition. But you know, there's individual things when it comes to a woman's life, for example, there's more widows than widowers. And widowhood is a astronomically important risk factor for cognitive decline and dementia. Also women specifically with abdominal obesity, enlarged waist circumference, visceral fat, as the belly size gets larger, the memory center of the brain gets smaller. And we now know that in women specifically, women have a 39% increased risk of dementia when they have enlarged waist circumferences over a certain degree. And

they're impacted more so than men. When I think of a woman and I think of body composition, I'm really paying attention to body fat. And I'm not just paying attention, like weight, I don't care about. For women, I care about what's percent body fat and where is the fat? Is it visceral or is it otherwise? Cellulite on the thighs? I don't care.

Oh, thank God. Belly fat? Thank you. Thank you. Great. You don't have cellulite on your thighs. You're on the Atiyah Isaacson program. Thank goodness this is a podcast. No one can see it.

You beat me in the spin class. You were a hoss in there. I did. That was impressive. I was dying. So where the fat is, is key. Like in men, I really believe, and I think evidence is coming around to support this, but muscle mass in men is more important as opposed to body fat, especially visceral fat in women as a specific individual sex-specific risk factor to results. So I was going to ask you about that, Richard. Do you think that part of the sex difference is that men have more lean mass than women? So it's that they have greater capacity for glucose

disposal and that that could be an independent predictor beyond the loss of hormones? I don't know. I think we need to tease this out. We're honestly doing one of the, if not the only, one of the very few studies where we're looking at pretty comprehensive brain imaging on women and men between the ages of 40 to 65. Lauren, you don't qualify yet because you're still a baby. Thank you. But one day you'll jump in. We're going to be able to answer this question, I hope, in the next five to seven to 10 years or sooner, but I don't know the answer to that question. So Lauren, you finally decide you also now want to be a part of this prevention program.

You're watching your uncle hopefully have his disease course slowed. You're watching your mom in the final stages of her life. What is the hardest thing for you to hear from Richard once you get through that initial diagnostic workup and battery of tests? What are the things you're now starting to confront about yourself? What do you learn, first of all? Oh, God, where do I begin? I mean, I learned a lot. Well, I mean, first, I learned my APOE status, which is that I'm a 3-4. Okay. So that means you got a 4 from mom and obviously a 3 from dad. Right. And, you know, I felt okay. I didn't throw, you know, it's funny, my brother had done 23andMe a couple of years before, before we knew Richard, before anything. And he got it back and it was

like, you know, and this is early on in 23andMe. So I don't even know if it said APOE4. It said like Alzheimer's risk. Yes. And he freaked out. But then by a few years later, I think it was like, you know, and it even could have been the information that came with that along with Richard, which is this is not the genes that he had been talking about before, which are you're going to get Alzheimer's. This is even a 4-4. This is a 3-4. And there are things that we can do to modify my risk. And so I, again, as I touched on as someone who's like, 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, yes, I have a three, four, let's

celebrate. But like, I felt, you know, okay, I have this information. Science is telling me there's something I can do. Why don't I do it? But it was easier in the beginning. I kind of, have I been a patient at the clinic four, five years? Five, five, six years? At least four or five years. Yeah, at least. You know, and I kind of like half started. I was like, you know, a little better at my diet and a little less sugar. And, you know, and I were, I exercised, but not, not what I needed to be doing. And then certainly then, and in the year leading up to when I met you, Peter, was, you know, I was directing a movie that year. And that is certainly not the time where you have all the space in your life to take control of your health. So that, it certainly, I fell off the wagon during

like sitting on my ass in an editing room for eight or nine hours a day was, I didn't exercise before that. You know what I mean? It felt like power in a way. And it took me a while to figure out how to harness that power and what lifestyle changes I needed to adopt and to change. And certainly took both of you at different points in my journey to help me and guide me. And I'm lucky for that. But to me, it felt exciting. You know, people often are like, aren't you scared? Why would you want to know? Blah, blah. And I'm lucky for that. But to me it felt exciting. You know people often are like aren't you scared? How do you why would you want to know blah blah and I'm just like why don't you want to know? Science gives us tools. I don't want to live in the dark and not use the few tools that I've been given at this point. That seems way worse to me. So I felt very lucky that I

was you know getting to access your smart brains and of course other people that I've met and, and take some control over my genes. It is an interesting point you raise Lauren, because, uh, and I may have even told this story on a podcast before, but I remember maybe 2014 or so I had a husband and wife that were both in the practice and simultaneously coming in and did blood tests on both of them. And we always do screen for ApoE on the way in. And each of them came back 3-4, 3-4. They have three children.

So one, I'm explaining to them what the E4, E4 means for them. And I'm also saying, look, you know, your kids are young now. But at some point, it's going to make sense, probably in their 20s, to do a screen on them. Because there's a 25% chance that each of them will be a four, four, a 50% chance that there'll be three, four and a 25% chance there'll be three threes. And I think because their kids were girls, I wasn't so worried about head trauma. If their kids were boys, I probably would have said I would even test sooner to really revisit, you know, if they, if, if, if they're thinking about playing football, I would even test sooner to really revisit, you know, if they're thinking about playing football,

I would probably reconsider that in the case of an E4. Richard, I'd like to hear your thoughts on that, by the way. Anyway, the point of the story is I got a real heated call from their PCP a couple of weeks later saying, how dare you test them for this gene? I mean, what are you trying to do? We can't do anything about this. So what on earth, what good comes of scaring them with the fact that they have an E4 gene? And obviously that led to a discussion. I actually think that person has since then changed their tune a little bit on that front in large part, thanks to the work that Richard's done. But Richard, just a quick digression there. Is there, what's the evidence on people with an E4 gene being better off without head trauma? Not that anybody does well with more head trauma, but are E4s more susceptible to head

trauma? Well, just to take one step back, I mean, Peter, you, you did the right thing. I mean, this is when the conversations need to start. I mean, for example, eating fatty fish, people with APOE4s just don't absorb for just one example. And I can just so many things, but eating fatty fish from early in life, again, I'm not a pediatrician, so I'm not recommending little kids and 12 and I don't even know what or when to start, but omega-3 fatty acids and E4 brain should be started as early as possible and at reasonable doses to really protect the brain. Head trauma is something that's a little confusing. My opinion on this has shifted a little bit, you know, my nephew, Bobby, my sister asked me about this, you know, should he be playing

football? And, you know, of, I have some agit in my stomach. But if you have the four genes, sure, you may be at higher risk. And head trauma may certainly intermingle. Again, epigenetic risk, head trauma plus C4 potentially can increase risk. These are really difficult conversations to have. But knowledge is power. Lauren, you felt empowered. Are patients like, okay, I'm ready. Let's do it. At least I tried. I mean, it's better to try than not. When it comes to E4, I don't know when the best age is to learn. I guess that's a tricky question. But the reveal study showed that people that find out their ApoE4 status in the initial

six months, maybe there's a little bit more anxiety initially, but at the end, there's no negative psychiatric psychological outcomes. And, you know, the studies that we've published, I mean, I wrote our first paper on this in 2011, so like a decade ago. And like, just the fact that you could use genetics to personalize Alzheimer's care, that paper fell on its face. I don't even think it's been cited. Like it's one of those papers, you know, it just kind of sat.

