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Peter Attia MD#18 – Richard Isaacson, M.D.: Alzheimer’s prevention
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150 min read · 30,030 words- 0:00 – 0:04
Intro
- PAPeter Attia
[instrumental music]
- 0:04 – 8:02
Episode Preview and Guest Introduction
- PAPeter Attia
Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hey, everyone. Welcome to this week's episode of The Peter Attia Drive. This week, I have the privilege of interviewing a good friend, a collaborator, and an all-around interesting dude named Richard Isaacson. Richard is a neurologist who specializes in Alzheimer's disease. He is the director of the Alzheimer's Prevention Clinic at Cornell here in New York City. His life has been touched by Alzheimer's disease, and from a very early age, as Richard describes, he felt a calling to go into neurology. It is clearly his life's work. He's an absolute expert in Alzheimer's disease, but specifically has chosen to focus his efforts on the prevention of Alzheimer's disease as opposed to the treatment of Alzheimer's disease. And actually, this puts him in the minority of neurologists. Professionally, as I said, he's an associate professor of neurology at Cornell Medical College here in the city. He's also an attending neurologist at NewYork-Presbyterian Hospital. He grew up not too far from here in Long Island or thereabouts, and actually one of my favorite little tidbits I learned about him is he went to a high school called Connetquot High School, and he was recently named among the most distinguished alumni. So his photo now hangs alongside fellow recipients Rosie O'Donnell and Bob Costas, so that's pretty impressive. He's a little bit of a Doogie Howser. Started college at 17, finished medical school at 23. So as I think I point out in the podcast, he finished medical school before I actually started medical school. Did his internship in Miami before ultimately doing his training at Beth Israel and Harvard. Ultimately, he has wound his way back to New York. And as we get into great detail in this podcast about what his work is, and I think more importantly, how it can help people listening to this or their loved ones. And also, I think we, I think are very open about the limitations in this space and what we do and don't know. Richard has developed... And I should say Richard and his team, let's be honest. Like all great people, they're sort of surrounded by a team of great people. They've developed something called ALZU, so that's www.alzu.org, which might be one of the single most important resources for people with Alzheimer's disease or early cognitive impairment and their family members. So we'll obviously link to that very prominently, but I think that's something that will-- If, if, if you take nothing else from this podcast other than a sort of visit to alzu.org, that would be terrific. Richard and I get into a lot of stuff. I think this podcast probably runs about two and a half hours. And we talk, at the initial part, by the way, we get into something that was not at all planned. But when Richard came over, I don't think in all the time I've known Richard, which has been about three and a half or four years, I didn't notice how much he was into, like, bling phones. And when he whipped his phone out, I just couldn't stop laughing. So the first, like, ten minutes of this podcast are us talking about this ridiculous thing that I hope we have pictures of to link to in the show notes. Obviously, the show notes are usually timestamped, so you can skip past the patty cakes and get to the meat of the discussion should you want. But that said, I can't highly enough recommend listening to Richard talk about his slot machine addiction and his funny phones. We talk about the etiology of Alzheimer's to the best of our ability to understand it. We talk about the incidence, prevalence, and the distinction between those two. We talk quite a bit about the distinction between men and women. As some of you may know, there seems to be a bias towards women getting Alzheimer's disease more commonly than men, and both Richard and I agree that that's probably not just an artifact of women living longer. There must be something else going on there, and we explore that topic. We go into great detail about what we believe the state of the evidence is, which admittedly at this point is still relatively early, about what steps people can take to reduce their risk of Alzheimer's disease. And we get really into the semantics of this. What is the difference between risk reduction and prevention? And we talk all about the politics of that and how those have changed. We give-- When I say we, meaning I discuss with Richard, and Richard gives a great overview and primer on APOE. We've had a lot of questions on APOE, and we've deliberately punted those from the AMA because I knew that this discussion with Richard was coming up. So for many of you to have questions about the APOE gene, I think you'll find that interesting. And I'll tell you something that I learned even in this discussion was so much of the subtlety around other genes that are named and unnamed at this point or SNPs that we know about versus don't know about that also seem to be predisposing to Alzheimer's disease. Unfortunately, this is a disease that is going to touch pretty much everybody who's gonna listen to this podcast indirectly or directly. In other words, if you're listening to this, there's a non-trivial chance that you already know somebody who's afflicted with Alzheimer's disease, and tragically there's an even greater likelihood that at some point you will, whether it be a, a parent, a loved one, or a friend or something like that. So I'm relatively unabashed in my praise for Richard's work, and I'm relatively shameless in my plugging for people to fund this type of research. The type of research that Richard does is relatively unsexy. People don't really know what to do with clinical research that is focused on Alzheimer's prevention, and probably somewhere in the vicinity of like 10 basis points worth of resources, meaning like one tenth of 1% of resources are going into funding this type of work. And after this podcast, Richard and I went out for dinner and we talked about a gift that a patient of mine gave Richard. It was about a $50,000 gift or a $40,000 gift, which is obviously a lot of money, but in the grand scheme of the types of dollars that people are pouring into this research, it's not that much. And Richard was able to walk me through what came of that gift from that particular patient, and I was so blown away that I got, I came home from dinner and I actually emailed him to tell him the impact of his actual dollars. And I will say this, having spent a lot of my time around biomedical research, it is very rare that a $40,000 gift can move the needle. So if anybody's listening to this and they do feel touched and compelled to get involved in this space, whether it just be through the standpoint of education and understanding or through funding research, I think Richard's team at Cornell is doing exceptional work. So finally, I'll just close by saying a couple of housekeeping things. One, there's a weekly email that has grown immensely in popularity, so I wanna make sure that people who are interested in receiving such an email know about it. You can sign up for it on the site. Every Sunday morning I shoot out an email that kinda highlights things that are interesting to me over the course of the week. I promise to do my best to make it not lame, such that it's actually an email worth receiving. Remember on the show notes for this podcast and every podcast are always found on our website, and we put an unbelievable amount of time into that. In fact, more time goes into that than goes into the podcast. The podcast, you know, two and a half hour discussion, I might spend two hours preparing for it. Bob and Travis, two of our analysts, spend double digit hours preparing those show notes, and the feedback has been excellent. So for those of you that maybe aren't utilizing those, this might be something to consider. And of course, if you do find this enjoyable, by all means please go to Apple, leave a nice review on iTunes, and I guess you can leave a review if you don't like it as well, but I won't push you quite as hard. So without further ado, uh, welcome to my interview with Dr. Richard Isaacson. [upbeat music] So Richard, thanks so much for coming over, man.
- RIDr. Richard Isaacson
Sure. Thanks for having me.
- 8:02 – 15:38
Luxury Vintage Phones and Bling Collecting
- PAPeter Attia
It's not a far walk, is it?
- RIDr. Richard Isaacson
Four minutes.
- PAPeter Attia
Very well. What do you think of the coaster I gave you?
- RIDr. Richard Isaacson
I don't know if that was intentional, but we have, uh, someone with dementia pugilistica on the coaster, Muhammad Ali. And my brother's a Parkinson's specialist, so he would be the right one to talk to, but, uh, yeah, amazing guy.
- PAPeter Attia
I gave you my Muhammad Ali coaster without even thinking about the implications of that.
- RIDr. Richard Isaacson
Serendipity or synchronicity, which one is that? I'm not sure.
- PAPeter Attia
Okay, so before we start this, I just learned something about you today that I have known you for a while, I thought I knew everything.
- RIDr. Richard Isaacson
[laughs]
- PAPeter Attia
But as we were just getting ready to record, I was like, "Oh, uh, by the way, let's just stick our phones on airplane mode," and you whipped out your iPhone and you put it on airplane mode, and then you whipped out this white and gold diamond studded thing.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
Can you tell our listeners what that thing was?
- RIDr. Richard Isaacson
Yeah. Well, I'm a very practical guy, so I collect luxury vintage cell phones. It doesn't connect to the internet. Every 75 text messages the memory gets full, so I have to delete them all. It's very practical. Yeah, I collect vintage luxury cell phones.
- PAPeter Attia
The word collect implies you have more than just that white thing that's-
- RIDr. Richard Isaacson
Seven. Seven, yeah.
- PAPeter Attia
Describe what it has on it.
- RIDr. Richard Isaacson
Well, it's, uh-
- PAPeter Attia
Besides the alligator skin on the back
- RIDr. Richard Isaacson
Sure. It's white alligator. It came from Africa, it then went to Italy, and then it, the skin was then shipped to the UK. I had to get all the passport, I had to get all the paperwork 'cause it got stuck in customs for, Fish and Wildlife had that phone in customs for like three or four weeks when I ordered it because they couldn't verify that that wasn't an endangered species. So they found all the paperwork, then I had to get the paper trail of where the fabric came from. It's, uh, alligator, white alligator. It was actually assembled though, the phone was assembled in the UK. And it's got white sapphire keys. It's a pseudo BlackBerry, it's actually a Nokia. The Nokia's actually from 2008. The phone was built in 2010. In 2010 this was the phattest phone on the market, so it's-
- PAPeter Attia
And that's PH phat.
- RIDr. Richard Isaacson
PH, phattest.
- PAPeter Attia
For, for the young people.
- RIDr. Richard Isaacson
With a PH [laughs] yes. So we have white sapphire keys. We have 18 karat gold trim, white alligator, of course, say that a few times, surrounded-
- PAPeter Attia
Were you dating anyone at the time you got this?
- RIDr. Richard Isaacson
You're very perceptive actually. Uh, but wait, I didn't talk about the diamonds. It's called a diamond pillow.
- PAPeter Attia
Am I allowed to include a picture of this thing in the show notes?
- RIDr. Richard Isaacson
[laughs] Absolutely.
- PAPeter Attia
I'm looking at it as you're describing it, and I can't freaking believe everything you're saying except that I'm looking at it. So I know that whoever's listening to this right now is thinking, "What are these two clowns talking about?" But they need to see this thing.
