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Peter Attia MD#138-Lauren Rogen & Richard Isaacson MD: Alzheimer’s disease prevention—patient & doctor perspective
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125 min read · 25,357 words- 0:00 – 3:10
Intro
- PAPeter Attia
[intro music] 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 wanna 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 wanna learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. [upbeat music] My guests this week are Lauren Miller Rogen 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 two thousand eighteen 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 have been talking about doing this podcast for about a year. In fact, we were gonna 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, 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 gonna find this episode both touching and enlightening. So without further delay, please enjoy my conversation with Lauren Miller Rogen and Richard Isaacson. [upbeat music]
- 3:10 – 13:45
Lauren’s deep family history of Alzheimer’s disease
- PAPeter Attia
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 gonna 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, and kind of understand your personal journey, um, 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.
- LRLauren Miller Rogen
Thank you for having us. You know, I feel like longtime listener, first-time guest.
- PAPeter Attia
[chuckles]
- LRLauren Miller Rogen
Very excited to be here. [chuckles]
- RIDr. Richard Isaacson
Longtime listener as well. Yeah, I'm, uh, I hang on every word of, of most of the podcasts, especially... Well, I had to listen to Tom Despring's podcast like 14 times. I'm still like need to listen to it on repeat, but.
- PAPeter Attia
Lauren, let's start with you. I mean, I want people to really get an understanding of, 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?
- LRLauren Miller Rogen
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 fifties or early sixties, but he was in a nursing home I think from the time I was around eight or nine, maybe ten, 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 at the table, and I thought that was hysterical. And he would, you know, s- 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 'cause 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 was clearly wasn't eating and... 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, 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, and 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, any way at all. It was a lot at 18 and, 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, it's like, well, they're grandparents. They're, you know, this happens to them even though, you know, my th- 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 would always say, "When I get Alzheimer's, when I get Alzheimer's." And I would say, "Stop saying that. Don't say that." Like, 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, you know, 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.
- PAPeter Attia
You're just out of college, and you're being confronted with the idea that your mom is not even in her mid-50s 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?
- LRLauren Miller Rogen
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 'cause I didn't... I think, you know, when you talk about something, it seems real all of a sudden. It's really happening.
- PAPeter Attia
Even your father?
- LRLauren Miller Rogen
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, you know, 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. You, 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-
- PAPeter Attia
Mm
- LRLauren Miller Rogen
... her out of that classroom. It was just who she was was fading away and changing right in front of our 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.
- PAPeter Attia
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?
- LRLauren Miller Rogen
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, early on and I read in Teen Magazine, if there's ever something difficult you wanna 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 have 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-
- PAPeter Attia
Mm-hmm
- LRLauren Miller Rogen
... Alzheimer's. And she told me that she wasn't scared for her. She was scared for me and my brother and my dad. 'Cause 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 em- or emotionally even to really know the fear there.
- PAPeter Attia
So you mentioned that this is around the time when, I mean, it's now hitting you with the full force.
- LRLauren Miller Rogen
Yeah.
- PAPeter Attia
And I assume it's much less or, I mean, maybe somewhat, but probably less about what the implications are for you and much more about the loss of her.
- LRLauren Miller Rogen
Yeah, which of course, you know, I was in my early 20s, so that was only about me. But [laughs] um, 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 had 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, 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 Sea Breeze [laughs] 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.
- PAPeter Attia
Mm-hmm.
- LRLauren Miller Rogen
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. It's gotta be there. I know I can find it. Like I'm the kind of person who's like, "If I'm gonna do something, I'm gonna do it," you know? I'm 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
- 13:45 – 24:30
The influence of genetics, epigenetics, and lifestyle on Alzheimer’s disease risk
- LRLauren Miller Rogen
that was it.
- PAPeter Attia
So I wanna give you a chance to just sort of catch your breath a bit.
- LRLauren Miller Rogen
[laughs]
- PAPeter Attia
And Richard, I, I wanna sort of ask you a couple of questions right now, not necessarily specifically about Lauren's mom, 'cause I wanna 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 wanna 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, let's just start with the genetics of this.
- RIDr. Richard Isaacson
Sure. So I first have to start with just I hate this disease. I just like hate it. I hate hearing these stories. [laughs] Uh, now you're gonna make me cry, Lauren.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
I'm being... I'm on a podcast. Come on. I'm on record. I, I can't, I can't-
- LRLauren Miller Rogen
Well, no one can see us, so it's fine.
- RIDr. Richard Isaacson
Okay, good. Perfect.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
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 per- I mean, it robs the person of who they are, but it, 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 f- the friendship years and, and that's just... So I hate this disease. Alzheimer's disease starts in the brain decades before the first symptom of memory loss begins, and I didn't learn that in medical school. 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 ha- at, in their, 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, m- her mom and her dad. Why? Why is this happening? And Lauren, I, we have some small world coincidences which we learned about later.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
But like my brother, he's a neurologist. He's, 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, 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, you know, 40s or 50s. But you know, Lauren, your family was different, and we'll talk about this later, but when I hear a, a family history like this, I, I say, "Well, well why do certain people in, in the, 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, I maybe made that up, but what is, 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 h- think about is why is this happening? A- and number one, I say, "Okay, genetics." There's, there's gotta 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, you know, just synergize together to, to potentially make a late onset Alzheimer's case start earlier. So, so these are the some of the things like, you know, detective work things that I think about. But no, it's not typical.
- PAPeter Attia
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?
- RIDr. Richard Isaacson
Sure. So there's the typical early onset genes. There's really only three, uh, 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. Um, I've seen over 1,500 patients easily, probably close to 2,000 patients over the last, you know, 15 plus years. Literally two hands. That's all I got. Lauren, you actually introduced me to one, an amazing, amazing person, great individual, and someone that I... Oof.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
Uh, she may have that gene, but I, I will not- say that she will get Alzheimer's. So, so for the first time in my career, I've, I've not only f- we not only figured out that someone has an early onset gene, which means you're gonna 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 ApoE4, 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 gonna 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, that's what the books say. Except in that one person that you introduced me to, Lauren. We're gonna, we got time. She's in her 20s. We're gonna-
- PAPeter Attia
Yeah
- RIDr. Richard Isaacson
... we're gonna, we're gonna get this up for her.