I mean, now we write papers that like specifically the entire paper is about if you're E4 versus not E4, do this versus that. And I don't know, one day, I hope it's soon, we're going to know all these genes and people, when they get their preventative health screenings, we're going to, it's not just E4, we're going to get a whole bunch of genes. And primary care doctors, I hope one day soon, five years, 10 years, who knows, are going to basically do these genetic screens on multiple genes and give people targeted personalized

plans for disease risk reduction as early as possible. So anyway, I support you doing the E4. I would say though, that most doctors are not aware of this. So it's not exactly the doctor's fault, but understanding genetic type to personalized care is the future of medicine. What other genes are there? We've talked about obviously the three that are of greatest concern, but fortunately the three that virtually nobody's ever going to have to hear about or deal with, the PSEN1, 2, and APP, APOE4 sucks all the air out of the room. There are a couple of other genes, Richard, in this space that we're just starting to become aware of. Can you speak to

a couple of those and did any of those figure into the detective work you did in Lauren's family? I learned a lot about Lauren's family. And it was in part because of my brother. It was in part because of actually you and your brother, Lauren. And I just met so many different people. I mean, I really got to know your family tree pretty well between videos and talking and all this sort of thing. And your family is one of the first, I would say first 12 to 15 families that we ever really, you know, did some super deep, deep dives on. I mean, I looked at all sorts of different things in your family. And I guess what I would say is, huh, do I really want to call out one gene or another? Or even just generally, like even independent of Lauren's family, Richard, when we think about

some of these other genes that are now kind of starting to become of interest to us, TOM40, TNF, what can you say about these and how they impact our understanding of this disease? I hesitate to call out any one specific gene because this is a complicated topic, but there are around 30 or so Alzheimer's risk genes that have been found that I think are very important. But aside from just those risk genes, and, you know, you could say CLU and PICLAM or whatever you call it, and BIN1, and, you know, I could just name a whole bunch. And TOM40 is really important because not all APOE4s are created equal.

I believe, this is confusing, and it's even been confusing for me, but the Tom40 that's next to the E4 is really, can influence, in my opinion, I believe, I'm not certain, but I believe that the different Tom40 chain length or whatever it is, one E4 can behave one way and another E4 can have a lower or higher risk depending on the gene next to it. So there's a lot of confusion here with this polygenic risk thing, but Tom 40 is important. But when we take a step back and I look at Alzheimer's as a medical condition, it's a medical condition that causes neurologic manifestations. I think Alzheimer's is a medical disease. I love being a neurologist. It's fun. The brain is interesting. I possibly could have, should have been an internal

medicine specialist. I am really intrigued by all the lower organs, as the neurologist would say, below the neck. No disrespect to the lungs and the liver and everything else. But no, it's a medical condition. And whether you're on the lipid path or the inflammation path or the potentially infectious path or the head trauma path, there's so many different things that can trigger brain related pathology. So I'm very interested in the vascular genes, vascular like FTO and other cholesterol, LDL and PCSK9 related genes. Like I'm interested in those things because that can have an increase or decrease depending on polygenic risk.

Longevity genes, what about like FOXO and CLOTHO? Like there's gotta be, I know that there are genes that kind of protect you against the Alzheimer's risk of the other genes. So I really look at the metabolism genes. I look at the vascular risk genes. In Lauren specifically, Lauren was one of the first people that we found another gene that kind of co-interacts with APOE to even be even more interesting because maybe this gene related

to TNF, TNF-alpha, which we can talk about, when someone has that TNF-alpha gene and also has an APOE4 gene, well, they're also at higher risk than someone with E4 without the TNF. So again, we're trying to put the pieces of the puzzle together of why the heck did your mom get this? And we can pin it on exercise and we can pin it on one thing, but it's not just one thing. It's not like your mom didn't get Alzheimer's because she didn't exercise. Your mom would have gotten Alzheimer's anyway, if she would have exercised rigorously, which no one knew back then. Sure. Would she have delayed it? I firmly believe so. But your mom was different than your uncle in other ways too, because your uncle did not

have that TNF alpha related gene. And now, because we found this gene, I mean, this is like imprecise science. This is like, I would call it better than back of a napkin, but not perfect science. We're doing things with you, Lauren, now that are trying to get ahead of the curve and trying to make that TNF-alpha gene have a less of a negative impact on your trajectory. So between Peter and I, we've really kind of hit you with certain things that can potentially help that. So I guess what I would say is polygenic risk is probably the answer. And I think there's something else you've said that the other analogy is not all E4s are created equal. I don't think that can be overstated enough. And the analogy in the cardiovascular world is LP little a. I've seen so many patients with elevated LP little

A's and in some of them, it absolutely tears through the family with premature heart disease that you can spot a mile away. So just in the same way you look at Lauren's family history and a mile away, you say it's APOE4, You'll look at people having heart attacks in their 40s and dying in their 50s from heart disease. And you say that's, that's LP little a until proven otherwise. And then there's other patients that show up with elevated LP little a very, even very elevated LP little a normal, apparently normal risk of cardiovascular disease. So even though this is technically not the correct term, it's almost like there's variable penetration of the gene as 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 a couple of years ago, you finished,

you're off the editing floor. You're off the cruise ship. W weren't you living on a cruise ship for a while i mean good luck long too many days yes it's been about two three years that you really switch this into overdrive yeah i mean you've you've really become the poster child for i'm going to do every single thing in my power every day to reduce the risk of this beast. I guess I just get the sense from you, like you don't seem to push back on this. Like you've, I guess it's in part because it's come from within you and not, it's not been thrust upon you. Is that, do you think that's the reason that it's been so easy? I want to use the word easy because I don't think it's easy, but. Yeah. I think when you see what I have seen over the last 15 years, you know, why wouldn't I do anything I possibly can to avoid what I saw over the last 15 years?