- RIDr. Richard Isaacson
It's called, like, a diamond pillow. Like, that's what they market it as. But, [laughs] anyway, it's on airplane mode so I can keep it on the table.
- PAPeter Attia
No, no, I, please keep it on the table because that thing is fantastic.
- RIDr. Richard Isaacson
Oh, wait, wait, wait. Check this out. The ringer, this is no joke, I mean, I'm being recorded so you can, like, verify this, but the ringer for these phones was recorded by the London Symphony Orchestra specifically for this phone line.
- 15:38 – 24:38
Early Life, DJ Rush, and the Path to Neurology
- PAPeter Attia
Okay. Well, on to the mundane. I was reading through something, 'cause we've known each other for several years now, but there are, like, a bunch of things you just don't know about a person until you realize, "Oh, you know, I'm gonna sit down with Richard and talk with him. I wanna learn at least, like, five things about him that, like, tell me a little bit about how he got to where he got." And so I'm reading through this, and the two things that I learned... Well, now three, given this cell, this bling phone thing. But the two things that I learned about you were you had finished medical school before I had started medical school. You finished med school at 23. The other thing I learned about you is you were a rip-roaring DJ.
- RIDr. Richard Isaacson
DJ and recording producer. My name was DJ Rush. I had a recording studio in my basement growing up with my bar mitzvah money, actually. I, uh, took all the money and bought out this other guy's, older guy's old recording studio. So I got, like, again, it's all about value. So I spent, like, three grand, which was a lot back then, huge amount of money, but it was all of my bar mitzvah money, all the presents, and I got, like, 12, $15,000 of recording equipment, and magically I set up a recording studio. And I actually put an ad in the PennySaver. I'm dating myself now. I grew up in, uh, in Suffolk County in Long Island, in Commack. And, uh, I put an ad in the PennySaver, and people in Queens were my best customers 'cause people in Queens would usually go to the city and pay all this money for recording, but then they would come out east to Suffolk County, and that's how I made money in high school.
- PAPeter Attia
Did that help you fund college or anything like that?
- RIDr. Richard Isaacson
No. I was a computer tutor. I had, like, 400 bucks in cash from computer tutoring for college that I got to use. Uh, no, I didn't-
- PAPeter Attia
You ended up spending that money. You reinvested it. You reinvested the recording-
- RIDr. Richard Isaacson
Yeah, in music equipment. Random, weird guitars shaped, the NJ Warlock, like, this weird looking guitar thing. Yes, I like weird.
- PAPeter Attia
It's not weird, man. It's beautiful.
- RIDr. Richard Isaacson
Appreciate it.
- PAPeter Attia
Embrace it. When you went to med school, did you know that you wanted to be a neurologist?
- RIDr. Richard Isaacson
Sorta, yeah. If you don't think I'm a dork for collecting luxury vintage cellphones, this is even more ridiculous. But- I was in summer camp in sixth, seventh grade, and it was teen travel, and we would go to, like, I think we were on a trip to Tennessee actually, and, um, we were heading on down to Nashville, and on the bus I brought... [laughs] I shouldn't giggle, but Neuroanatomy Made Easy and Understandable.
- PAPeter Attia
It's like Neuroanatomy for Dummies-
- RIDr. Richard Isaacson
Exactly
- PAPeter Attia
... part of the same series.
- RIDr. Richard Isaacson
Yep, yep. That's exactly what it was, and this is, I was in sixth, seventh grade, and my brother was a neurologist.
- PAPeter Attia
Your brother's older?
- RIDr. Richard Isaacson
He's older. Yeah, he's 13 years older than me. So he was finishing med school also at 23. He did a six-year program also. I was 10, so, um, I got his hand-me-down books. He would leave them in the room, and I would, I guess, read them. So I think I was interested in the brain, but I could never, even though I had this book, I would read this book 100 times, I have no conception of neuroanatomy. I just, like, it's just, like, way over my head, even though I started studying it when I was 11.
- PAPeter Attia
So you guys are from an underachieving family. You also had an uncle, I believe, that was diagnosed with Alzheimer's disease when you were quite young. Is that right?
- RIDr. Richard Isaacson
Yeah, so my uncle was diagnosed when I was in high school, and I always knew I was going to be a neurologist. I didn't know exactly which area or which field. I think the brain was interesting. I also kind of chose neurology because it was the most challenging. I wanted to be challenged for my career. But honestly, when I was in residency, I guess I just felt a connection to older people. I didn't exactly have grandparents. I only had a grandfather who passed away when I was eight. I didn't meet any of my other grandparents. They passed away before I was born. And I don't know, I just felt a connection to older people, so that was part of it. I guess I could have seen myself doing Parkinson's disease. I, actually, in some ways, the plan was to go to, like, a, as best of a residency as I could so I could then one day join my brother in practice, live in Florida. But I wasn't sure about Parkinson's. I liked it. I liked Alzheimer's also. I liked cognitive neurology. Um, I actually trained in Beth Israel Deaconess Medical Center in Boston, where cognitive neurology really was born. It's the first place in the United States. A picture of Norman Geschwind was in the, uh, conference room. So, um, long story short, I think cognitive neurology was always challenging and interesting, but I didn't just want to do phenomenology, like, ooh, look at this aphasia or look at this whatever. I wanted to treat patients, and I think because I understood what it was like, you know, Alzheimer's is terrible. It's just, like, a terrible, terrible, horrible disease. I don't want to get, like, you know, emotional and upset, but it's just terrible. And this, like, my Uncle Bob, uh, introduced my parents, so that's number one, so that's why I'm here today, and this is a completely true story. I was three. My Uncle Bob was in the Navy, and I was at my Aunt Carol's house also in Long Island, and I jumped into the pool. I sank to the bottom, and everyone was inside, and my Uncle Bob ran out, jumped in, and saved me.
- PAPeter Attia
Mm.
- RIDr. Richard Isaacson
Uh, to this day, I actually avoid water. I hate swimming. I hate o- I don't go in the ocean. I don't go in baths. I mean, I stay away from water as-
- PAPeter Attia
You were traumatized by that near drowning.
- RIDr. Richard Isaacson
Oh, yeah. Oh, yeah. I can't even, I don't want to go near a pool. I don't go in pools. I don't like the feeling of water. My Uncle Bob obviously was a special guy, but just to see, like, he was the life of the party. That was, like, that relative where he had a saying, "What a party," like, at, at all the weddings and, and whatever. So, uh, just to see someone like that become what he became and then just to see what the toll took on his daughter and sons, just, it was just a terrible, horrible disease. So I think I empathized with it, I understood it, and that's really where I chose to forge the career path.
- PAPeter Attia
I think it's so interesting how many people in medicine have a story about a moment that, either a moment or an interaction or a relationship that became so pointed in their decision to enter medicine. I don't think that's absolutely necessary. I mean, I think many people enter medicine for sort of less specific or less tangible reasons, but, but I'm always amazed by these stories, so I appreciate you sharing that. Let's fast-forward a little bit and talk about, you finished residency in Boston.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
And then did you come back to New York?
- RIDr. Richard Isaacson
No, so I actually left New York for longer than I was in New York. I graduated at 17. I spent six years in Kansas City. This is a six-year medical program, and so I finished early. This is how the way most other countries do it in Europe and in Asia, but actually the unique part about our program was medical school from day one. So I'm 17 years old, University of Missouri in Kansas City. I had my lab coat, and literally Tuesday and Thursday I was in the hospital, and Monday, Wednesday, Friday I was in college, and it was a very unique, um, blended program, and I couldn't ask for anything more. I had literally six years of medical experience. I was doing tons of medicine. I was doing electives throughout the country, throughout the world. I did a, a history of neurology tour throughout Europe, uh, for one of the elective months. So I just got-
- PAPeter Attia
Mm.
- RIDr. Richard Isaacson
So much medicine exposure. Usually medical students get two years of clinical medicine. I had, like, six years intermittently of clinical medicine.
- PAPeter Attia
Mm.
- RIDr. Richard Isaacson
So I did that, then I popped over to Miami for a year to do medicine training and then to Boston for three years, and then I, uh, headed back to Miami. My mom was down there. My family's down there. So I headed back down there, and I was in Miami for eight and a half years.
- 24:38 – 29:42
Miami, the Regenerates, and Moving to Cornell
- PAPeter Attia
So then what got you to New York?