- PAPeter Attia
And those, Richard, really represent far less than 1% of the total cases are made up of APP, PSEN1, PSEN2. Uh, for what it's worth, I've never actually seen one. I, for me, those only exist in the literature. The interesting aside, by the way, is there's s- some people speculate that the index case of Alzheimer's disease was actually one of those, and s- and some of our understanding of this disease may be incorrect as a result of that, but we'll, 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 are just thinking some aggressive combination of other things.
- RIDr. Richard Isaacson
Yep, and it's, um, 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 people, 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 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, 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 ApoE2, a three, or a four. It's called an allele or a variant. A lot of people call it a mutation, but it's not a mutation. So you get a, 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 ApoE 3/3, that's a pretty, you know, neutral risk, kind of boring, no big deal. ApoE 2/3, okay, maybe they have some protection. And one four, ApoE 3/4, for example, increases risk a little bit. And then two fours, ApoE 4/4s 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, 4/4s, I have dozens of patients in my practice that I absolutely think that they are not gonna get Alzheimer's disease. They, they're gonna 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. You know, if someone has a four, we're gonna tell them to do certain things. Someone doesn't have a four, we're gonna 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 gotta be something else. The devil is in the details there.
- PAPeter Attia
Richard, I wanna 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 the what we call the wild type or the E3 variant?
- RIDr. Richard Isaacson
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. Um, 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, of a bad pathologic protein called amyloid. It's a sticky stuff that builds up in, 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, a, a cholesterol-like, vascular-like pathway. There's a ton more I can talk about it, but, you know, 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 kinda understand. I, I kinda get it. I, I, I feel good about it. I know that may sound callous or strange, but, like, 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, I know what I'm up against. It's the person that actually doesn't have
- 24:30 – 29:30
Lauren’s mother’s disease progression and the enormous stress it causes for family members
- RIDr. Richard Isaacson
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, I'm f- I feel relieved sometimes when, when we find it in a person.
- PAPeter Attia
All right. Well, I think we'll, we'll talk a little bit more about this, but Lauren, I wanna kinda hear more from your story. So as you're now kinda 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, 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, you know, 10 years ago. How is she at that point? Which is still probably putting her in her late 50s, right?
- LRLauren Miller Rogen
She had just turned 60. So at that point she could still walk. She was-- There were moments where she knew us. Uh, no, she knew us. She knew that we were her family and that we were her loved ones, 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, [chuckles] I, I always was the kind of, you know, girl who like envisioned my wedding, and it was to 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 then 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, uh, 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, 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.
- PAPeter Attia
Hmm.
- LRLauren Miller Rogen
Which was, you know, really hard to handle. But then miraculously, [chuckles] 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 kn- 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 hadn't, she wasn't teaching anymore. Uh, 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, 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, but overall, it was, 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, it [chuckles] was clear that it was killing, it was gonna 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 'cause 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.
- PAPeter Attia
I mean, these are some of the things that we're gonna 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 100 times to do something for it and I'll always say yes, so-
- LRLauren Miller Rogen
[laughs]
- PAPeter Attia
You always apologize when you ask me.
- LRLauren Miller Rogen
Don't say that. Don't say that.
- PAPeter Attia
[laughs] Um, but, but, but I really, I'm really so
- 29:30 – 34:45
The various manifestations of Alzheimer’s disease depending on the location of pathology
- PAPeter Attia
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-
- LRLauren Miller Rogen
Yeah
- PAPeter Attia
... we're waiting for these things to happen, people need help in caring for this. And, and I, I suppose there's no disease where that's more true than, than this one.
- LRLauren Miller Rogen
Absolutely.
- PAPeter Attia
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, 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?
- RIDr. Richard Isaacson
Yeah. So there's, um, actually a, a couple who I believe are both pathologists, um, Braak and Braak, B-R-A-A-K. And what they did was they kind of came up with the Braak staging of, of pathology where the, where the amyloid protein and then the pathology of Alzheimer's spreads over different parts of the brain. And, you know, 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, it's a neuropsychiatric disease, changes in sleep, and then the person, as the pathology spreads, they can no longer take care of themselves. What we really, uh, 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, 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 dysexecutive syndrome. Well, what does that mean? Executive function is higher order processing, judgment, planning. You know, you find a wallet on the floor, what do you do with it, right? Peter would take the money out, put the money in his pocket-
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
... throw the wallet back on the floor. You know-
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
You know, Lauren, she's very empathetic and compassionate. She'd look at the, the license, you know, she'd say, "Oh, I'm gonna go find this guy. I'm gonna go to the ends of the earth to find this person's wallet." So that's executive function.
- PAPeter Attia
Maybe. [laughs]
- RIDr. Richard Isaacson
Maybe. Depends. Depends on the s- yeah.
- PAPeter Attia
Depends on how much is in there.
- RIDr. Richard Isaacson
Exactly.
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
That's one form of Alzheimer's. You know, 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, 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 tauopathy. 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 lo- localized to the memory centers in the brain, uh, 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, you know, for example, there's 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, they act funny. They may be weird. They may be, you know, confused, but it's not exactly a memory problem. It's a, it's a visual perception problem. So, you know, I don't want to be cheeky, but like-
- PAPeter Attia
I mean, Richard, no, no, this is, this is very interesting, and I- 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, I mean, that's, 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, the, about the only thing they have in common is unregulated cell growth, but thereafter, they're very different diseases, uh, 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, 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 th- this notion that someone could have a form of Alzheimer's that largely spares their frontal cortex and therefore preserves some higher order functioning
- 34:45 – 39:15
The three stages of Alzheimer's disease
- PAPeter Attia
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?