I want to do everything I possibly can to not go through that myself, to not put that on my husband or my family. that myself, to not put that on my husband or my family. And I feel like I've been given an opportunity to at least try. So why wouldn't I? Well, it is really amazing to watch how Seth basically acts the same way, right? It's sort of like, he's sort of in it with you, right? It's kind of like, well, okay, you're both on the complete risk reduction pathway. Well, I mean, only since this pandemic have I really gotten him into exercise in a way, and he's still not where I am. And of course, obviously all of us, I'm not, you know, exercising the way I was before all of this, but yeah, we eat, we eat, you know, we eat every meal together.

So we eat the same things. And he has certainly changed his eating habits, which has been wonderful. And he supports me. And yeah, he goes along with it. We don't have the same genes, but like, why wouldn't he also care about his brain? He's still got one. You know, as Richard said, just because he 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 is supporting me most of the time. That doesn't mean he's not always like orders too much at dinner or orders extra things. And I'm like, I have to have a bite of that or, you know, but exercise is always very supportive of. But it also speaks to, I think the difference between having a spouse or a family member that can kind of go through the journey with you, whether it's cancer, Alzheimer's disease, heart disease, whatever it is that a person is really trying to make these lifestyle changes to work against. And so we've spoken a lot about exercise. Certainly on other podcasts, we've spoken a lot about nutrition. How does one improve glycemic control? How does one ensure maximum insulin sensitivity and glucose disposal? Richard, can we talk about some of the other tools in the toolkit

that we have with Lauren and frankly, a number of the other patients that we take care of that are high risk in some way? I mean, in our practice, Richard, as you know, we define patients as high risk, meaning you come into their care, basically, if their family history is notable, they have at least one copy of the four gene or they're over 60. You check one of those boxes. Richard is a part of your care. And then we kind of have a protocol that obviously you're the poster child for Lauren. What are some of the other things that we're doing on that protocol, Richard? Sure. So to give you an evidence-based answer, let's start with that first and then we'll go to a case study of Lauren. So within the last year, we published the results

of our clinical trial that Lauren, thank you. You're a part of, thank you for participating. You forced your arm upon me, but we said, okay, I have. You're a part of, thank you for participating. You forced your arm upon me, but we said, okay, I have to sign the consent. And I think you guys win the prize for the most family members in, I think you guys may be tied for the most family members in the study. But we have a study that we published in the journal Alzheimer's and Dementia, the journal of the Alzheimer's Association. And Peter, thank you. You are a co-author on that study. You really fundamentally helped me understand and developed the approach towards maximizing human performance from both, not just physical activity, but nutrition. And just, you got me to understand, quick shout out for Peter.

I give you all these shout outs, Lauren, because you're the best. But Peter, quick shout out. You got me to understand the difference between lifespan, longevity, healthspan, which is kind of quality, and brainspan. And really, that's what we mostly focus on, but there's a lot of overlap. But what we did is we did a study because we had to prove whether or not this individualization of care could work. And in this study, we found that on average, people got 21 different interventions. Again, that's average. Lauren, how many things did we tell you to do? Probably around there. I can count. I have your list. Definitely around there. I mean, I'm on a lot of supplements. And then of course,

there's the lifestyle stuff, the sleep and the food and all this stuff. I'm just loading up one of your things from December 2019. So a major important part of this is also regular follow-up. So a major important part of this is also a regular follow-up. So every six months we repeat body composition measures, which is we use the term ABCs of Alzheimer's prevention management. So the A is for anthropometrics or body composition, body fat, muscle mass, stuff like that. The B is the blood-based biomarkers. We look at your cholesterol markers. We look at your inflammation, your metabolism, your nutrition, genetics are in there too. And then C is cognitive function. So we assess and track all of these things. And at each, every six months, depending on what the repeat is,

depending on what your memory function is and what your cholesterol is and all this, we'll keep refining or fine tuning so that we can, you know, this is really an iterative process. So basically we keep tracking. And then in your case, because of your APOE4 and because of your, and I have permission to talk about this, I guess. Okay, great. Because of your APOE4, we really honed in on exercise and also more high intensity interval training, really, really focusing on that. In terms of nutrition, we, and we checked your omega-3 levels

in your blood, red blood cell DHA levels and EPA and whatnot, we had you eat fish, but also omega-3 fatty acids via capsules, a very specific type and brand that we often recommend. I have nothing to disclose. I wish I did. I could pay my student loans, but nothing to disclose from any supplement or vitamin companies. But omega-3 fatty acids are key, pretty reasonable dose, omega-3s, DHA, and EPA, based on studies that, thankfully, this was proven this past year, but we've had you on this for the last several years, that people with the APOE4 gene require higher doses of omega-3s. So even eating fish just wasn't enough. So we also have you on roughly 2,000 milligrams or so of DHA and something or other of EPA. We also put you on a very purified form of cocoflavanols that have been studied in multiple randomized trials.

We gave you a very specific type of curcumin, a type of more nanoparticle version, again, nothing to disclose, but that may have anti-TNF-alpha effects, may help with inflammation. So we put you on a reasonable dose of that. We put you on specific types of B-complex vitamins. This was to address your homocysteine. Homocysteine is an amino acid in the blood that is an independent risk factor. So if you have high homocysteine, you are more likely to have brain shrinkage over time and impaired memory function. But only in people with high homocysteine,

we can give B-complex vitamins, B12, B6 in tiny amounts, and then a folic acid. If we can control that and the person has sufficient levels of omega-3s, then you can slow brain shrinkage, brain atrophy, and improve memory. So we've modified that risk factor, homocysteine. We optimized your vitamin D. I think your vitamin D wasn't terrible, but it was lower than it could be. I think 60% of people, for example, in Florida are vitamin D deficient. That makes no sense. The first time I saw you, my vitamin D was not good. I can remember that. It was like 19 or 17. Definitely not good. And I remember being like, I got to sit outside more and not wear as much

sunscreen because I'm obviously I'm the palest human ever. And so I wear a lot of sunscreen, but like we've helped that. Is there a level, Richard, that you try to, do you want to see vitamin D within a certain range? Yeah, great question. So in a study in neurology, I think it was Little John and other studies, I can name several. Cedric Anweiler also has some great work on this. But the best that I can do across the board in a general answer is 30 is kind of normal, but what is optimal? I'm thinking closer to 40 to 50, maybe more likely 50. In someone that has two ApoE4 variants, so an ApoE44, based on a study in the European Journal of Nutrition a couple years back,