- RIDr. Richard Isaacson
I guess in life one needs to make a decision kinda where one goes and one, what priorities one has. Miami was amazing. I had amazing opportunities. Um, I wrote a book back in 2010, and then it came out, like, first week in 2011, called Alzheimer's Treatment, Alzheimer's Prevention: A Patient and Family Guide. And, um, I put together in this book this plan about what I do for my patients. I used to... I was known in Miami for spending a lot of time with patients. And when patients would leave, they would always have, like, 10 things to do or 15 things to do, and that was very unique because most people, the neurologists, there's a saying, it's called diagnose and adios, and neurologists don't treat disease, we admire it. Well, not me. I'm going to because of my family history, because of whatever, one thing leads to another and I wanna do anything and everything as long as it's evidence-based and safe. So I was known for jamming the printer in the neurology [laughs] department 'cause my recommendations was, like, sometimes 10 pages, 15 pages, and I put together a nutrition little pamphlet and this. And, you know, it got to the point where I was jamming the printer so much that I went to Kinko's, I had it bound. It was more expensive to bind it, so I wrote this book, and I would give the book to the patient. It was, like, printed out, like, $2 to print out the book. So I would give the book to the patients, and then magically The Today Show called one day needing an expert about, like, music and Alzheimer's disease, which I had, I talked about publicly. Next thing I know, I'm selling hundreds of books online and put up a website and all that kinda thing. So why do I tell this story? I tell the story not to sell books. I don't care about selling books. But when I wrote the book, I got a lot of flack because in the title I wrote Alzheimer's Treatment, Alzheimer's Prevention. This plan, what is this plan that you're telling people to do? Show me the evidence. You know, there's FDA-approved drugs that may work marginally, but what is all this other stuff you're doing? It's crap. So, you know, I talked to the Alzheimer's Association on the phone and they said, "No, you can't say this." And I talked to the... Actually, a colleague, I shouldn't really say this, but there's a colleague on the, down the hall from me in, in my academic appointment. I knew his wife did this. I shouldn't be saying this. Again, it's being recorded, but whatever. His wife wrote a really negative, scathing review about my book. It was actually probably him writing the review. And I said to myself, "But I really believe in this." I'm not trying to sell books. I don't give a crap about books. I made the book large print, and it costs more money to print, and I make less money per book, and I don't care. I want better quality pages. But... And I just... I don't want to say that someone questioned my integrity or whatever, but I guess someone questioned [laughs] my integrity, and I, I'm not trying to sell something and believed in it. And the only way to prove in a rigorous way that multimodal interventions work, whether it's patient education, lifestyle interventions, pharmacologic management, everything, the only way to prove that that works, the only way to do that is in a large academic medical center, and I basically interviewed in, uh, New York and Boston. I, I was about this close to going back to Boston. I had a great offer at Harvard. Would've been a major stepping stone in my career to be that age and that level to be an associate professor and, you know, director of an Alzheimer's clinic. But they wouldn't let me use the term prevention. So then I came to interview at Cornell and, uh, my chair said, "Oh, yeah, Alzheimer's prevention, that's probably gonna be something new. Sure." And, uh, the dean, as she was signing my letter back in 2012, said, "No, I gotta meet this guy." So July 4th weekend 2012, I'm all like, "Uh-oh, I was about to move to New York. What's happening?" And I go meet her, and I got a 15-minute meeting. I had to sell her on... 'Cause it's literally the only place in the country that I, that was, I was allowed, 'cause I called around and whatever. I wanted to start this Alzheimer's prevention thing. And she interviewed me and she, you know, had read, had my CV. It was, like, I think-
- PAPeter Attia
This was the dean of Cornell's medical center.
- RIDr. Richard Isaacson
Dean of Cornell Medical School. Dean of-
- PAPeter Attia
This is, like, the CEO of the medical center.
- RIDr. Richard Isaacson
Ex- exactly. The dean of the medical school says, "No, I'm not signing this guy's letter. We're not starting an Alzheimer's prevention clinic. That's crazy. I have to meet him." And I was given 15 minutes on my, on her calendar to plead my case, and, uh, the first question she had for me was-
- PAPeter Attia
Did you bring in a bling phone?
- RIDr. Richard Isaacson
No, but I was so prepared. I had, like, a collated folder and I had a USB with all the evidence and I was ready to go. And I walk in and she looks at me. She looks down at my CV and she looks at me and she says, "How old are you?"
- PAPeter Attia
She doesn't know you're Doogie Howser, man. You-
- RIDr. Richard Isaacson
She was expecting the traditional bearded, bow tie, older, 50s, whatever, 60s neurologist type, and I didn't look like that. So, um, we talked about my age and my [laughs] training and the 23 thing, which-
- PAPeter Attia
Which by the way, today is probably not even legal.
- RIDr. Richard Isaacson
Pro- [laughs]
- PAPeter Attia
[laughs] Yeah.
- RIDr. Richard Isaacson
Probably. Exactly. And then in the last two minutes of, after talking about the age and how the CV got so long, I basically said, "Listen, I'm serious. This is my plan. I'm not overpromising. Alzheimer's starts in the brain decades before the first symptom. People don't know that." I don't even think she realized that. When someone's diagnosed with dementia, it didn't start that day, it started decades before. I explained this to her. The new criteria had just came out, the new diagnostic criteria had come out, like, that summer, and she said, "Okay, I'll let you do this prevention thing," and, uh, that's it. Th- the only place that I could have gone in the country, possibly the world, who knows, to do what I have tried to do and what I've actually been able to accomplish in the last five and a half years is New York City. It's just, uh... A- and while Cornell and NewYork-Presbyterian has been... The, the saying for NewYork-Presbyterian is, "Amazing things are happening here," and I'm not trying to give a commercial, but there's just no other place that I would've been able to do this.
- 29:42 – 38:03
How Alzheimer's Is Diagnosed and Distinguished from Other Dementias
- PAPeter Attia
So you mentioned the diagnostic criteria, so let's start from the beginning because at least once a week I get a call from a friend or a patient saying, "I think my mom or my dad is in the early stages of Alzheimer's disease," and I say, "Well, tell me why. Tell me a bit more," and they're like, "Well You know, my mom's just having a harder time remembering things, she's repeating herself, or my dad is, you know, having a hard time fill in the blank, right? So how is the diagnosis of Alzheimer's disease made and how does it differ from other types of dementia?
- RIDr. Richard Isaacson
Alzheimer's disease has traditionally been a clinical diagnosis, meaning you talk to a patient like you were doing, you get a history of progressive short-term memory loss, and when that memory loss and other cognitive changes, and sometimes sleep trouble and behavior changes, depression, agitation, whatever, so cognition, sleep, psychiatric comorbidities, when all of these cognitive brain symptoms cause activities of daily living to be no longer able to be done by that person, then that person has something called probable Alzheimer's disease dementia. So in the past, the clinical way was to talk to the patient, progressive short-term memory loss, common things happen commonly, it's probably gonna be Alzheimer's disease. Now, it's about 60, 70% of the time. When people get older, sometimes they forget things. They lose their keys, you have a word on the tip of your tongue, but you remember it later. You find your keys later. That can be non-pathological changes associated with age. So there's something called age-related cognitive change or cognitive aging is even the more appropriate term. Cognitive aging is separate from Alzheimer's disease, but it doesn't lead to a pathological diagnosis in the brain, and it doesn't lead to alterations in activities of daily living. People can still take care of themselves. They can still f- pay bills and function independently. So Alzheimer's disease is the most common form of dementia, but there's different forms of dementia also. There's frontotemporal dementia, which is more of a behavioral problem. There's dementia with Lewy bodies, and that's similar to Parkinson's disease symptoms along with dementia.
- PAPeter Attia
It was reported that after Robin Williams' death that he had Lewy body dementia superimposed on whatever else people had speculated was going on. Is that true or is that just a rumor?
- RIDr. Richard Isaacson
Uh, no, that's true. I've heard his wife at a, she was honored at the American Academy of Neurology last year and I, and she talked about this and he, I didn't treat him, I don't diagnose, can say only from a periphery, but it seems from what I've heard, some of the paranoia, the hallucinations, the slowed movements, the vivid dreams, acting out dreams, it seemed pretty consistent with-
- PAPeter Attia
And would those be different from a patient presenting with the more typical Alzheimer's disease? In other words, are those slightly more unique to Lewy body dementia?
- RIDr. Richard Isaacson
Yeah, so you know, by far Alzheimer's disease-
- PAPeter Attia
Which I've been told, by the way, can only be diagnosed in an autopsy.
- RIDr. Richard Isaacson
Yeah, I mean, it, I'm a clinical diagnostician, so it's a new era, it's a new l- world. So when your friends or your patients call you and say, "Does my mom have Alzheimer's disease?" You listen to the story. Neurologic diagnosis should be made based on the history 80 to 90% of the time. So I, I still always defer to the clinical impression. But in 2018, '19, '20, et cetera, it's just a different world. We can do biomarkers. So we can do scans and does the person have amyloid in the brain? Well, that's Alzheimer's. But then again, people with Lewy body dementia also have amyloid, so it's confusing. But long story short, when people have progressive short-term memory loss and, and other cognitive changes, it's probably Alzheimer's until proven otherwise. The key thing is that we wanna rule out reversible causes, so make sure they don't have thyroid trouble or B12 deficiency, things like that. Pretty uncommon, 5% of the time, 8% of the time, whatever it is, and a lot of times people have a thyroid problem or a B12 deficiency, you'll fix it and maybe the symptoms will get a little better, but they may have Alzheimer's anyway. So we wanna rule out reversible causes. We always have to do some brain imaging, either a CAT scan, gotta rule out a tumor, or a MRI. Now the American Academy of Neurology states you can do any brain imaging. Um, in my clinical practice we always recommend an MRI. Um-
- PAPeter Attia
And what phase of MRI?
- RIDr. Richard Isaacson
Just a regular MRI, no contrast. I just wanna make-
- PAPeter Attia
T2? Is it, which image are you looking at, the T1 or the T2?
- RIDr. Richard Isaacson
Well, I wanna look at everything. You know, is there a vascular burden? Could this be vascular cognitive impairment by itself? Could this be vascular and Alzheimer's? 'Cause about 35% of the time you have Alzheimer's and vascular cognitive impairment. So you just wanna get a sense of what it looks like. But, but to me, when I look at an MRI, I look for atrophy, shrinkage of the brain, and if the frontal lobes, which is the planning, processing, higher order thinking part of the brain, and the temporal lobes, which is the memory center of the brain, especially the part of the brain called the hippocampus. Hippocampus I think in Latin means seahorse, basically looks like a little seahorse thing when it's cut. And if there's a hole in the hippocampus, you know, where the big space of shrinkage, even without all the fancy biomarkers, which we'll talk about, progressive short-term memory loss and atrophy in the brain in certain Alzheimer's specific areas, especially the hippocampus, is Alzheimer's still proven otherwise. Now again, it's a new era. We can check for amyloid in the brain. We can look for amyloid and tau in the spinal fluid. You know, even soon we'll be able to do tau scans. Tau protein is another like amyloid pathologic protein that gets built up in the brain of a person with Alzheimer's and, and you can look at these biomarkers to make a definitive diagnosis, does this person have Alzheimer's? The only main reason to do that is if we're gonna think about a clinical trial, because if you get into a clinical trial, the only way to do that is to have Alzheimer's in the brain and in the past, and we'll talk about why have so many Alzheimer's drugs failed, why have studies left and right failure, failure, failure. There was one study that, you know, this was only like five or six years ago before the era of biomarkers, there was one study where 40% of the people with a clinical diagnosis of Alzheimer's disease in the study did not have amyloid in the brain. But they were getting anti-amyloid treatments.