- RIDr. Richard Isaacson
Well, I'll try not to bias my answer because-
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
... 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, that sounds like Alzheimer's disease. That sounds like progressive short-term memory loss plus behavior changes plus, you know, other things. So it sounds like she started in the mild cognitive impairment phase with the symptoms. So there's, there's three phases of Alzheimer's, um, three stages. Maybe we should take a, take a step back for listeners. The first stage is actually the pre-clinical 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.
- PAPeter Attia
That's crazy. I've never heard that before, that number. You know, that's wow.
- RIDr. Richard Isaacson
Yeah. I, I try to keep that close to my, my vest because-
- PAPeter Attia
And how, how do, how do we know that, Richard?
- RIDr. Richard Isaacson
That's what the studies say. You know, 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.
- PAPeter Attia
You're gonna bring this one to journal club next month.
- RIDr. Richard Isaacson
What a great, what a great idea. I love those journal clubs.
- PAPeter Attia
That sounds like the nerdiest club of all time, but okay. [laughs]
- RIDr. Richard Isaacson
Oh my, and, and we, and we've discussed you, and we've disc- no.
- PAPeter Attia
It is nerdy.
- RIDr. Richard Isaacson
It is pretty freaking nerdy, and we record it, and then we watch it, and we-
- PAPeter Attia
Oh my God.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
I was, I was captain of my math team at Colmac High School.
- LRLauren Miller Rogen
Well, there you go. Never- never mind. It sounds really cool then. [laughs]
- RIDr. Richard Isaacson
Thank you. Thank you. Um, also the alma mater of Lauren's mom.
- LRLauren Miller Rogen
Mm-hmm.
- RIDr. Richard Isaacson
High five. Go Comac.
- LRLauren Miller Rogen
Mm-hmm.
- RIDr. Richard Isaacson
Um, and Lauren's uncle and some others.
- LRLauren Miller Rogen
Mm-hmm.
- RIDr. Richard Isaacson
Um, anyway, so this preclinical, presymptomatic phase is by far the most important phase, I think, well, maybe, um, 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, uh, 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, uh, um, many people would be very pleased and, um, thankful that, um, if symptoms started at 52 and she was able to attend your, um, wedding at 60, I mean, that's horrible, but better than it could have been-
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
... in, in the grand scheme of things.
- LRLauren Miller Rogen
At least she was there, you know? I have friends who, who unfortunately lost-- had weddings without parents there, so because they had lost them already, so.
- RIDr. Richard Isaacson
Yeah, absolutely. So, so these are the stages.
- 39:15 – 58:00
Richard’s deep exploration into Lauren’s family history revealing clues about a diagnosis and a roadmap to successful disease mitigation
- PAPeter Attia
a, a minute. So Lauren, I wanna talk about how you made your way to, to Richard, because that's how you and I met. You and I met through Richard, but I wanna know how you and Richard met.
- LRLauren Miller Rogen
Sure. So, okay, I'll try to keep this somewhat brief. I feel like it might be long.
- RIDr. Richard Isaacson
This is a hilarious story. I'm sorry.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
I remember this like a video in my mind, but anyway, I don't wanna interrupt.
- LRLauren Miller Rogen
[laughs] 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. Uh, up until that point, like I said, I had been really dark and depressed, and I had been trying to work, and I, you know, I'm a screenwriter, and I was writing, but, like, 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, you know, an incredible event. We raised a few hundred thousand dollars, but was the, 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 20s and my husband in his late 20s 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 501 [c] [3] . But during that time, of course, we became Alzheimer's advocates, and I met many smart people and doctors and scientists and, 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, so incredible, and 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, an athlete his whole life, he was... and, and in 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, 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 reached out to a doctor that I knew and was like, "You know, my uncle's on the, the East Coast. I want to get him into the best of the best. Who is it?" And this person recommended Richard.
- RIDr. Richard Isaacson
The best of the be- the best looking, I hope?
- LRLauren Miller Rogen
The best looking Alzheimer's-
- RIDr. Richard Isaacson
Okay, perfect. Okay
- LRLauren Miller Rogen
... doctor there could-- Yes, exactly.
- RIDr. Richard Isaacson
Thankfully this is a podcast. Phew.
- LRLauren Miller Rogen
That's what my uncle was hoping for, was the best looking [laughs] Alzheimer's doctor.
- RIDr. Richard Isaacson
[laughs]
- PAPeter Attia
The one, the one with the best phones, I think is what it was really the-
- LRLauren Miller Rogen
The with, definitely the best phones. Well, I, 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, a horse on the back at the top. Are those not rhinestones?
- RIDr. Richard Isaacson
Br- diamonds. Hello.
- LRLauren Miller Rogen
Oh, tho- diamonds. Excuse me, those are diamonds. [laughs]
- RIDr. Richard Isaacson
It's a diamond pillow. Come on.
- LRLauren Miller Rogen
[laughs] Anyway, so gave me Richard's name and I went on his website and I found his email, his direct email address, 'cause of course I wasn't, I wa- again, I'm not the kind of person who's like, "I'm gonna be polite and keep my mouth shut and follow the rules to get to where I need to go." Like, I'm gonna do what I gotta 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, a few months later or something and I, you know, said, "I'm coming to New York. I wanna come see the clinic, come meet you." And then of course, you know, I'm seeing the clinic and talking to him and, um, then I was like, "I want in. I wanna be a patient. I wanna prevent Alzheimer's. Let me in. Help my brain."
- RIDr. Richard Isaacson
You literally like, I don't know how to do this, but like, like shot out your arm and said like-
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
... "Take my blood now."
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
"Let's do it." And like 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, uh-
- LRLauren Miller Rogen
Lucky for me.
- RIDr. Richard Isaacson
Yeah.
- LRLauren Miller Rogen
Lucky for me.
- RIDr. Richard Isaacson
Yes.
- PAPeter Attia
What kind of shape was your uncle in at that point in time? I 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-
- LRLauren Miller Rogen
Yeah
- 58:00 – 1:08:00
How exercise reduces Alzheimer’s disease risk, and the different risk between males and females
- RIDr. Richard Isaacson
What I would call your mom now is, you know, sh- maybe, maybe, you know, heard of the, the term skinny fat, right?