E44s are probably preferentially protected or E44s better have good vitamin D levels, I'll put it that way, at 50 or more, maybe it's 50 to 70. I don't think we know the exact answers, but a level of 17 to 19 when Lauren first came in to see me was definitely not sufficient. Aside from taking vitamin D, we recommend how to take it. It's a fat-soluble vitamin, so take it with a meal with a little bit of fat in it. That's key. Otherwise, it doesn't help with absorption. Getting some sun, from my perspective, 10 to 15 minutes between the hours of 11 to 1 when the UV or whatever it is is strongest. There's lots of

devil in the details here, but Lauren, we've been able to completely modify that risk factor. So that's been pretty good. And going back to the EPA DHA issue, do you give whatever amount is needed to reach a certain level in the red blood cell membrane? Or do you just say, look, we know that E4s are going to have a harder time assimilating. We're just going to give a higher dose. Again, our patients, we use this stuff very liberally. I think Lauren is on at least two grams combined EPA, DHA. So do you just leave it at the dose or do you like to rely on the omega quant type assay? I don't know that I have the perfect answer for this, but I titrate it up based on the person's red blood cell level. I try to get an index of at least 12 to 14 and higher is probably better. I think Lauren's is

like 14 plus, which is awesome. I also look at the cholesterol. So ApoB and Peter and I, I hate disagreeing with Peter on anything, but I still like LDLP, but I know I've been a convert to ApoB. If someone has high ApoB and LDL cholesterol, I really believe that we can even be more liberal and people need it even more. But the study by Hussein Yassin that was just published recently just showed that you really need to get at least to two grams of DHA alone to even get enough. They did a spinal fluid study. Thankfully, these people volunteered to get spinal taps. And I mean, Lauren, we're really hitting you with this stuff. And I'm really glad because the cumulative effect of APOE4 plus DHA and EPA over time, there's a cumulative effect.

And we really started right with you. So we hedged our bets a little because it was safe. And then it was proven five years later. So that was cool. But I don't know that I have a great answer. I also look at omega-6 to 3 ratio. And I know, Peter, I know you and I may not look at the same that way. I also look at trans fats in the blood. And I know that that's maybe an imperfect assay or science, but trans fats are no bueno when it comes to Alzheimer's risk. So I don't know. I think there's a lot of important aspects to omega-3s and fat assays, but I don't know that I know the perfect answer on how to do it. You spoke briefly about theracumin. We tend to reserve theracumin for those higher risk patients versus curcumin for most people. What's our belief for why theracumin? There's been some reasonable data suggesting that

despite the enormous increase in cost, when you switch to Theracumin, it's worth the cost. This is based on an important study from Small, Gary Small at UCLA. And they showed that when people randomized to this, it sounds kitschy, but like nanoparticles, ooh, that sounds cool. Nanoparticles can get through the blood-bra brain barrier. Well, that sounds like in some ways marketing, but then they did a study and like they had less, you know, amyloid accumulation. So like, okay, sign me up. Like it's safe. Yes, it has a cost to it, but it's not astronomically expensive. You know, I don't know what the exact effect is, but the effect size was large enough, even though it was a small study to, you know, when we talk about evidence-based and safe, I think there's enough evidence. It's

not perfect, but it's safe and it's not super, super, super costly. So, and especially with TNF, should Lauren be on both curcumin longa plus Theracure? Like, who knows? Like, I have no idea because of the TNF, but she's doing so much exercise that maybe we don't need to do it, but I'm babbling, but basically I don't know the answer. I just think it's, it's a reasonable option, even though it's not perfect. Okay. Well, another supplement that I'm a huge fan of is magnesium L3 and eight. What are your thoughts on that? And, and I'll explain to folks what it is. L3 and eight is a transporter that gets magnesium into the brain much more easily. So normally if

you take magnesium, it's not going to get too much in the brain. There is actually some interesting clinical data in humans suggesting that magnesium L3 and eight in patients with MCI improves symptoms. So again, one has to take a leap of faith to say, well, if you give it to people prior to MCI, it would even delay progression from phase one to phase two and potentially from phase two to phase three. So what are your thoughts on that, Richard? Yeah. So I actually learned a little bit about this from you. I've been a magnesium glycinate kind of guy for a while because just kind of from the headache community as a neurologist, it's very well tolerated and that kind of thing. But I think the data on threonate is compelling. I think it may also help with sleep,

if I'm not mistaken. And I've had some success with that and then some pretty, shall we say, stressed out type A people. So it's not at the very top of my list, but it's somewhere in the middle-ish, you know, middle to, it's not super low, but it's, again, evidence-based enough and completely safe. So when it comes to Alzheimer's prevention, we don't want to give anything to anyone that has any degree of, you know, risk because what if they're not going to get Alzheimer's anyway, then we've done our patients harm and we take the oath, do no harm. So I'm pro MEG three and eight, but I don't have as much evidence. It's lower on the evidence list. How do you think about, you've already kind of alluded to this,

but I want to make sure we round it out around what we would call E4 specific maneuvers, right? So let's assume you have two theoretical patients in front of you that you believe are both at higher risk than you'd like. One of them is an E4 patient. Another one is not. Given what we know about E4, how does that change your thinking? You've already made several points in reference to this. One of them, for example, is, boy, there's no ambiguity around the benefits of exercise in E4 people. People with E4 tend to require higher doses of EPA and DHA. They tend to benefit disproportionately from vitamin D. Are

there any other things that are unique to patients with E4? Yeah. So we wrote a paper on this. That's open access. It's in the Journal of Prevention of Alzheimer's Disease. It's called Clinical Application of ApoE and Alzheimer's Prevention, a Precision Medicine Approach. Kara Berkowitz is the first author. She's awesome. She was a med student at Cornell. Peter, we lost her to surgery. I don't know how that happened. You surgeons. But she wrote this terrific paper and did several other papers with us too. So I mentioned this paper first because this is a complicated topic. Let's just start by saying physical exercise is, I believe, likely preferentially effective in people with the E4 variant or more. Brain imaging studies show that E4 carriers exacerbates the effect of having a sedentary lifestyle and Alzheimer's pathology. So someone