- PAPeter Attia
This was later found with a scan or on autopsies?
- RIDr. Richard Isaacson
Different studies have done it different ways. So the take home point here is that Alzheimer's is a little confusing. You can make a clinical diagnosis, but the clinical diagnosis isn't always correct, so that's why we need to think about biomarkers in certain situations.
- PAPeter Attia
You talked a lot about short-term memory. Where do you see changes, when do you see changes in other parameters of cognition such as executive function or processing speed?
- RIDr. Richard Isaacson
So when I think about the brain, I think about different areas and I don't wanna say like pin the tail on donkey, but it's like, you know, pin the tail on the part of the brain that's manifesting a, a change in cognition. So you know, memory There's short-term memory, there's long-term memory. In able to have a memory, someone needs to be able to pay attention to something, so another area of the brain in terms of cognitive function is processing speed or attention, and they're pretty similar. Then there's executive function, which is higher order processing, judgment, planning, things like that. There's other things. Language is important. Learning is important. If you can't learn something, how can you remember it? So what we do is we try to really hone in on exactly what the cognitive domain or cognitive area is deficient. So for example, when you have someone call you and say, "Oh, my memory's terrible," well, is it really memory? That's what cognitive assessments do. When my nephew was texting... I can't say when I'm texting 'cause my phone's from 2010, but when my nephew is texting at the-
- PAPeter Attia
But you could text in Chinese though.
- RIDr. Richard Isaacson
I could. Oh-
- PAPeter Attia
If you had the other one.
- RIDr. Richard Isaacson
Oh, the other one. Oh, that's a great phone. Next podcast I'll bring that. Someone's texting and not paying attention, and then I ask my nephew a question 20 minutes later, it's not like they forgot. They never even-
- PAPeter Attia
Yeah, they never assimilated.
- RIDr. Richard Isaacson
Exactly. They never encoded it, it never got into the memory. So, so we always want to make sure, is this an attentional thing? 'Cause for example, common things happen commonly. Dementia, common, but depression is also very common, and a pseudodementia of depression is very common. So if someone says, "Oh, I can't remember," but if they're depressed, whether it's a serotonin issue, whether it's whatever, and you do the testing, they're not able to be attentive during the exam, so they're not remembering. If you treat the depression, for example, serotonin drugs or whatever else, well, then the attention gets boosted and then the memory comes back. So it's not a dementia due to a neurodegenerative condition, it's a pseudodementia due to depression. So there's a lot of things out there, and that's why getting to the, the root of the which area of the brain is truly not working is key. Short-term memory, long-term memory, processing speed, attention, that kind of thing.
- 38:03 – 49:36
Cognitive Testing and the Rise of Brain Health Centers
- PAPeter Attia
It was about three or four years ago when I realized I wanted to start including cognitive testing in our assessments in our practice. And so Dan Pelchar, who, uh, was one of our analysts at the time, I said-- I tasked Dan with this problem. I said, "Dan, I want you to go out there and I want you to learn everything about cognitive testing so that we can get the best in class. You know, we're gonna do the best blood testing imaginable. We're gonna do the best this, the best this, the best this, the best cognitive testing." Well, that turned out to be a fool's errand-
- RIDr. Richard Isaacson
Oh, wow
- PAPeter Attia
... because he came back with, I don't know, 27 different tests that one could do. Some of these were clinical tests, like the NIH had a toolkit with all of its tests within it, but then there were a bunch of commercial tests you could do online and, you know, looked at this stuff and, I mean, my take on the sort of commercially available ones... 'Cause there was one problem that immediately became obvious to me, which is it took a great deal of skill to administer a subset of these tests. So immediately said, "We're not gonna do those tests 'cause, like, we don't have the skill to do it and we're not gonna invest the time to do that because we don't have the patient volume. Like, we're not an Alzheimer's clinic," right? So we, we figured we have to use an off-the-shelf thing. And I was like, "These all strike me as, like, kind of bullshit." But I was like, "Look, here's the definitive assessment we're gonna do." I, and I had Dan... Maybe I shouldn't be saying this story online, but it's probably legal. If not, let's bleep this part out please, Bob. I basically had Dan and a bunch of his buddies, like, get together one night at their place, they're all over 21 by the way, and take the test. Each of them took the test, like, there was, like, f- six guys, each took the test, and then do a shot. I provided the alcohol. And then redo the test, and then do a shot, and then redo the test, and then do a shot, and I think they did this for six rounds. And my question was, if the test is truly a measure of cognitive capacity that cannot be learned, their performance should deteriorate. If you can learn the test, then their performance should stay flat or even get a little bit better as they become inebriated. And of course, their performance was flat. So, like, six hours later, you know, whatever, they're eight drinks into this thing, they're hammered, they're doing just as well on the cognitive test. At that point I was like, "Okay, we are not gonna solve this problem using over-the-counter commercial tests." And that's when, you know, you and I already knew each other, but that's when I was like, "All right, Richard, what is going on with this cognitive testing thing?" And then I came into the clinic, I met you, I met Holly, I met the team, and I was like, "Oh yeah, we're never doing this." [chuckles] Like, "We're gonna send our high-risk patients to you guys because this is way too much work."
- RIDr. Richard Isaacson
Oh.
- PAPeter Attia
It's, it's really complicated.
- RIDr. Richard Isaacson
Oh, this has been complicated for decades. And you know, just to t- tell a quick story. I mean, first of all, our battery, the cognitive test we do is we, we do about a little more than half on computer because, you know, we use the NIH toolbox. We also use odor identification, which is important, and that's hard to have a practice effect on. Some tests are less practice affectable-
- PAPeter Attia
Mm-hmm
- RIDr. Richard Isaacson
... other, other tests are common to expect that. We use pen and paper tests. So what we've done is we've put together an hour and 20, 30 minute battery that kind of is the greatest hits that tries to look at people that are, you know, in the normal/very early phases of Alzheimer's. The, the problem is, is that most of the cognitive tests out there have really been scaled or, or used and validated and, and meant for people with dementia.
- PAPeter Attia
So they're not sensitive to pick up people with early cognitive decline who do not have dementia.
- RIDr. Richard Isaacson
Exactly. And the newer tests just don't have the robust validation in, in people who are normal versus normal, no amyloid in the brain, versus normal with amyloid in the brain. And until we have thousands of people that do that, any off the shelf, and certain- any s- some are better than others for sure, we just don't have the perfect solution. W- this actually is a great time to talk about this, but this past weekend we had the first ever Alzheimer's Prevention Clinic and Brain Health Clinic Symposium where all of us, so there's six, uh, centers like this, like ours now. We were the first in 2013.
- PAPeter Attia
Where, where are the other five?
- RIDr. Richard Isaacson
In 2014, the Alzheimer's Risk Assessment and Early Intervention Program in the University of Alabama at Birmingham, uh, opened 2014. Very different model than us. It's a two-visit model sort of thing. They get an MRI and they do-- It's just a different way to do it. Great person down there, David Gelbard. Then actually we opened a satellite clinic in Puerto Rico.
- PAPeter Attia
Yeah, I remember.
- RIDr. Richard Isaacson
Um, the Alzheimer's Prevention Clinic and Research Center Puerto Rico. Doing amazing. Everything was great. And then-
- PAPeter Attia
Then the hurricane.
- RIDr. Richard Isaacson
Oh, boy. She didn't have power for six months. She's picking up the pieces. You know, patients coming for prevention, patients just need to come to, like, get electricity and get psychological counseling for the PTSD after the storm. She's calling it PTSD en Pueblo. I think that's what she, she calls it. So that was a tough time, but we're still running. We have the Brain Health Center at, uh, North Shore Hospital in Chicago in Evanston, Illinois, and that's been running strong.
- PAPeter Attia
I'll be there next week.
- RIDr. Richard Isaacson
Oh, cool. Yeah, good, good people over there. They have a very heavily focused on electronic medical record to try to track these things. Newest center is actually two. One's in Boca Raton, Florida, at, uh, Florida Atlantic University in Boca Raton. The Dementia Prevention Initiative, Jim Galvin is like, if you think we do a deep dive, Jim Galvin does the deepest dive. I mean, we're talking to, like, the magma of the earth. He does from bone density to metabolomics and proteomics to EEG. I mean, if there's an outcome measure, he does it, but that's his expertise and he's super great at that. Um, and then the newest center is opening at, uh, the Pacific Jonsson Cancer Institute, but it's, uh, Providence Saint John's, and it's called the Pacific Brain Health Center in Santa Monica, California. Really great people that were recruited from UCLA. David Merrill's one of them. And we're all, for the first time, trying to collaborate and trying to harmonize these measures 'cause honestly, I don't know what the right measures are. We're trying to create an additional free cognitive assessment that can be done online, but the toolbox can only be done on computer and iPad. The versions that we built were actually on the phone.
- PAPeter Attia
Mm.
- RIDr. Richard Isaacson
So we built six versions of something called the face name associative memory test. We worked with, uh, Doreen Rents to help us with this. She's amazing. She validated this where if you do poorly on a face name associative memory, that predicts amyloid in the brain. So what we've done and then we then created all these-
- PAPeter Attia
Do you remember how predictive it was?
- RIDr. Richard Isaacson
Don't quote me on that kind of stuff, but, um, it's pretty predictive. It worked pretty well. I don't remember from the paper. But we created these tests, and it was not the NIH per se. It was a different reputable organization. Because the words Alzheimer's and prevention was in our name, they didn't want to use our tools or really be associated with our program [chuckles] so we've been getting tomatoes thrown at us for quite some time. And for example, this symposium we had this weekend, we had all these brain health centers, we all get criticism and, you know, we all get criticism because, for example, we don't even know what are the right tools to use, which are the best cognitive tests, which is this, which is that. So we've been getting criticism for a long time. However, thankfully, the tide is turning, and it's kind of a, a new day and a new era. For example, even the, you know, last year, the Alzheimer's Association put out 10 tips for brain health to preserve cognitive health. That's amazing. This year at the Alzheimer's Association meeting in Chicago, the amount of the words prevention that were used was, I couldn't believe it. Prevention this, prevention that. Now, now you know that there's a big, big, big debate on, you know, Alzheimer's prevention or Alzheimer's risk reduction, which is the most accurate term. We just got our foundational methods paper accepted.