- LRLauren Miller Rogen
Yeah.
- RIDr. Richard Isaacson
Um, skinny-
- LRLauren Miller Rogen
Yeah
- RIDr. Richard Isaacson
... on the outside-
- LRLauren Miller Rogen
I would say that
- RIDr. Richard Isaacson
... um, you know, fat on the inside. Um-
- LRLauren Miller Rogen
Mm-hmm
- RIDr. Richard Isaacson
... you know, and your, maybe, I don't know what your mom's waist circumference was in high school versus her waist circumference in her, you know, 40s and 50s, but I-
- LRLauren Miller Rogen
Much larger. [laughs]
- RIDr. Richard Isaacson
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 s- talked about or thought about, you know? You know, in the '80s it was like, you know, that was like when 10,000 steps came about, you know? Like, who came up with 10,000 st- well, sorry, I know who came up with it, but I understand that there's some better than nothing in, in calculating, but 10,000 steps is like so antiquated. It's like s- it's like, you know, literally the '80s 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.
- LRLauren Miller Rogen
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. She, you know, 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, you know, her genes were leading her toward.
- RIDr. Richard Isaacson
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 reach out to-
- LRLauren Miller Rogen
Yes, that was in your podcast, I remember
- RIDr. Richard Isaacson
... that was, yeah, and I, and I, I would, I refused to answer it. I was like out walking the dogs the other day and someone, someone asked me the same question. I'm like, "Well..." But, 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 like no one knew any of that even a few years ago, let alone a decade ago. So optimization of physical activity is key. And, and your uncle, just so we can paint the picture, your uncle was like, he was a machine.
- LRLauren Miller Rogen
He, I was gonna say he was a beast, yeah.
- RIDr. Richard Isaacson
He was rip-- I mean, I'm, I'm-
- LRLauren Miller Rogen
Yeah
- RIDr. Richard Isaacson
... you know, he could put Pete, I don't know, him and Peter next to each other, be close. Um, you know, I'm, I'm scrawny or whatever compared, but he was ripped. He just looked great. He, he-
- LRLauren Miller Rogen
His leg muscles were like-
- RIDr. Richard Isaacson
Oh
- LRLauren Miller Rogen
... oh my word. Yeah.
- RIDr. Richard Isaacson
My goodness, and because of that, your metabolism is better, all these different things.
- PAPeter Attia
Richard, was he 3-4 or 4-4?
- RIDr. Richard Isaacson
Uh, he was 4-4 also.
- PAPeter Attia
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 3-4, his sister's the 4-4, and that explains the 15-year gap. But to have them both be 4-4, 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?
- RIDr. Richard Isaacson
Yeah. So I would have answered that question just like you did with 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 gotta figure it out. Go, why, why do women... No, no, no. Two out of every three brains of, of Alzheimer's are, 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 the 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, you know, be a different part of the conversation, and, and which types and what this and what that. But the bioenergetic shifts during the perimenopause transition, you know, 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.
- LRLauren Miller Rogen
I don't know what you're talking about.
- RIDr. Richard Isaacson
No, not at all. Not at all.
- LRLauren Miller Rogen
[laughs]
- 1:08:00 – 1:14:45
Why knowing your APOE status is important, and whether certain people should be wearier of head trauma
- RIDr. Richard Isaacson
you don't qualify yet 'cause you're still a baby.
- LRLauren Miller Rogen
Thank you.
- RIDr. Richard Isaacson
But, but one day, um, you'll, you'll jump in. We're gonna 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.
- PAPeter Attia
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, what are the things you're now starting to confront about yourself? What, what do you learn, first of all?
- LRLauren Miller Rogen
Oh God, where do I begin? I mean, I, [laughs] I learned a lot. Well, I mean, first I learned my APOE status, which is that I'm a 3-4.
- PAPeter Attia
Okay. So that means you got a four from mom and obviously a three from dad.
- LRLauren Miller Rogen
Right. And you know, I felt okay. I didn't throw... You know, it's funny, my, my brother had done 23andMe a couple 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, 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 isn't 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 gonna do it, I wanna do it and dive in on it. So I... Don't get me wrong, I wasn't like, "Yes, I have a 3-4, 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 of the clinic four or five years? Five, five or six years?
- RIDr. Richard Isaacson
Four, at least four or five years. Yeah, at least.
- LRLauren Miller Rogen
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 wor- I exercised, but not, not what I needed to be doing. And then certainly then, and, 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, uh, 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? How do you, why would you wanna know?" Blah, blah. And I'm just like, why don't you wanna know? Science gives us tools. I don't wanna 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.
- PAPeter Attia
It is an interesting point you raise, Lauren, because, uh, and I may have even told this story on a podcast before, but I, 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, and each of them came back 3-4, 3-4. They have, uh, 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 4-4, a 50% chance that they'll be 3-4, and a 25% chance they'll be 3-3s." And, uh, I think because their kids were girls, I wasn't so worried about head trauma. If their kids were boys, I probably would've said I would even test sooner to really revis- you know, if they, if, if, 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, and obviously that led to a discussion. I, I actually think that person has since then changed, changed their tune a little bit on that front, in large part thanks to the work that, that Richard's done. But, um, uh, 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, are E4s more susceptible to head trauma?
- RIDr. Richard Isaacson
Well, well, just to take one step back, I mean, Peter, you, you did the right thing. I mean, this, this is when the conversations need to start. I mean, for example, eating fatty fish, people with ApoE4s just don't absorb for just as, just one example, and I can just so, 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, and 12 and f- I don't even, I don't even know what or when to start, but omega-3 fatty acids in an E4 brain should be started as early as possible s- 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, um, you know, should he be playing football? And, you know, of course, I have some AGT in my stomach, but, you know, I, ah, you know, if, if you have the 4 gene, sure, you may be at, at a, at higher risk, and head trauma may certainly intermingle, again, epigenetic risk, head trauma plus E4 potentially can increase risk. These are really difficult conversations to have, but knowledge is power. Lauren, you, you felt empowered, you know?