with E4, really, really, really better exercise. And it's like, no joke, it's got to be really important. And the intensity of the exercise is key. Tobacco use, just worse in E4s. I'm not telling you that a non-carrier can smoke, but I think it's worse. Alcohol use. Alcohol is really confusing and the data on alcohol kind of 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 little bit different. This is really confusing, but there's probably an E4 impact. But what I would say that while light to moderate alcohol consumption, I mean, more on the light side, like four to seven drinks may be beneficial for non-carriers of E4, decreasing alcohol intake or even abstaining may be even more so helpful for

carriers, but this is tricky and I don't really know the answer to that. Cognitive engagement, if you don't use it, you'll lose it. Staying cognitively engaged is critical. There's some difference with E4s and cognitive engagement strategies, but I think the jury's out a little bit. The dietary stuff is, you know, just specific dietary types is key. Omega-3 fatty acids we talked about are probably preferentially effective, but you need to be at higher dose. You know, there's a randomized trial underway now to try to understand, you know, the impact of high saturated fats and a high glycemic index diet on cognitive function for E4 carriers, but that's not published yet. I guess I want to be cautious

in saying this, but I think people with E4s are probably, you have to be more cautious and careful in terms of high saturated fat, you know, MCTs. I'm pro MCTs if they're the right MCTs, and this is a topic for another discussion. And I'm pro MCTs if it's not specifically more so likely in people without the E4 variant. There's more window or more leeway to be able to use them. But MCTs is a really tricky topic, but I personalize MCT use based on this, but this is a whole thing. So I don't know how much down the rabbit hole to go. I have another question about, this is one we've all spoken about and yet I'm still very much unclear. And I'm curious as to where your thinking is evolving, which is THC in any form, be

it edible, be it inhaled. I mean, what do we know? And acknowledging that it's probably complicated, right? Because there are probably benefits that come in terms of stress reduction, certainly if it facilitates sleep. But what do we know on that front? And are we ever going to get good answers? Because the epidemiology is obviously heavily negatively biased based on the cohort that's studied. This is a hard one. I'm not negative on THC specifically. I think there's

something with the CBD and THC connection. I think it depends on the amount of CBD versus THC. You know, if I had to choose, you know, if someone's going to use THC or CBD, edible to me makes more sense because of, you know, less smoking is better, but I don't know. That's just what I believe, but I'm not, I don't think that's grounded in perfect science, but I guess I would say, I don't know. If every one study you read where it helps Alzheimer's pathology, But I guess I would say, I don't know. If every one study you read where it helps Alzheimer's pathology, you can read another study where it causes greater pathology. So I'm not anti-CBD, THC. I'm not pro. I'm kind of in the middle. I think it's an individualized decision. And I think if someone's going to use CBD or THC because, for example, hey, when I take it,

my sleep is better. I feel better. Okay. But that's subjective. I want to know objectively, you know, let me see your fitness tracker. Let me see your ring. Let me see your, whatever you do to track things. And these, these, all these gadgets may or may not work great in different people, but I think one has to really, the term here would be an N of one study where you make one specific change and then you compare what happens to that person over the three months, say, or six months of only taking that one thing and does cognitive function improve or does sleep metrics improve? I think the THC-CBD story is a precision medicine answer.

Well, speaking of cognitive testing, Lauren, how many times now have you been through the battery of cognitive tests that Richard puts people through? I don't know. Is that a cognitive test to see if I even know that number? I don't know, maybe, but six, seven times? I don't know if you know that right off the information in front of you, but something like that. Enough that I'm starting to learn the tests. Is it intimidating when you sit down and do it? Because I've had some patients that don't want to do it. Well, okay. Because I had a bad time, I visited Richard the day that Like

Father came out, which was because of a number of reasons. Perhaps the most stressful day and emotion, one of the most emotional days I'd had in a while. And it was not good. And my brain was a million different places. And of course, my body was not in a while. And it was not good. And my brain was a million different places. And of course, my body was not in the best of shape leading up to that. And it was bad news. And Richard was so unhappy and so mad at me. But it was a good, you know, kick in the behind to get myself back on track because I had been making progress. Then I lost that progress. So of course, the test that I think now I've come in twice since then. Twice. Yeah. Yeah. I psyched myself up a bit and I'm like, I'm nervous and, you know, get, get all into it. But

fortunately I've done well. But is that true, Richard? I mean, do we really think like, I guess, do we know that the cognitive test reflected her change in effort around the preventative measures? Or is it confounded by the fact that she was having a very, very stressful, distracted day? Even though both of those are true, is the test really able to distinguish those things? I mean, my blood work wasn't great that day either, but I'll let Richard answer. Yeah. You know, it's, it's really interesting. And I have the whole trajectory here. I mean, this is worth its weight in gold, like all these, all this, these tests. Now let me take a step back and talk about cognitive assessments. Now, when we do a cognitive battery related to Alzheimer's prevention, we use something, it's a modified form of the Alzheimer's prevention cognitive composite. These are

mostly computer-based tests, the NIH toolbox, as well as other kind of traditional tests that people with mild cognitive complaints kind of come in and take. But we use a battery that is sensitive to detect changes in brain function before symptoms. And different cognitive domains or different cognitive areas are related to Alzheimer's disease pathology, as well as other things like vascular pathology, vascular cognitive decline, or age-related cognitive decline. So I'm not going to portend that our cognitive assessment battery is anywhere close to perfect. It is as good as cognitive testing can be because people can have

good days and bad days. But it's funny, Lauren, I remember you that day. That was a whole day. Didn't we do a video shoot that day? Well, that was the day you filmed Seth and I went for other blood work and then I just was in such a state I couldn't even stay. Oh my, that's right. That's right. I remember that day. And my in-laws were with us. Yeah. That was a lot. Yeah. That was a whole day. So I guess what I would say is there are certain, when someone doesn't sleep well, then the thing that I would expect to have a bad effect on cognitive testing that day would be related to processing speed and attention. When someone has, let's just say, early Alzheimer's before symptoms, I'm more paying attention to certain types of memory tasks, certain types of naming

tasks. When someone has vascular risk factors, I'm more concerned with how are they doing in executive function measures. So when I see homocysteine and vitamin D and the cholesterol, I correlate that or I associate that in my brain with different cognitive domains. So this is hard to explain, but like Lauren, you felt like you did bad that day because maybe emotionally you were whatever, but looking back on it, if you take that into consideration, it made sense that you were having a stressful day. However, in the next couple of years, when I think I may have scared you

because I got upset. I mean, I was concerned. I think you saw the concern. I think Seth was there. We all did. Yeah, I mean. My in-laws were there. They were concerned.