- PAPeter Attia
Mm-hmm.
- RIDr. Richard Isaacson
And the paper, as we titled it, was "The Clinical Practice of Alzheimer's Prevention: A Precision Medicine Approach." Went through the review process. Now, this is the journal Alzheimer's & Dementia, the journal of the Alzheimer's Association. It's the number one journal of all Alzheimer's journals. It's the number four ranked clinical journal in neurology.
- PAPeter Attia
Mm-hmm.
- RIDr. Richard Isaacson
Okay? Great. Its impact factor, 12.75, whatever it is. This is the first time they've ever published anything from us, so that's good news. But one of the six reviewers said, "No, you can't use prevention in the title. You have to change it to risk reduction." That then led us to write another paper, which I hopefully will be submitting soon, called "Alzheimer's Prevention Versus Alzheimer's Risk Reduction: Transcending Semantics for Clinical Practice," because there's a big difference in my mind about prevention versus risk reduction. There's also implications 'cause when you say prevention, the patient sitting in front of you gets that. When you say risk reduction, what kind of message is that to the public? It's confusing. So there's this whole semantic argument. We went through this with our paper.
- PAPeter Attia
Yeah. I had a different experience several years ago that has given me an, a window into understanding where this resistance comes from. So it was probably four years ago, and I was asked to give a grand rounds and discuss breast cancer, but specifically to discuss the use of metformin in the, uh, risk reduction of breast cancer. And so I gave this long talk about, you know, all of these topics, and one of the implications of my talk was that if metformin could be effective in reducing the risk of breast cancer, the question then became could dietary choices also impact breast cancer? And so one of the questions was posed, if a woman has breast cancer, is she better off eating ice cream or not eating ice cream? And I said, "Look, all things equal, my intuition is she's better off not eating ice cream given that most breast cancers are quite insulin sensitive. They're very sensitive to IGF and a number of other growth factors." This one person in the room who is very senior, quite an opinionated individual who I'm not overly fond of, basically leapt up and down and said, you know, "This is complete bullshit. The moment you start suggesting..." And I, and I had to ask, like, 12 questions to get at the layer of the hostility, but it became very clear to me where the hostility stemmed from, which was an understandable opposition. It was if you start talking about breast cancer prevention, if you start suggesting that a person with breast cancer can change the way they eat to reduce their risk of death from this disease, you are implying that the patient brought this disease on themselves. Now, again, I think that's an error. I think there's a logical fallacy there, but I believe that that logic exists in Alzheimer's disease as well. I think that when, when we talk about Alzheimer's prevention, somehow it is being turned into, well, then you're saying patients are bringing this on themselves. It's their fault. There could be something done to prevent this, therefore... You know, and we don't like that message. So that's what my intuition tells me is this opposition, and unfortunately, I think that type of third grade JV poor understanding of logic and risk is basically slowing down progress in this space immensely, as evidenced by the fact that you can't get a grant. I mean, this was true a year ago. You can tell me if it's true today.
- RIDr. Richard Isaacson
Oh, things are much better now. [chuckles] Things are totally different now.
- PAPeter Attia
There was a day when you could not get a grant to study Alzheimer's prevention if you had the word prevention in the grant title.
- RIDr. Richard Isaacson
Zero. We have three NIH grants now. Actually, I just got a like a fourth little part. So we have like 3.1 NIH grants. I mean, that's not-
- 49:36 – 58:21
Prevalence, Death from Alzheimer's, and Whether It Is Preventable
- PAPeter Attia
So let's start with the following. How do you define in your clinic what a high-risk patient means? What is the definition of a high-risk patient?
- RIDr. Richard Isaacson
Anyone with a brain is at risk for Alzheimer's disease.
- PAPeter Attia
Well, let's take a step further back than that. What is the prevalence of Alzheimer's disease in the United States today?
- RIDr. Richard Isaacson
No one knows. You'll see 5.1 million Americans, 5.3 million Americans, 5.7 million Americans. This is all estimations based on like one county in Illinois from like years ago, and then it's been extrapolated and, and posted all over.
- PAPeter Attia
So why don't we have those data the way we do for cancer, for example?
- RIDr. Richard Isaacson
Alzheimer's is confusing. I mean, there's Alzheimer's dementia, and probably around four or five million people have it, but the best numbers were recently published, uh, the most updated was that 47 million Americans have pre-clinical Alzheimer's disease, meaning Alzheimer's in the brain, but no symptoms.
- PAPeter Attia
Sorry, meaning based on something you would see on an imaging study or a lumbar puncture or... 'cause those would be basically the only two ways you could see something in the brain today, 47 million people would have that finding, that also must be an estimate, but do not yet have cognitive impairment?
- RIDr. Richard Isaacson
Yep. So five-ish million people have dementia due to Alzheimer's. Forty-seven million Americans have Alzheimer's in their brain, but no symptoms yet. There's people before that with no Alzheimer's in their brain and no symptoms, and we don't know if they're gonna get it yet. And then there's a kinda gray area in between called mild cognitive impairment due to Alzheimer's disease, and we don't exactly have the best numbers on that, but it's somewhere between the transition phase between pre-clinical, pre-symptomatic Alzheimer's and dementia due to Alzheimer's. It's stage one, stage two, and stage three.
- PAPeter Attia
When I talk to my patients about death, which if you're trying to practice longevity, you have to be able to talk about death, I share with them the obvious, which is once you've reached about the age of 40, assuming you're not a smoker, your probability of dying from cerebrovascular disease, cardiovascular disease, cancer, or Alzheimer's disease is north of 75%. And almost without exception, the, in, within that constellation of diseases, the one that people fear most is Alzheimer's disease.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
But a, a, a very few patients actually understand what it means to die from Alzheimer's disease, and this becomes a bit challenging when one starts to look at death certificates, and maybe this is part of the problem in coming up with an accurate estimate of that. How do people actually die when they have Alzheimer's dementia?
- RIDr. Richard Isaacson
Yeah, so Alzheimer's disease is a indirect cause of death. You know, for example, when someone gets a urinary tract infection, that urinary tract infection may be treated by antibiotics because the patient will say, "Oh, it, it hurts. I'm going more frequently. Test my urine and give me an antibiotic." But when someone has Alzheimer's dementia, they're not able to convey this.
- PAPeter Attia
And that UTI becomes pyelonephritis, which becomes sepsis, which can kill them very quickly.
- RIDr. Richard Isaacson
Exactly. So some people will put Alzheimer's on their death certificate, and other people-
- PAPeter Attia
And some will say urosepsis.
- RIDr. Richard Isaacson
Yeah. So there's never gonna be great numbers. Alzheimer's is the impetus to death in most patients for sure. They can't report their pain. Close, uh, call him a friend, but he's a patient in the clinic also. Good guy. Uh, I've seen his mom, and his mom was just diagnosed with cancer and, um, she was complaining of abdominal pain, something nonspecific. She saw a doctor, doctor said, "Oh, you know, he's got dementia, he's got some belly pain. You're probably constipated. Here, take some constipation meds." Didn't get better, didn't get better, didn't get better. Turns out she may have pancreatic cancer, and she had a gallbladder something, and now she had to put a stent in, right? Only when she turned yellow did they figure out what the cancer was. So Alzheimer's disease dementia causes a person not be able to express themselves and not be able to care for themselves in certain ways and, and the caregiving has to happen for them. And, um-
- PAPeter Attia
So you see a lot of these aspiration pneumonias.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
You see... You know, my closest friend, uh, one of my closest friends, my roommate in medical school, I just went back to his father's funeral two weeks ago. His father just passed away. He had Alzheimer's disease, but it was very sudden onset, and within the course of eight months, his health deteriorated so quickly, and ultimately he died from cellulitis, obviously. But you can see that this is someone who probably at the very end was at risk for these things because of all these other changes. So, and I've also seen people die from just failure to thrive. They have Alzheimer's disease, and they just can't eat it. They don't want to eat. They completely lose their appetite. They become anorexic, and they be- you know, sort of almost drift into a vegetative state, where unless you would force feed them, they will die relatively quickly. But this also strikes me as part of the challenge of trying to get a handle on a disease that has such a ubiquitous face at the end.
- RIDr. Richard Isaacson
You know, Alzheimer's disease is a life course disease. At every moment Someone is either potentially having silent pathology building up. Alzheimer's is a life course disease, and, and each phase of life, Alzheimer's is a confusing, difficult disease to manage. Ah, you know, end of life, it's more obvious, but towards even the beginning of life, you know, people that are born with the APOE4 gene, for example-
- PAPeter Attia
Which we're gonna talk about a lot
- RIDr. Richard Isaacson
... the most commonly researched gene, um, start off with a smaller brain.
- PAPeter Attia
So you think of Alzheimer's disease the way I think of cardiovascular disease, which is this disease begins at birth. Everybody's on a different plane-
- RIDr. Richard Isaacson
Yeah
- PAPeter Attia
... based on a number of hereditary or acquired risk factors. Your path is not set on that slide. You get to determine it, but your track might be a bit set.
- RIDr. Richard Isaacson
Yeah. You know, you asked me before, uh, what's your high-risk patient? What does that look like? And I, I said, I didn't mean to be glib, I meant, I just was honest. If someone has a brain, they're at risk for Alzheimer's. Okay. Well, everyone has a brain, so go deeper.
- PAPeter Attia
Not, not everyone, technically. I have some counterfactuals.
- RIDr. Richard Isaacson
Not talking politics, not going there. Uh [laughs]
- PAPeter Attia
How did you know that's what [laughs] I was going to say? I wasn't even gonna, yeah, go there.