- SPSpeaker
Yeah.
- RIDr. Richard Isaacson
Our, our patient's like, "Okay, I'm ready. Let's do it if, and if I, I, at least I tried." You know? 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, that's a, that's a tricky question. But, you know, the Reveal study showed that people that find out their ApoE4 status
- 1:14:45 – 1:21:45
How Richard uses genetic testing to personalize care
- RIDr. Richard Isaacson
in the initial six months, maybe there's a little bit more anxiety initially, but, but, but at the end, there's no negative psychiatric psychological outcomes. And, you know, the, the studies that we've published, um, you know, I wrote, 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, and I, I don't know. One day, I hope it's soon, we're gonna know all these genes and, and, and people when they get their preventative health screenings, we're gonna-- It's not just E4. We're gonna get a whole bunch of genes, and primary care doctors, I hope one day soon, five years, 10 years, who knows, are gonna 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 personalize care is the future of medicine.
- PAPeter Attia
What other genes are there? We've talked about obviously the three that are of greatest concern, but fortunately, the, the three that m- virtually nobody's ever gonna have to hear about or deal with, the PSEN one, two, 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?
- RIDr. Richard Isaacson
I learned a lot about Lauren's family, and it was in part 'cause 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, um, in your family. And I guess what I would say is, huh, do I really wanna call out one gene or another? I-
- PAPeter Attia
Or even just generally, like even independent of, 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, TOMM40, TNF, what can you say about these and how they impact our understanding of this disease?
- RIDr. Richard Isaacson
I hesitate to call out any one specific gene because this is a complicated topic. But, you know, 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 PICALM or whatever you call it, and BIN1, and, you know, I could just name a whole bunch. And TOMM40's really important because not all ApoE4s are created equal. I believe, um, this is confusing, um, and it's even been confusing for me, but the TOMM40 that's next to the E4 is really can influence, uh, in, in my opinion, I believe. I'm not certain, but I believe that the different TOMM40 chain length or whatever it is, one E4 can behave one way, and another E4 can have a lower or high, or higher risk depending on the gene next to it. So there, there's, there's a lot of confusion here with this polygenic risk thing, but TOMM40's important. But, you know, 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've, should've been an internal medicine specialist. I am really intrigued by all the lower organs, as the neurologists would say, below the neck. No, no, 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, and other cholesterol, LDL and, and PCSK9-related genes. Like I, I'm interested in those things because that, th-that can have an increase in or, or decrease depending on polygenic risk. Longevity genes, what about like FOXO and Klotho? Like there's gotta be, there's-- Well, 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, was one of the first people that we found a-another gene that kind of co-interacts with ApoE to even be even more interesting because maybe this gene related to TNF, TNF-alpha, uh, 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, 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, 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've gotten Alzheimer's anyway if she would've exercised v- rigorously, which no one knew back then. Sure, would she have delayed it? I, I firmly believe so, but your mom was different than your uncle in, in other ways too, 'cause, you know, 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 kinda hit you with certain things that can potentially help that. So I guess what I would say is polygenic risk is probably the answer.
- PAPeter Attia
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, the analogy for 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, ver- 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
- 1:21:45 – 1:36:30
The “ABCs” of Alzheimer’s prevention, lifestyle interventions, and Lauren’s personal protocol for reducing her risk
- PAPeter Attia
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-- Y-you're off the, uh, the, the editing floor.
- RIDr. Richard Isaacson
You're off the cruise ship. Weren't you living on a cruise ship for a while?
- LRLauren Miller Rogen
I mean-
- RIDr. Richard Isaacson
Good luck
- LRLauren Miller Rogen
... too long, too many days, yes. [chuckles]
- PAPeter Attia
It's been about two, three years that you really switched this into overdrive.
- LRLauren Miller Rogen
Yeah.
- PAPeter Attia
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."
- LRLauren Miller Rogen
Mm-hmm.
- PAPeter Attia
I guess I just get the sense from you, like you don't seem to, 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 e- I, I don't wanna use the word easy 'cause I don't think it's easy, but-
- LRLauren Miller Rogen
Yeah. I think when you see what I have seen over the last 15 years, [chuckles] you know, why wouldn't I do anything I possibly can to avoid what I saw over the last 15 years? I wanna do everything I possibly can to not go through 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?
- PAPeter Attia
Well, it is really amazing to watch how Seth basically acts the same way, right? It's sort of like-
- LRLauren Miller Rogen
[chuckles]
- PAPeter Attia
He's sort of in it with you, right? It's kind of like, well, okay. W- you're both on the complete risk reduction pathway.
- LRLauren Miller Rogen
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, we're, 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, as Richard said, just 'cause 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, "Well, I have to have a bite of that," or you know. But exercise he's always very supportive of. [chuckles]
- PAPeter Attia
But it, it also speaks to, I think, the difference between having a spouse or a family member that can kinda go through the journey with you, whether it's cancer or Alzheimer's disease, heart disease, whatever it is that, that a person is really trying to make these lifestyle changes to, to work against. And, 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, with Lauren and, 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 4 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?
- RIDr. Richard Isaacson
Sure. So to give you an evidence-based answer, let's, let's start with that first and then we'll go to a, you know, a case study of Lauren. So within the last year we published the results of our, of our clinical trial that Lauren, thank you, you're a part of. You- thank you for participating. You forced your arm upon me, but we said okay.
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
After you s- consigned the consent, but... And I think you, you guys win the prize for the most family members in the-- I think you guys may be tied, um, for the most family members in the study. But we had a study that we published in the journal Alzheimer's & Dementia, the journal of the Alzheimer's Association. And Peter, thank you. You are a coauthor on that study. You're, you really fundamentally helped me understand and developed the approach towards maximizing human performance from both n-not just physical activity, but nutrition and just... You, you got me to underst- Quick shout-out for Peter. I give you all these shout-outs, Lauren-
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
... 'cause you're, you're the best. But Peter, quick shout-out. I mean, you got me to understand the difference between lifespan, longevity, healthspan, which is kinda quality, and brainspan. And, uh, really that's what, that's what we mostly focus on, but there's a lot of overlap. But what we did is we did a study 'cause we had to prove whether or not this individualization of care, uh, could work. And in this study, um, we found that on average people got 21 different interventions. You know, again, that's average. Um, Lauren, how many things did we tell you to do? Probably around there. I've-- I can count. I have a, I have your list right here.