Yeah, I mean, I didn't know I was going to call your brother. Like, what do I do? Like, I was, you know, I don't want to involve other people with HIPAA and all that kind of stuff. But I was like, how do I address this? And I just said, I'm sorry you're having a crappy day, but here's the deal. Like, this is what's going on. And I'll be frank.

I was getting worried. Things weren't going in the right direction. You were doing good and then bad and then good and then bad. And then your cruise ship situation and then the stress. And I said, Lauren, I'm sorry, it's got to change now. And I think maybe that's when we got Peter involved or maybe a little before that. We hadn't sat down with Peter. We'd been talking about Peter. Yeah, that's right. So all I can say is in the two plus years, whatever, since that time, Peter, I know you've been cautious about cognitive tests because of the variability, the imprecise time. Peter, I know you've been cautious about

cognitive tests because of the variability, the imprecise nature, and I agree with that, but you can't fake, Lauren, your last set of cognitive tests, you can't fake this. You have optimized your cognitive function, in my opinion, period, like no discussion. You said there's an element of practice effects. Now, I totally agree with that. There are certain tests- But because I have a four, that doesn't help me. Wow. Look at you, little encyclopedia. See, I can learn. That's higher order processing. There you go.

Wow. Dr. Miller-Rogan, you're learning. Good job. Correct. EPOE4s are more resistant to practice effects. And also men's brains and women's brains have different strengths and weaknesses, for example, verbal memory. So when we really digest your trajectory of cognitive function over the last several years, I'm going to be honest. I don't know that I've really talked about this too much in public or on a recording, but your brain is functioning. And again, you can take all the practice effects you want. There are certain tests here that I believe are resistant enough. And it's not like you're taking these every day. You're taking these like every, you know, six have visual proof. Your brain and biomarkers, your blood-based biomarkers, you're optimized. You're different. Your brain is firing on more cylinders. Let's just say we'll average out the first three sessions, right? I mean,

there's just no comparison. You're more than a standard deviation above normal. Like you're processing speed. I know, my standard deviation above normal. Like you've improved, like your processing speed. I know my brain is above normal. I know. Yeah. Well, no, I mean, it's interesting because I really want to see if you feel anything, but just, can you tell the difference? But the most important test that we do for age related cognitive decline, you're, you're several years older and I know you're 30 something to 30 something big deal. Well, no, the brain ages in that, in that timeframe, your brain is younger now than it was five years ago. Like you're greater than 90th percentile on all these different tests. Your, you know, your memory function is a standard deviation above the mean. And when you started out, it like was 0.87 standard deviations below

the mean. Yeah. I mean, I remember this, Lauren, because our very first meeting was at Cornell and we were going over your results. And I remember we were kind of looking for an explanation for how it could have been so poor. And the best explanation that you came up with, which frankly I thought was a viable one, was you said, look, I did well in school, but I did poorly on standardized tests. And is it possible that my cognitive score is low because I'm not a good standardized test taker? So it's been very exciting to watch this progression. One element of the standardized test I want to ask you about, Richard, is odor. You put another one of our patients through this test recently, and I was very surprised to learn. So he came back, is it 10? Nine, nine item test. Nine. And in this case, the patient correctly

identified eight. And I remember thinking, oh, that's awesome. And you this case, the patient correctly identified eight. And I remember thinking, oh, that's awesome. And you were like, if it had been seven, I would have been really concerned. And with eight, it was, we're going to do a retest. Why is odor identification so important in this disease? Yeah. I mean, there's so much subjectivity to cognitive assessments. You could be sleep deprived. You could be sleep deprived. You could be like, you know, distracted by, I don't know, you forgot to silence your cell phone. You could, I don't know, it's warm in the room or cold in the room and Lauren's always freezing.

So, you know, we got to get the temperature just right for Lauren. Lauren's coming, you know, regulate the temperature. You don't do that. No, I'm kidding. And then Seth's coming. Oh, change the temperature, change the thermostat. No, as we get older, we change. Now he's the cold one and I'm kidding. And then Seth's coming. Oh, change the temperature, change the thermostat. No, as we get older, we change. Now he's the cold one and I'm the hot one. I know I've been huddling during this because the air is low, but no, it's, that's, honestly,

it's the funniest thing. The older he gets, the colder he is and the hotter I am. And of course, it used to be different. Anyway. Fascinating. So odor is more objective rather than subjective. So odor is more objective rather than subjective. And odor identification, like what is that? Well, it's your ability to recognize a smell and name what it is. And again, in med school, decreased odor identification. The first thing I thought of was Parkinson's disease. That's something that's common in preclinical Parkinson's. So before someone gets the tremor and the slow movements and the shuffling gait,

meaning the walking is slow and the rigidity, odor identification, loss of smell is something that can be a harbinger of badness for a neurodegenerative disease to come. Well, the studies have shown that loss of smell or lack of the ability to precisely identify certain smells can be a harbinger of Alzheimer's disease as well. My mom had a very poor sense of smell and not an amazing sense of taste either, but sense of smell was she never had a good sense of smell. That's impactful. With COVID, I mean, it's a different thing. And Peter, you and I talked about this, but I lost my smell for five, six weeks, which is a little bit longer than some people. And we can talk about- Has your smell returned back to normal? So I'm seven months out now. And you know,

just for folks know what we're talking about. You, you had a pretty good case of COVID. I did. Yeah. I had one of these cases where, Oh, I'm fine. Three, four or five days later. I'm like, you know, okay, cool. I'm going to, I'll exercise tomorrow. And then on day nine, 10, I went with my O2 sat dropping and all that stuff. And I'm Peter help and Paul help. And what the heck I called every doctor in my Rolodex, did an EKG on myself in my office at midnight. Cause I wanted to stay the heck out of the ER. My O2 sat was 94 PTSD time, but they wouldn't have admitted me cause it was above 90. But anyway, I had a pretty reasonable case of COVID and my smell after five weeks started to come back. I mean, like ahead of the thing of bleach, I smelled nothing. I mean, like zero. I'm like real smell sensitive. Then I had phantom smells for a while. I was like, uh-oh, the dog peed. Uh-oh, Bon Bon, Kitty. My dog's name is Kitty. How's Zelda doing, by the way?