- RIDr. Richard Isaacson
Excellent. So moving right along. At every point in the life course, a person's risk may change. So early life, midlife, and late life, there's different risk factors for Alzheimer's. And, you know, I agree with you that some people can do everything right and still get Alzheimer's. However, based on population attributable risk models, being conservative, one out of every three cases of Alzheimer's disease may be preventable if that person does everything right. Now, the other two out of three cases, well, hmm, it may not be preventable. Maybe we can delay it. Could we delay it by two years, three years, five years, six years? I have some hot off the press data I sent you right before I arrived-
- 58:21 – 1:12:39
APOE Genotypes, Polygenic Risk, and Deterministic Genes
- PAPeter Attia
Let's talk about APOE, 'cause everybody, you know, I was actually doing an ask me anything yesterday, well, this, the AMAs, and, um, there was a great question about APOE4, and I just punted it 'cause I knew you and I were talking today. So I was like, ah, I love the speed round when I can say, "Next." APOE is a gene.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
It exists mostly in three types, though I, I'm told there are actually a couple of others. But for the large part, there's an APOE2, an APOE3, and an APOE4.
- RIDr. Richard Isaacson
Yep. You get one from mom and one from dad, and that way everyone either has a two three or a three three or a three four or a four four or whatever permutation.
- PAPeter Attia
There are six combinations.
- RIDr. Richard Isaacson
Yep.
- PAPeter Attia
The approximate prevalence, the three threes represent probably what, about 55, 60%?
- RIDr. Richard Isaacson
Yep. You got it. Neutral risk.
- PAPeter Attia
So we call that unity risk, right? Those are the single risk. The two twos are very rare. I've actually never seen a two two.
- RIDr. Richard Isaacson
I've seen one.
- PAPeter Attia
Okay. They're reported at less than 1% of the population.
- RIDr. Richard Isaacson
Maybe two. I think I've seen two.
- PAPeter Attia
And they come with a risk reduction, I believe, of about 20%. At the far end of the spectrum, you have the four four. Now, that used to be reported as 1% of the population, but I see that so often that I think that's closer to 3 or 4% of the population.
- RIDr. Richard Isaacson
You know, in our 600-person cohort, we have 37.
- PAPeter Attia
But you're selecting for high risk.
- RIDr. Richard Isaacson
Of course.
- PAPeter Attia
Yeah. I don't select for high risk, but I still feel like it's about 4%.
- RIDr. Richard Isaacson
Yeah. Yeah, in our cohort, it's like six.
- PAPeter Attia
Now, this is interesting. The very first time I started paying attention to APOE gene, which was about 2011, 2012, the literature said the four four patients relative to the three three patients have a 25-fold increase. I, today we see that number, I think, continually being downward revised. So for my four four patients, the good news that I g- I have three patients in my practice who are four four. The good news for those patients is, look, these numbers are getting better and better. I, I, I mean, you and I, I think offline would agree unofficially it might be closer to four to six X.
- RIDr. Richard Isaacson
I don't even think you can-
- PAPeter Attia
Are you even, are you even more optimistic?
- RIDr. Richard Isaacson
No. Well, I'm just gonna be frank. Alzheimer's and APOE is confusing, and having two copies of E4 does absolutely not mean you're gonna get the disease, and it's a polygenic risk when it comes to-
- PAPeter Attia
Yeah
- RIDr. Richard Isaacson
... the disease. You know, you can have two copies of E4 but n- never have a family member and never get the disease. I don't believe it's medically correct to You know, it's hard to s- you know, split hairs or whatever. I, I don't even think you can say it's 2% or 5% or 20% or whatever percent higher or how many fold, whatever, because you can't know until you know what the other person's genes are.
- PAPeter Attia
Yeah, it's very hard to do, and I think the best that people are doing in these large population-based studies is saying acknowledging the heterogeneity of those other risk factors, all things equal. The last, you know, paper I read basically said 8 to 10X. So again, maybe that's still an overestimate. I believe it is an overestimate, and I think it's certainly an overestimate with all of the interventions we're gonna talk about, but the point here is that's a heck of a lot better than a 20 to 25-fold risk.
- RIDr. Richard Isaacson
Oh, yeah.
- PAPeter Attia
Then you have the three 4s. Now, they represent quite a bit of people. That's like 20 to 25% of the population.
- RIDr. Richard Isaacson
Solid 25.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
In our cohort it's about 40.
- 1:12:39 – 1:19:55
Why Women Face Higher Risk and the Question of Hormone Therapy
- RIDr. Richard Isaacson
So ApoE plus age, higher likelihood of amyloid Then you add in gender. Women plus APOE plus 65 and over, much higher likelihood of amyloid. So again, it's a poly- not just a polygenic, but a poly risk whatever. It amplifies or increases the likelihood of amyloid deposition.
- PAPeter Attia
So you just brought up something interesting, which was the question of females.
- RIDr. Richard Isaacson
Oh, yeah.
- PAPeter Attia
I've always found it hard to believe that the increased risk women see is explained only by their age, meaning their survival advantage over men.
- RIDr. Richard Isaacson
Definitely not.
- PAPeter Attia
Do you... I mean, this, I think I know what my answer is, but I'm, I don't want to, uh, what's the term? I don't want to lead the witness. What is your view for why you think women are at a higher risk than men, all things equal?
- RIDr. Richard Isaacson
Well, you know, you can take different roads to Alzheimer's disease. Diabetes will put you in the fast lane and this and that. Women are definitely in the express lane, and why are they in the express lane? I think it has something to do with, and sure there's, you know, something about life course and, you know, having lots of children versus less children, that can impact it too, and there's a whole variety of things. You know, more stre- you know, whatever du jour study you want to read to attribute this. But my feeling is the perimenopause transition has bioenergetic impacts on the brain and, you know, I believe that Alzheimer's disease is a mitochondrial-based disease. Mi- the mitochondria are the battery of the cell. The mitochondria can cause all sorts of bad diseases from Parkinson's to ALS to whatever, Huntington's, uh, possibly. Actually, that's something separate. So long story short, people think of Alzheimer's as amyloid and tau. I think amyloid is the garbage that accumulates, and if you don't take the garbage out, you, you're going to get sick. But the upstream effect is mitochondrial dysfunction, and there's something about the mitochondrial bioenergetic pathways. I'll just talk in generalities 'cause I'm not an expert at this, but I think there's something about the perimenopause transition, the bioenergetic shifts in the brain that are fast-forwarding a woman to Alzheimer's disease. So I think it's hormonal. How do we intervene?
- PAPeter Attia
Meaning you believe that it's the withdrawal of sex hormones that is accelerating the process of either mitochondrial decline or something that is leading to the accumulation of waste product being manifested as amyloid and tau?
- RIDr. Richard Isaacson
Yeah, it's brain aging accelerator due to the menopause transition, and that's why I think that the, where we're going with our research, and we have a whole sub-research program to look at this, is what is the critical window of opportunity to intervene? Now, how do we intervene and when are the key questions. Do you intervene before menopause, perimenopause? When do you intervene? What do you do? What progesterone, estrogen? Should you use a pill or a cream or a patch? Do you use it for two years, five years, seven years? Do you have to balance the decision based on breast cancer and other things? You know, blood clots and smoking. So I go by my gut in almost all things medical and can say that my understanding of this is kind of like if I had to use a television analogy, maybe we're at the black and white television, but at least we can see a picture, and we're not at color and we're not at high def. But I think that my understanding is evolving, and I think it has to do with brain bioenergetic pathways and an individual woman's risk versus a man's.
- PAPeter Attia
Now, that's interesting because you also brought up Alzheimer's disease has been referred to as Type 3 diabetes or brain diabetes, which of course is also an energetics pathway. So that would suggest that there seem to be at least two, maybe three or more completely distinct, which is not to say there's no overlap between these, but paths towards the disease, because the other one we didn't even talk about was the vascular path.
- RIDr. Richard Isaacson
Two or three? I think there's like-
- PAPeter Attia
Yeah, you, you-
- RIDr. Richard Isaacson
... 12 or 16.
- PAPeter Attia
Yeah, yeah. I mean, I, I talk because I'm sort of a simpleton on this topic. I generally refer to it as three or four different paths to the same place, where you have the same final common pathway. Everybody's accumulating amyloid beta and tau, but you can get there through microvascular disease, which then becomes basically a d- disease of hypoxia. You can get there through diabetes, which then becomes an energetic problem. You can get there, as you described, through a separate sort of mitochondrial dysfunction. I mean, you can think of a dozen things that could lead to mitochondrial dysfunction, among them the one you describe, which to me strikes me as the Occam's razor explanation for why women would disproportionately have this difference from men.
- RIDr. Richard Isaacson
You know, there's this great paper about this by Shelke and Attia.
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
I've read it. It's great.
- PAPeter Attia
[laughs] You know, there was an interesting paper, Richard, about, uh, three years ago. It was a very small paper. I, I don't even remember how many women were in it, but I remember it was v- surprisingly small, and it was, if I recall, also heterogeneous in APOE type, and it asked the question, if you took these women who were either perimenopausal or early menopausal and you treated them with HRT, did you improve cognitive performance? Now, if I believe the result of that study was you did only in the women that had an E4 gene, but not in the women that did not, to which my interpretation was maybe you were just underpowered to detect a difference in the non-E4s, but because the E4s come with another risk, you didn't need that many women to see the benefit. So is it your practice today in the clinic to use hormone replacement therapy in perimenopausal women?
- RIDr. Richard Isaacson
Yeah. This is a tricky one. You know, I've, I know what I know, and I know what I don't know, and I have a very specific scope of practice. I've never, uh, prescribed statins. I've never, I don't treat cholesterol per se, although actually thanks to you and others I've learned a lot about plant sterols versus Zetia, and, you know, I'll make, um, tacit suggestions and I'll use omega-3s and that kind of thing with cholesterol. Same thing with hormones. I would never prescribe-
- PAPeter Attia
Do you have physicians that you, that are willing to work alongside you in these areas?