- PAPeter Attia
Definitely around there. I mean, I'm on a lot of supplements, and then of course there's the, the, the lifestyle stuff, the s- the sleep and the food and, like, all the stuff.
- RIDr. Richard Isaacson
I'm just re-loading up one of your things from December 2019. So a major important part of this is also, um, regular follow-up. So every six months we repeat, um, body composition measures, uh, 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, um, 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 will, we'll keep refining or fine-tuning so that we can, you know... This is really an iterative process. So basically we, 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.
- PAPeter Attia
Mm-hmm. Yeah. [laughs]
- RIDr. Richard Isaacson
Because of your ApoE4, um, we really honed in on exercise and also more high-intensity interval training, really, really focusing on that. In terms of nutrition, we, we-- and we checked your omega-3 levels in your blood, red blood cell, um, 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, I wish I did, I could pay my student loans. But, um, nothing to disclose from any supplement or vitamin companies. But omega-3 fatty acids are key. Pretty reasonable dose omega-3s, DHA and EPA, um, 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, of EPA. We also put you on a very purified form of, uh, cocoa flavanols that have been studied in multiple randomized trials. We gave you a very specific type of, uh, curcumin, a type of, uh, more, uh, nanoparticle version. Again, nothing to disclose, um, but that may have anti-TNF alpha effects, uh, may help with inflammation. So we put you on a reasonable dose of, of that. We put you on, um, specific types of B complex vitamins. This was to address your, um, homocysteine. Homocysteine is an, uh, 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, and impaired memory function. But only in people with high homocysteine we can give B complex vitamins, B12, B6 in tiny amounts, and then, uh, 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, and improve memory. So we've modified that risk factor, homocysteine. We optimized your vitamin D. I think your vitamin D wasn't, um, terrible, but it was, you know, lower than it could be. I think 60% of people, for example, in Florida are, are vitamin D deficient. That makes no sense.
- PAPeter Attia
The first time, the first time I saw you, I-- my vitamin D was not good.
- RIDr. Richard Isaacson
Oh.
- PAPeter Attia
I can remember that. And I, and I remember-
- RIDr. Richard Isaacson
It was like 19 or 17. Yeah
- PAPeter Attia
... I remember it was definitely not good, and I remember being like, "I gotta sit outside more and not wear as much sunscreen," 'cause I'm, obviously I'm the palest human ever. [laughs] And so I wear a lot of sunscreen, but, like, we've helped that. [laughs] Is there a level, Richard, that you try to-- Do, do you wanna see vitamin D within a certain range?
- 1:36:30 – 1:40:00
Unique treatment for people with the ApoE4 variant
- PAPeter Attia
How do you think about-- You've already kind of alluded to this, but I wanna 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?
- RIDr. Richard Isaacson
Yeah. So we wrote a paper on this that's open access. It's in the Journal of Prevention of Alzheimer's Disease. Um, it's called "Clinical Application of ApoE in Alzheimer's Prevention: A Precision Medicine Approach." Cara Berkowitz is the first author. She's awesome. She was a med student at Cornell. Peter, we lost her to surgery. Sh-- I don't know what-- 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 mention 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, or more. Brain imaging studies show that E4 carriers exacerbates the effect of having a sedentary lifestyle on Alzheimer's pathology. So someone with E4 really, really, really better exercise. Um, and it's like no joke. It's gotta be really important. And, and the intensity of the exercise is key. Tobacco use, just worse in E4s. Like, I'm not telling you that a non-carrier can smoke, um, but, uh, I think it's, I think it's worse. Alcohol use. Alcohol's really confusing, and the data on alcohol kinda darts all over the place, but a few drinks a week is kinda where I'm at now. You know, f- uh, men and women m- 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, uh, this is, this is tricky and I don't really know the answer to that. Cognitive engagement, if you don't use it, you lose it. Staying cognitively engaged is, like, 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 go- 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 wanna 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, I'm pro MCTs if they're the right MCTs and, and this is a topic for another discussion. And I'm pro MCTs if it's not specifically more so likely in, in people without the E4 variant. There's more window or more, um, 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, I don't know how much down the rabbit hole to go.
- PAPeter Attia
I have another question about--
- 1:40:00 – 1:41:45
Richard’s mixed opinion on CBD and THC as a tool for disease prevention
- PAPeter Attia
This is one we've all spoken about and yet I'm still very much unclear and I'm, 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, and acknowledging that it's probably complicated, right? Because there are probably benefits that come in terms of stress reduction, certainly if it im- if it facilitates sleep. But what do we know on that front and are we ever gonna get good answers? 'Cause the epidemiology is obviously heavily negatively biased based on the cohort that's studied.
- RIDr. Richard Isaacson
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. Um, you know, if I had to choose, you know, if someone's going to use THC or CBD, uh, 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, in perfect science. But I guess I would say I don't know. I- If every one study you read where it helps Alzheimer's pathology, you can read another study where it, you know, it causes greater pathology. So I'm not anti CBD, THC. I'm not pro. I'm kind of, I'm kind of in the middle. I think it's an individualized decision and I think if someone's gonna use CBD or THC because, for example, "Hey, uh, when I take it my sleep is better, I feel better," okay. But that's subjective. I wanna 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
- 1:41:45 – 1:50:00
Cognitive testing procedures, and how Lauren’s tests furthered her commitment to her disease prevention protocol
- RIDr. Richard Isaacson
over the three months, say, or six months of only taking that one thing and does cognitive function improve or does what, does sleep metrics improve? I think the THC CBD story is a, is a precision medicine answer.
- PAPeter Attia
Well, speaking of cognitive testing, Lauren, how many times now have you been through the battery of cognitive tests that Richard puts people through?