How's Zelda doing, by the way? Well, honestly, I've been worried a few times. I don't know if you saw me. I was checking to see if my microphone has picked up her snoring. Oh. Because she's right across from me, and she has been snoring so loud this whole time. So if anyone has heard that, it's just Zelda. Oh, no, it's golden.

Yeah, Bon Bon had his second snoring surgery. But he's great now. He's awesome. King Charles Cavalier Fan Club of America, we're talking to right here. Anyway, so I had phantom smells, and then my smell is basically back, but I'm like a little smell sensitive. Can't explain it. So that this COVID may change our ability to use smell sensitivity for Alzheimer's related testing. But anyway, we'll cross that bridge later. Sorry for the tangent. What about hearing? Because you see these reports from time to time that say, we've got to get more aggressive with

hearing aids in people. The moment a person has even the slightest amount of hearing deterioration, we've got to correct it. The implication being that hearing loss will have a causative role in Alzheimer's disease such that correction of it can delay or prevent versus just the obvious correlation between hearing loss and dementia, given the obvious age association. What's your thought on that? Yeah, I don't, I don't know that I have a perfect answer, but hearing loss, when they've done the studies, the Lancet commission 2020 report came out and basically showed that hearing loss is like the most impactful modifiable risk factor that they found in their study, which is like striking, like a huge number of cases of dementia could be potentially reduced if a person gets

early recognition of hearing impairment and gets it addressed. Now, why is sorry, why is that? Yeah, this is confusing. And this is a quote, unquote, new risk factor. I mean, it's been around for, you know, the evidence has been emerging for years now, but I don't know. Is it because you're, and I hate to say, I'm not an expert in this at all, but you're just, you disengage, you can't hear, you kind of, you're in your own little world. You miss social cues, you have different interaction levels. I actually don't know the answer to this. And this, the classic line, we need more research to truly be able to figure this out. I mean, I feel like it's one of those things, Richard, that we, because we're constantly updating our protocol and I've been thinking for about the past three

months, do we need to now take those high risk patients that we described and say, everyone's got to go to an audiologist. And of course the implication is you're going to get people in their thirties and forties that have low, low, low grade hearing loss. Are they actually going to want to wear hearing aids or is it just going to be, Hey, we're going to use more noise cancellation stuff and sort of try to protect hearing longer. But I I'm curious as to this, it also strikes me that from the precautionary principle, there's no downside to protecting your hearing. And as much as one can do that, I don't see a downside to it. I think we, meaning doctors, need to do a little bit of, I'll say a better job. Doctors have it

really hard. So this is not doctor's fault. It's like our medical system is in disarray and broken beyond. I have no idea how to fix it with 10 minutes or 15 minutes per patient. I have lots of empathy for, tremendous empathy for physicians working out there, but in the trenches, but hearing screening, I think is something that should be part of at some age, at some point, an evaluation. Real briefly, though, I want to go back to Lauren's odor identification. So this is a weird comment, and I've never really also said this on a recording, but Lauren, this is not the first time that I've seen patients that have really firing on all cylinders, done 23 of the 25 things we told you to do, like compliance out to Wazoo,

10 out of 10. Your odor identification, this is weird, and this may be a red herring, completely random or whatever, your odor identification has improved. I think it's because, and maybe this again goes against my four, it's because now I know the difference in the cards between the coffee and the gasoline smell, which used to really throw me off. Gotcha, okay. So even with an objective test,

we still have subjectivity with learning effects and stuff like that. Now when I smell it, I'm like, okay, really be sure. Is this the coffee or the gas? All the other ones are easy, but between those two, those always trip me up. Gotcha. Interesting. Just to get back to one thing, Lauren, yes, I have objective data, but data is only as good as data is, and all of our tests are imprecise. And Peter and I talk about this a lot. Sure, your calculated cardiovascular risk when we put all your numbers in a calculator, much lower. Your calculated Alzheimer's risk based on the different scales, much lower. Like we're doing a great job. Like in terms of living longer-

Knock on wood. Yeah, knock on wood. Yeah, we're really doing well. Do you feel anything different in your brain or not so much? And just be honest. Do you feel anything different in your brain or not so much? And just be honest. No, no. And, you know, and I don't, I don't know how much we want to get into any of this, but I'm on my own hormonal journey and often wonder, you know, if that plays a part in it. I, I've always been someone who's enjoyed sleep.

We kind of talked about that and like, you know, I, I like sleep and I, I know, I like sleep and I can, I love a nap. As I get older and my hormones become bigger players in my health, I sometimes think that has to do with it. But overall, do I feel cognitively better? It's hard to say, but physically I feel better. My overall health is, I can tell that it's better from a total body energy. The way I can approach a situation, I feel like I have a different type of body energy, if that makes any sense. Cognitively, you know, knock on wood, I fortunately feel like someone who is pretty in control of their cognition most of the time. So, you know, do I have moments, yes, where I'm like, I feel tired or weird or even that, you know, like you said, that brain fog, which I don't think I understand at this point, but the black and white answer is yes, I feel better. Do I feel

greatly better? I'm not sure. I mean, to me, I think there's an emotional piece here too, right? Which is we go back to 10 years ago, there's this depression that basically feels like there's something inevitable that's going to happen to you. And I think, you know, by now Richard and I are very much in the camp of saying there's no reason to believe you're going to get Alzheimer's disease. Like there's really no reason to believe that. If you stay this course that you're on, you get to be like normal people in their eighties. So maybe that's the greatest single benefit of all this is that it changes the way you feel. I wasn't physically in such rough shape that I could really pinpoint a difference,

but emotionally, yes, so much of the fear has dissipated because I have control in a way that I didn't before. I see my blood work. I see numbers going from red to green, and that gives me a hope that, you know, I think translates into my physical being, but also into my, into my cognitive health as well. I don't want us to close without talking a little bit about Hilarity for Charity, which we started talking about a little bit, but bring us up to speed on the, on

specifically what the mission is, how you decided to pick the lane that you guys are going to be in. Specifically what the mission is, how you decided to pick the lane that you guys are going to be in. You know, we touched on this a little bit before, but I have been so fortunate in my terrible journey. I think I've had the best situation of a horror show that could happen with Alzheimer's. And that one, my family was able to afford care for my mom. care for my mom. And that too, I have, because of my relationships and the advocate that I've become, I have met smart people like you guys who have helped me take control of my brain health. And so HFC, what we've done with that is try to help other people be at least a part of that situation. And so I like to think of HFC as sort of like, this is our non-official, you know, mission statement, which is like, we're here for your brain today and

tomorrow. Meaning that, you know, we're here for people today through care, through our numerous support groups, which are personalized and which we really take the time to connect people to people who would understand their situation. Early on, I went to a support group where, you know, I was like 26 and upset about my mom. And there was a guy there who was like 56 and who was upset about his mom. And not that I didn't feel bad for this person, but also like, I did not feel bad for this person, you know, because I was like, you're 56. You have your mom at 56. Like, I'm 26. And so, you know, we really try to recognize that in our care, we put people together who would understand a situation.