- RIDr. Richard Isaacson
I mean, I have preventative cardiologists that we see eye to eye. I have primary care doctors that I can see eye to eye with. I have one [chuckles] reproductive endocrinologist in Texas, uh, who we see eye to eye and we speak the same language. I don't really have an endocrinologist or a hormone doctor that I can refer patients to where we can have cogent conversations, because I think the area is just so hazy, the level of evidence is so hazy, and I'll just tell you my... You, you said APOE4 may have something to do with. I also think metabolic status has something to do with this. Roberta Brinton has looked at you know, women with vascular risks, so high cholesterol, diabetes, you know, high blood sugar, whatever, that maybe those patients are the one that respond preferentially to hormone replacement therapy.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
But there's a lot of precision medicine in here that is very hazy. That being said, my kind of off-the-shelf answer would be women early on in the perimenopause transition for the first two, five, maybe seven years, hormone replacement may be a good idea. I just... And probably is a good idea, but I just don't know if you need to take a pill, which pill, what ratio of what to what, and is a cream probably better. I'm may geared towards the latter, but I actually just don't know. There's a study with alprenolone, which I think is gonna be very interesting. So I, I just-
- PAPeter Attia
I have strong feelings about this, so we're gonna go have dinner after this.
- RIDr. Richard Isaacson
Yes, sir.
- PAPeter Attia
We're gonna talk for probably two hours just about this topic.
- RIDr. Richard Isaacson
[laughs]
- PAPeter Attia
This is a huge passion of mine, and I know what's happening right now. Someone's listening to this and they're going, "Wait, just tell us the ans-" And, and no, I don't wanna get into... I don't wanna jump on my soapbox about this, 'cause I wanna come back to talking about this.
- 1:19:55 – 1:29:28
Precision Medicine, MTHFR, and the ABCs of Prevention
- PAPeter Attia
So you alluded to one of the most interesting things in your clinic now. I don't know, are we... Is the manuscript submitted so that, uh, I'm talking about the matrix of MTHFR by APOE biomarker versus cognitive thing. That, is that submitted yet, published?
- RIDr. Richard Isaacson
We literally have... So just, just, just give you a brief snapshot. So we started the Alzheimer's Prevention Clinic in 2013. Took about a year and a half, just under two years to get the IRB approvals and get all of our ducks in a row with getting the cognitive assessments and the IRB approved and whatever. So since March of 2015, um, the last three and a half years and change, we've been, uh, recruiting patients into a registry where we basically follow patients across primary prevention, secondary prevention, and tertiary prevention of Alzheimer's disease dementia, and I can define those in a minute. So when we have this data, we are deep, deep, deep in the data analysis phase, and we literally have, no joke, m- over 1,000 pages of results, data tables, graphs, and I've only scratched the surface.
- PAPeter Attia
So let's explain the intervention. Taking a step back, you're saying, "Look, we're gonna stratify patients by four things. One, genetics." And the genes you looked at were APOE and MTHFR.
- RIDr. Richard Isaacson
Yes.
- PAPeter Attia
Can you say a little bit about MTHFR for the listener?
- RIDr. Richard Isaacson
MTHFR is confusing. When I started the program, I thought MTHFR was a whole bunch of whatever, and now I don't believe that anymore. MTHFR is methyltetrahydrofolate reductase gene, something like that. MTHFR, if you have multiple mutations-
- PAPeter Attia
Do you know how many patients have come to me and said on their test when they look at MTHFR, they're like, "Why does it say motherfucker?"
- RIDr. Richard Isaacson
[laughs]
- PAPeter Attia
And I'm like, "No, actually it's methyltetrahydro-" [laughs]
- RIDr. Richard Isaacson
[laughs] Exactly. So it's quite an interesting gene. You can Google and find all sorts of stuff out there. But MTHFR does have a role in Alzheimer's risk, but to me it is, you know how you can take different roads to Alzheimer's?
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
It's one of those roads.
- PAPeter Attia
It's a metabolic road through homocysteine. I mean, is that what your hypothesis is?
- RIDr. Richard Isaacson
Exactly, yeah. And, um, basically methylation, detoxification, you know, whatever word you wanna use. I don't, I don't love using these words 'cause I just, it's very hazy. But if you have multiple mutations, two mutations in one of your main MTHFR genes, the 677 gene, you know, and this is the back of the napkin. I'm not sure if this is technically correct, but just for listeners, the person may have problems or be inefficient at metabolizing B vitamins, and because of that, they're in the, the downstream cascade of biochemistry, homocysteine goes up and it's a marker for something not working efficiently and well and detoxifying, whatever you wanna say. When it comes to MTHFR, homocysteine in people with Alzheimer's risk, and this is precision medicine, where if someone has an elevated homocysteine but they're treated with B vitamins, they can slow overall brain atrophy and improve memory. However, that will only work if you have optimized omega-3 fatty acids. So this precision component of understanding the person's individual biology is necessary because if you don't have high homocysteine, you probably don't need this stuff.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
You probably don't need B complex vitamins. So in, in this case, MTHFR is helpful in terms of looking at the gene, because if someone is taking the regular B vitamins, if you look on a B12 it says cyanocobalamin.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
If you look at folic acid, it says folic acid. We're giving the person extra folic acid and cyanocobalamin. We're giving them the B vitamins, but their homocysteine's not coming down. They may need a more metabolically active form. And there's different racemic mixtures and there's different biochemical blah, blah, blah that we can talk about and different forms and different companies that make it. Actually, the company that I use for my practice, you told me about because literally reliably-
- PAPeter Attia
Yes
- RIDr. Richard Isaacson
... I, it's in that little bottle and the yellow bottle and-
- PAPeter Attia
It always works. [laughs]
- RIDr. Richard Isaacson
It always works. It absolutely always works. So you know, and, and you can do the prescription version. That actually probably always works, too. [laughs] It's just a little more expensive, but it definitely always works. So I'm going around the block to get across the street 'cause this is complicated, but when a person is not responding to traditional B vitamins, I will then step it up and give them methylcobalamin B12 and methylfolbic whatever, folic, folic acid, methyltetrahydrofolate, whatever version of folic acid. And the combination, that is usually enough to get the homocysteine down. So this is a nice example of precision medicine and pharmacogenomics in our Alzheimer's prevention practice, and I think the table or the, the image that you're referring to is when we basically take all of our patients and we map different people with different genes. Do they respond to different things?
- PAPeter Attia
That's right. It's every, the X axis would be, or the top of the table would be each of the APOE combinations, so here's all six of them. And then each of the MTHFR combinations, there's two genes, four combos per gene, so eight of those. And then it's basically in response to the lifestyle intervention program Where did we see an improvement along which biomarkers and/or which element of cognitive testing? But I guess just to be clear, we're not gonna be able to show that table here. That's not yet published?
- RIDr. Richard Isaacson
Right. Oh, no, no. I mean, that's on page 700 to 900.
- PAPeter Attia
Yeah, yeah.
- RIDr. Richard Isaacson
Yeah. So, you know, the first paper that we got accepted-
- PAPeter Attia
I'd show that to patients all the time, but I mean-
- RIDr. Richard Isaacson
That poster's great.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
Yeah, that's a poster we presented last year, but you, you have to put the cart before the horse or whatever-
- 1:29:28 – 1:36:16
Funding Prevention Research and the Case for Precision Medicine
- PAPeter Attia
This is the thing. Can I just, I'm just gonna get back on my soapbox. Goddammit. I'm allowed to do this, I guess. This is the one perk of having your show. If you're listening to this and you're in some way touched by Alzheimer's disease, either because you have a family member who's got it or you're concerned about anything like that and you're considering, like, funding research in Alzheimer's disease, I can't emphasize enough the importance of funding the type of research that Richard does, whether that means funding Richard directly or somebody else, because Alzheimer's prevention is so underfunded. It is an embarrassment to this disease state. And so—and I've had patients who have said to me, you know, "A loved one just passed away, and I'd like to throw $100,000 at something for Alzheimer's research." And I think to myself, luckily, those patients like to give that money to you because you can do more with $100,000 in your clinic.
- RIDr. Richard Isaacson
Immediately.
- PAPeter Attia
$100,000 doesn't buy you five animals to do a study on a drug that has a 99.6% chance of not working. Let me repeat that. The success rate of pharmacology for Alzheimer's disease is 0.4%. In other words, 99.6 of drugs brought forth to treat Alzheimer's disease are abject failures. Now, if you are interested in the philanthropic side of Alzheimer's disease and you want to put more money in that pot, you must ask yourself the question, which is, what is the definition of crazy? Is it throwing more money into the same pile that's taking the same approach to a disease that's not working, or is it possibly looking to this novel idea of Alzheimer's prevention? Okay, rant over, off the soapbox. Let's go back. [chuckles]
- RIDr. Richard Isaacson
And it's funny, like, if I would've had $75,000 more three years ago- I would have had the right biomarkers so I could definitively say about which omega-3, which this, which that. I could have, for $75,000... You know, we've gone through $8 million in five years. Okay. That's not too bad, actually, I mean, for a major research program. 5 million of it philanthropy, 3 million NIH and other grants. $75,000 extra, I could have definitive evidence about which omega-3s to take. Is it ALA, DHA, EPA? I think it's DHA and EPA, but I wasn't doing the right biomarkers 'cause I couldn't afford the right test.
- PAPeter Attia
Wow.
- RIDr. Richard Isaacson
So for the littlest, tiny investments, you know, we have a data set with 3,000 pieces of data on every patient. We have such a deep phenotypic characterization. I have thousands of pages of data. I don't know how I'm gonna write this up. I need to hire two full-time people for $50,000 per person. We can churn out papers, you know, two papers every few months. So the take-home point is, in an imprecise world, in an imperfect world where I don't have unlimited funds, we have to be cautious. So we've done the best we can, but oh man, I wish if we could have TNF alpha, interleukins, and CD50s, and I, ugh, I wish we could do all this stuff.