- LRLauren Miller Rogen
I don't know. Was that a cognitive test to see if I even know that number? [laughing] Um, I don't know, maybe, but six, seven times? I don't know if you ha- know that right off the information in front of you, but something like that. Enough that I'm starting to learn the tests.
- PAPeter Attia
Is it intimidating when you sit down and do it? 'Cause I've had some patients that don't wanna do it.
- LRLauren Miller Rogen
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, 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 [chuckles] and so mad at me, but it was a good, you know, kick in the behind to get myself back on track 'cause I had been making progress then I lost that progress. So of course the tests that, that I think now I've come in twice since then?
- RIDr. Richard Isaacson
Twice, yep. Mm-hmm.
- LRLauren Miller Rogen
Yeah. I psych myself up a bit and I'm like, "I'm nervous and," but I'm like [chuckles] you know, get, get all into it. But fortunately I've done well.
- PAPeter Attia
But is that true, Richard? I mean, do we really think-- Like, I guess do we know that, 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 and-
- LRLauren Miller Rogen
I mean, my blood work wasn't great that day either, but I'll let Richard answer.
- RIDr. Richard Isaacson
Yeah, you know, it's, it's really interesting and I, 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 intake. But we use a, 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 gonna portend that our cognitive assessment battery is anywhere close to perfect. It is as good as cognitive testing can be, 'cause people can have good days and bad days. But it's funny, Lauren, like you-- I remember you that day. That was a, that was a whole day. Didn't we do a video shoot that day with-
- LRLauren Miller Rogen
Well, that was the day you sh- you sh- you filmed Seth, and I went for other blood work, and then I just was in such a state I couldn't even stay.
- RIDr. Richard Isaacson
Oh my, what a-- That's right. That's right. I remember that day. Um-
- LRLauren Miller Rogen
And my in-laws were with us. [laughs]
- RIDr. Richard Isaacson
Yeah. Uh, that was-
- LRLauren Miller Rogen
It was a lot.
- RIDr. Richard Isaacson
Yeah, that was a whole, 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, I'm more concerned with how are they doing in executive function measures. So when I see homocysteine and vitamin D and, and the cholesterol, I, I correlate that or I, I, 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 y- I think I may have scared you 'cause I, I got ups- I mean, I was concerned. I think you saw the concern. I think-
- LRLauren Miller Rogen
Mm-hmm
- RIDr. Richard Isaacson
... I think Seth was there.
- LRLauren Miller Rogen
We all did.
- RIDr. Richard Isaacson
Yeah, I mean-
- LRLauren Miller Rogen
My, my in-laws were there. They were concerned. [laughs]
- RIDr. Richard Isaacson
Yeah, I mean, I didn't know-- I was gonna call your brother. Like, what do I do? Like, I was, uh, you know, I didn't want to involve other people with HIPAA and all that kind of stuff, but I, 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-
- LRLauren Miller Rogen
Yeah
- RIDr. Richard Isaacson
... 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 you had a cruise ship situation and then the stress. And I said, "Lauren, I'm sorry, it's gotta change now." And I think maybe that's when we got Peter involved or maybe a little before that.
- LRLauren Miller Rogen
We hadn't sat down with Peter. We had been talking about Peter.
- RIDr. Richard Isaacson
Yeah, that's right. So all I can say is in the, in the two-plus years, whatever, since that time, Peter, I know you've, you've been cautious about cognitive tests because of the variability, the imprecise nature, and I, 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, I totally agree with that. There are certain tests-
- LRLauren Miller Rogen
But because I have a f- because I have a four, that doesn't help me. [laughs]
- RIDr. Richard Isaacson
Wow, look at you, little insight-
- LRLauren Miller Rogen
See, I can learn. [laughs]
- PAPeter Attia
That's higher order processing. There you go.
- 1:50:00 – 1:57:30
The relevance of sense of smell and hearing in Alzheimer’s disease risk and prevention
- PAPeter Attia
this progression. O-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?
- RIDr. Richard Isaacson
Nine. Nine-item test.
- PAPeter Attia
Nine. And in this case, the patient correctly identified eight, and I remember thinking, "Oh, that's awesome." And you were like, "Mm, if it had been seven, I would've been really concerned," and with eight it was, "We're gonna do a retest." Why is odor identification so important in this disease?
- RIDr. Richard Isaacson
Yeah, I mean, there's so much subjectivity to cognitive assessments. You could be sleep-deprived, you could be like, you know, distracted by, I don't know, you forgot to silence your cellphone. 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 gotta get the temperature just right for Lauren. Oh, Lauren's coming, you know, regulate the temperature.
- LRLauren Miller Rogen
[laughs] You don't do that.
- RIDr. Richard Isaacson
Yeah, no, I'm kidding.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
And then Seth's coming. Oh, t- change the temperature.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
Change the thermostat. Oh, geez.
- LRLauren Miller Rogen
No, as we get older, we change. Now he's the cold one and I'm the hot one.
- RIDr. Richard Isaacson
Oh, wow.
- LRLauren Miller Rogen
I know I've been huddling during this-
- RIDr. Richard Isaacson
[laughs]
- LRLauren Miller Rogen
... 'cause the air is low. But no, it's, that's the f- 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.
- RIDr. Richard Isaacson
Fascinating. Um, 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, that's common in pre-clinical Parkinson's. So before someone gets the tremor and the slow movements and the shuffling gait, meaning the walking is, is slow and, and, and then the rigidity, odor identification, loss of smell is something that can, you know, be a harbinger of badness for a neurodegenerative disease to come. Well, the studies have shown that loss of smell or, or odor, lack of the ability to precisely identify certain smells can be a harbinger of Alzheimer's disease as well.
- LRLauren Miller Rogen
My mom had a very poor sense of smell. And, and not an amazing sense of taste either, but sense of smell was, she never had a good sense of smell.