And of course, then there is the other aspect of it, which is, I think, what makes the greatest impact in people's lives today, which is our care program. You know, like I said, my family could afford care for my mom so that my dad could catch his breath and take a break and go to the grocery store if he needed or, you know, come have dinner with me if he wanted. And so many people are with their loved one 24-7, without a break, without relief. And that is a completely thankless job. And so we provide care for people and provide caregivers to go into people's homes and give the primary caregiver respite, give them a break. And then there's, of course, how we invest our dollars in research, which is in brain health.

HFC really focuses on activating young people in the fight against Alzheimer's. We don't think that people should wait till they're older to start talking about their stories or losing loved ones to Alzheimer's. And they certainly shouldn't wait, as we've talked about today, to start taking care of their brains. And so we really do our best to share what we've learned from you guys and educate people that it is never too early to start taking care of your brain and how important that is. That's really our focus. I wish that we raised the kind of money that would research a medication that could cure

Alzheimer's, but no one has yet given us $5 billion. I'm out here ready to receive it if someone is listening and wants to send it our way. But for now, I'm going to do what is practical, which is help people today with support and care and teach people how to take care of their brains for tomorrow. So that's who we are. So people can go to the website. They can obviously donate directly. Is there any other way people can get involved or be a part? I mean, there are all sorts of events. Yeah. What else can people do? Yeah. I mean, obviously this year, the event thing has sort of taken a turn for all of us

and all nonprofits, I think, are feeling the strain of not being able to host our normal fundraising events and, you know, and the strain of that being able to host our normal fundraising events and, you know, and the strain of that a lot of philanthropists who normally would donate our way feel that they can't this year because they are donating towards COVID-related organizations or even racial organizations, which, please keep donating. These things are very important. I'm not saying you shouldn't. But at the same time, people still have brains. And unfortunately, there are still millions of people in this country with Alzheimer's and their caregivers are in even worse situations now. So what we do is even more important these days. So yeah, you can go to our website. Of course, give us your hard

earned dollars. We're happy to do something good with them. But we also give people a space to share their story if they have one. We provide infrastructure if you want to throw your own Alzheimer's fundraiser. We've had so many amazing individuals over the years who have done their own fundraisers for whatever speaks to them. One of my favorites is a guy like drove, do you say a tuk-tuk? Do you say drove a tuk-tuk? I guess so. Rode one? Whatever. Pulled one across India and raised money for HFC.

Like how cool. But like that's what spoke to him. That was organic to him. And Seth and I always say when it comes to fundraising or philanthropy, like do what's organic to you. What makes sense for your life. So we provide an infrastructure if you want to raise money for us. We're happy to help you do it.

You know, again, if you need support, you can come to us. We have so many different options. We have an amazing partnership with the Rosalind Carter Institute in which we train caregivers. We give them one-on-one caregiving training, which is really, I think, so invaluable. I mean, the truth is there's no training to be a caregiver. Every day is a surprise and who knows, but there are certain tools that we can give people. And, you know, and I think we try to do it all in a way that is approachable. Certainly, you know, our original name is Hilarity for Charity. Now we're HFC because we want to seem like grownups and we want people to take us seriously. But we approach everything through a way that, you know, has some comedy that is certainly our work. But we often say Alzheimer's is so devastating and

it is so sad and people don't want to hear about it. So we'll tell them some jokes and trick them into laughing. And then all of a sudden we hit them with the facts and tell them how important it is. And we rope them in that way. I think overall, we're just trying to provide people the hope that I have found over the years. You know, we started this podcast talking about my dark, devastating times and like, that's not who I am anymore. And that's not my vision about all of this anymore. And I think there is so much control that can be had that we did not have even just a few years ago. And, you know, we through HFC are just trying to teach people that they have that control too. Well, Lauren, Richard, it has been such a pleasure to sit down

with you guys today. And it has been worth every bit of the weight from almost a year ago when we wanted to first do this. And no one would have imagined a year ago, all that was going to happen in the next 12 months. But it's also, it's also given us a chance to see one more year of your incredible progress, Lauren. So thanks for being the poster child for what Alzheimer's prevention looks like. Well, we're trying. It's a journey, right? I don't know if I can be the poster child yet, but maybe in some time we'll see if, I think, you know, we'll keep going. No pressure. Just poster child for the journey. There you go. Well, hey, if we would have done this podcast a year ago, I could have only said one out of every three cases of Alzheimer's is preventable. But now, based on the latest data, four out of 10 cases of Alzheimer's may be preventable if that person does everything right.

So I'm going to have to change the signature in my email. I'm sorry. Is what you're saying to me. Who wrote that signature? Jeez. Someone wrote that signature. I don't know who it was. Unbelievable. Typos everywhere. Fired.

Peter, thanks for sharing our story. And Lauren, thank you for being courageous. And you're the one that puts, I mean, I get to sit here at this desk and hang out and like, you know, whatever. And you actually have to go home and do all the 27 things that Peter and I tell you to do. So thanks for being a good sport.

You do your own things. Yeah. Gotta do what you gotta do. I know you do. Yeah. And we're really grateful to your family for also feeling that it's been okay for you to talk about this because I know that these are things people don't want to talk about. And yet I think the understanding that, hey, we talk about these things that suck because they make, it makes a difference because there's a lot of people that are listening to this right now that can relate to what you're saying. Yeah, I hope so. Well,

there's so much that can be done. So I appreciate the chance to talk about it. All right, guys. Thanks so much. Thanks so much. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you Thanks so much. a bunch of things. One, totally kick-ass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these. Monthly AMA episodes or Ask Me Anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this. The Qualies, which are a super

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