- RIDr. Richard Isaacson
That's impactful. With COVID, I mean, it's a different thing. Like, you know, and Peter, you know, you and I talked about this, but I lost my smell for five, six weeks, which is a little bit longer than, than s- than some people, and we can talk about-
- PAPeter Attia
Has your smell returned back to normal?
- RIDr. Richard Isaacson
So I'm seven months out now, and w- you know-
- PAPeter Attia
Just for folks to know what we're talking about, you, you had a pretty good case of COVID.
- RIDr. Richard Isaacson
I did, yeah. I had one of these cases where, oh, I'm fine. Three, four, five days later I'm like, you know, "Okay, cool, I'm, I'll exercise tomorrow," and then on day nine, 10 I went fwooo, pkhhh, 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, um, 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 a head of a thing of bleach and 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, Bonbon, Kitty, you g-" My, my dog's name is Kitty. How's Zelda doing, by the way?
- LRLauren Miller Rogen
Well, honestly, I've been worried. A few g- I don't know if you saw me, I was checking to see if my microphone has picked up her snoring.
- RIDr. Richard Isaacson
Oh. [laughs]
- LRLauren Miller Rogen
Because it's, she's right across from me and she has been snoring so loud this whole time, so if anyone has heard that, it's, it's just Zelda.
- RIDr. Richard Isaacson
Oh, no, it's Golden.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
Yeah, Bonbon 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.
- LRLauren Miller Rogen
Yes.
- RIDr. Richard Isaacson
Anyway, so I had phantom smells and then my smell is basically back, but I'm, I'm, like, a little smell sensitive. Can't, can't explain it. So that, this, COVID may change our ability to use smell sensitivity for Alzheimer's related testing, but anyway, w- we'll cross that bridge later. Sorry for the tangent.
- 1:57:30 – 2:00:15
The emotional benefit of knowing you have control over your mental and physical health
- LRLauren Miller Rogen
those two, those always, uh, trip me up.
- RIDr. Richard Isaacson
Gotcha. Interesting.
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
You know, just to get back to one thing, Lauren, yes, I have objective data, but you know, 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-
- LRLauren Miller Rogen
Knock on wood.
- RIDr. Richard Isaacson
Yeah, knock on wood. Yeah, we're, we are really, we're really doing well. Do you feel anything different in your brain or, or not so much? And just be honest.
- LRLauren Miller Rogen
No. No. And you know, and I don't, I don't know how much we wanna 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, and like, you know, I, I like sleep and I, 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 phys- 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's pretty in control of their cognition most of the time. So, you know, do I have moments, yes, where I'm like, "Eh, 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.
- PAPeter Attia
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 [chuckles] you're gonna get Alzheimer's disease.
- LRLauren Miller Rogen
Yeah.
- PAPeter Attia
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 80s. So maybe that's the greatest single benefit of all this, is that it changes the way you feel.
- LRLauren Miller Rogen
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
- 2:00:15 – 2:11:49
HFC—a charitable organization founded by Lauren and Seth
- LRLauren Miller Rogen
in a way that I didn't before. I see, I see my blood work, you know? 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.
- PAPeter Attia
I don't want us to, to close without talking a little bit about Hilarity for Charity, which we started talking about a little bit, but, uh, bring us up to speed on the, on specifically what the mission is, how you decided to pick the lane that you guys are gonna be in.
- LRLauren Miller Rogen
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, and that two, I have, because of my relationships and be- 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, 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? 'Cause 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, d- 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 [sighs] completely thankless job. And so we provide care for people and provide caregivers, uh, to go into people's homes and give the primary caregiver respite and 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, 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 gonna 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.
- PAPeter Attia
So people can go to the website. They can obviously donate directly. Is there any other way people can get involved or be a p- I mean, there are all sorts of events. How... Yeah, what's, what else can people do?
- LRLauren Miller Rogen
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 a lot of philanthropists who normally would, 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, in even worse situations now. So what we do is even more important these days. So yeah, you can go to our website and 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 wanna throw your own Alzheimer's fundraiser. We've had so many amazing individuals over the years who have done their own fundraisers for what- 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-
- PAPeter Attia
[chuckles]
- LRLauren Miller Rogen
... 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 wanna 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, uh, partnership with the Rosalynn Carter Institute in which we train caregivers. We give them one-on-one caregiving training which is really, I think, so invaluable. I mean, there's... The truth is there's no, there's no training to be a caregiver. It's 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 'cause we wanna 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 you know, we often say Alzheimer's is so devastating and it is so sad and people don't wanna 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.
- PAPeter Attia
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 wait-
- LRLauren Miller Rogen
[chuckles]
- PAPeter Attia
... from almost a year ago when we wanted to first do this, and no one would have imagined a year ago all that was gonna 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.
- LRLauren Miller Rogen
Well, 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, uh, you know, we'll keep going.
- RIDr. Richard Isaacson
No pressure.
- LRLauren Miller Rogen
Just poster child for the journey.
- RIDr. Richard Isaacson
Yeah. [chuckles]
- PAPeter Attia
There you go.
- RIDr. Richard Isaacson
Well, hey, if we would've 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.
- LRLauren Miller Rogen
So I'm gonna have to change the signature in my email-
- RIDr. Richard Isaacson
I'm sorry
- LRLauren Miller Rogen
... is what you're saying to me?
- RIDr. Richard Isaacson
Who wrote that signature? Geez.
- LRLauren Miller Rogen
Some- someone wrote that signature. I don't know who it was.
- RIDr. Richard Isaacson
Unbelievable. I-
- LRLauren Miller Rogen
[laughs]
- RIDr. Richard Isaacson
Typos everywhere. Fired. Peter, thanks for sharing our story. And Lauren, thank you for-
- LRLauren Miller Rogen
Thank you for having us
- RIDr. Richard Isaacson
... being courageous. And, uh, 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-
- LRLauren Miller Rogen
You do things too
- RIDr. Richard Isaacson
... a good sport.
- LRLauren Miller Rogen
You do your own things.
- RIDr. Richard Isaacson
Yeah. Gotta do what you gotta do.
Episode duration: 2:11:50
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Transcript of episode AJmf1ZLwCuA