- PAPeter Attia
Yeah, and I, and I think the way to think about this if, again, if you're listening to this and you're trying to understand how should funding be allocated, you have to think about this as how would you hedge, right? So I'm not suggesting for a moment that no effort should be made at doing research around Alzheimer's treatment. I mean, the disease is devastating, and you don't have to meet but one person who suffers from this disease to think we should be throwing heaven and earth at figuring out how to treat these patients. The question is, how would you balance that portfolio? 'Cause right now, that portfolio is about 99 to one. $99.9 are going into treatment, $.1 are going into prevention. I'm asking simply, what if it were 90/10? What if it were $90 that go into treatment and $10 into prevention? In reality, I think if it were 10/90, we'd move the needle even more if we were willing to acknowledge that, hey, a lot of people can't be helped right now, which is an awful message to consider. So anyway, I do think that prevention suffers from a number of things. It's way squishier. There's always going to be a bias against the idea that you can get people to change behaviors, lifestyle behaviors. In other words, it's one thing to get a patient to take their pill. It's quite another thing to get a patient to change the way they sleep, the way they meditate, if they do at all, the way they exercise, the way they eat. These things are harder to do. That's the downside. The upside is if you can do those things, I think the evidence is pointing to you can have a much bigger impact.
- RIDr. Richard Isaacson
Oh, yeah, and if, when you do this precision medicine approach where you look at their cholesterol, inflammation, metabolism, we'll talk about in a second, nutrition, biomarkers, genetics, and you take all these factors and you look at their body fat and you look at their cognitive function, which we'll talk about, the ABCs, you can then give them a personalized precision medicine plan, and they end up getting that right plan, and then the outcome is better, and then they're going to have positive reinforcement to where they're gonna keep doing it. I have people that say, "I haven't been able to lose weight my whole life." Uh, you're doing the wrong thing. You run elliptical for 20 minutes three times a week. That's not gonna get you to lose weight. That may get you to maintain yourself a little bit, but not really. You need to do high-intensity interval training. You need to lose body fat. Here's your fat. Here's your this. Here's your that. When you attack it with knowledge about the non-one-size-fits-all approach and the N of one, do everything and everything based on your individual biology and genetics, that's when a person can have the most success. When they have success, it's positive reinforcement.
- PAPeter Attia
Yeah, and I think seeing those biomarkers improve. I saw three patients today in clinic, and in all cases, we're reviewing labs, and it's really-
- RIDr. Richard Isaacson
They love it.
- PAPeter Attia
Yeah, they really like to be able to... Especially the ones that dial into this stuff that think, "Oh, wow, look at how this change led to that, but not this, and what do I need to do more here?" And I mean, I guess in the end, one of the challenges is you and I both have a luxury that not, not a lot of doctors do, which is we have small practices-
- RIDr. Richard Isaacson
Right
- PAPeter Attia
... that allow us that luxury of time. And so hopefully some of these other tools you're developing will allow physicians to be able to scale themselves a little bit by saying, "Look, I, you know, Dr. Smith, might not have as much time as Dr. Isaacson to sit down and spend an hour with each patient going over this stuff, but I can at least point a patient to a tool that can help streamline this process."
- RIDr. Richard Isaacson
Yeah, when I'm sleeping without any PR, without any everything, just 'cause the way the internet works, when I s- go to sleep and wake up, my ex-girlfriend with the phone, the phone thing, who I was trying to show off and impress, she said, "Well, you work so much, and every time you give a lecture, okay fine, but make money while you're sleeping." Well, it's the same thing. I wanna help people and educate people when I'm sleeping. You're, you're right. I see seven patients in a day, sometimes five, 'cause it takes a lot of time, but when I'm sleeping, over 1,000 patients are on that free education website with two hours of interactive educational content about Alzheimer's prevention. That's how we impact lives, so-
- PAPeter Attia
I'm hoping that we can increase that from 1,000 to 8,600 patients while you're sleeping.
- RIDr. Richard Isaacson
I would l- I get the reference.
- PAPeter Attia
The astute listener will get the reference to that.
- RIDr. Richard Isaacson
[laughs] So does my pocketbook, absolutely. So, and it's everything's free, and we don't charge for any of this stuff, but that was an inside joke.
- 1:36:16 – 1:54:00
Metabolism, Cognitive Domains, Statins, Omega-3s and Theracurmin
- RIDr. Richard Isaacson
So I guess as we go back to the ABCs, so the other bio- blood biomarkers, um, that we could probably wax poetic and talk about for another several hours is metabolism, because I believe Alzheimer's disease is a metabolic disease in the vast majority of cases, and we look at, again, we could talk about this for an hour-
- PAPeter Attia
Is that becoming a mainstream view yet? I mean, that was such an out there view six, seven years ago. Is it less out there now? It's hard to ignore the fact that patients with type 2 diabetes have a disproportionate risk.
- RIDr. Richard Isaacson
What the amyloidocentric people and the Tauists, the amyloid and tau people are-
- PAPeter Attia
The Tauists.
- RIDr. Richard Isaacson
The Tauists.
- PAPeter Attia
I mean, that's a sweet title.
- RIDr. Richard Isaacson
That is cool, right?
- PAPeter Attia
I, I would like to be a Tauist.
- RIDr. Richard Isaacson
Yeah. I call it amyloidocentric, but other people say the Baptists. Baptist means bapadenuzumab, which is an anti-amyloid drug. Anyway, the Baptists, Tauists, whatever. I'm a mitochondrialist or, or whatever it is. What I would say is those people that don't get it, most people don't understand that the leaders in the Alzheimer's field that are, like, leading major initiatives, like two of the most major initiatives in Alzheimer's disease, one is led, actually both are led by non- ... clinical physicians that have never seen an Alzheimer's patient.
- PAPeter Attia
Soapbox rant number two coming up now. This would be a good time to hit forward by two minutes if you don't wanna hear the rant. You know, few things chap my ass more than the leaders in the field treating clinical diseases who don't treat patients. And I often get asked, like, "Do you one day see yourself not actually practicing medicine, but instead just focusing on the types of research and collaborative things that you wanna do?" And the answer is always no. The day you stop seeing patients is the day you stop getting humbled by and reminded of what the hell you do this for.
- RIDr. Richard Isaacson
Yeah.
- PAPeter Attia
And what you just said is staggering to me actually.
- RIDr. Richard Isaacson
Yeah. I, I'm not-
- PAPeter Attia
I, I would not have guessed that
- RIDr. Richard Isaacson
... yeah, when I found out this one person had no clinical training and basically did some radiology tra- I sh- I don't wanna talk about specifics, but ... And the other person, like, a related kinda field, but not psychiatry, not geriatrics, like, not the traditional anything, drives you crazy. And then, and then you have this conversation with them or, or you say, "Oh, hey, nice to meet you." And they say, "I heard about you." And you give me the scowl. They give me that scowl. At least they're saying now-
- PAPeter Attia
'Cause you're such a lowlife neurologist-
- RIDr. Richard Isaacson
Right
- PAPeter Attia
... who's, like, on the ground actually touching these patients.
- RIDr. Richard Isaacson
Yeah. Like, "I heard about you. You're that guy. Gr, gr, gr, you know, prevention, gr, gr, gr." At least they're saying multiple shots on goal. Maybe we need to look at other targets aside from amyloid and tau. That's at least what they're saying.
- PAPeter Attia
All right. We'll take it. That's progress.
- RIDr. Richard Isaacson
I'll, I'll take it. And the tomatoes are getting thrown at me less and less, which is good. So let's go back to metabolism.
- PAPeter Attia
And for a guy who doesn't cook, this is a highly inefficient use of tomatoes.
- RIDr. Richard Isaacson
Oh.
- PAPeter Attia
Like, if someone threw a bunch of tomatoes at me, I could make some nice sauce.
- RIDr. Richard Isaacson
Yeah. I've turned on my oven once, and that was in 2001.
- PAPeter Attia
Before you started storing your textbooks in there?
- RIDr. Richard Isaacson
My, my, my textbooks are... That was in 2001 I started putting my textbooks in there 'cause I had no room in Boston. I've, uh, actually, I've put my textbooks and other things in my oven for a long time. I l- I live in a tiny apartment. I have two dogs, two cats. Guy on the couch is a problem.
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
Guy's got a, a, a ... Venting. I gotta talk to my therapist after this.
- PAPeter Attia
Are you trying to figure out why your fiancée hasn't moved to New York yet?
- 1:54:00 – 2:11:42
Five No-Regret Moves: Education, Numbers, Exercise, Blood Pressure and Nutrition
- PAPeter Attia
What do you think of as kind of like the five most important things you tell a person? So let's say you're at a cocktail party and someone finds out what you do for a living. By the way, when I'm at a cocktail party, if I'm ever asked what I do, there are only two responses.
- RIDr. Richard Isaacson
I sell carpet or sofa beds.
- PAPeter Attia
Oh. [laughs]
- RIDr. Richard Isaacson
That's what my dad did. That's a great answer.
- PAPeter Attia
I'm either a shepherd or a race car driver.
- RIDr. Richard Isaacson
You look like a race car driver. You have-
- PAPeter Attia
I thought you were gonna say I look like a shepherd.
- RIDr. Richard Isaacson
No. [laughs] Well, you have that, uh, sheep thing in the corner over there.
- PAPeter Attia
Yeah, yeah. [laughs]
- RIDr. Richard Isaacson
[laughs] The sheep herding stick.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
Race car driver is a great-
- PAPeter Attia
It's just a great way to not have to talk about work
- RIDr. Richard Isaacson
... formula, Formula 1.
- PAPeter Attia
Yeah.
- RIDr. Richard Isaacson
Yeah, I like the-
- PAPeter Attia
I wish. But let's say you're at the cocktail party, someone corners you. In a moment of weakness, you explain exactly what you do, or they've listened to this podcast and they see your picture, and then they come up to you and they go, "Hey, you're Richard Isaacson." And they say, "Look, I'm 30 years old," right? "I'm as healthy as a horse. There is nothing wrong with me. I couldn't even begin to relate to cognitive impairment. But you know, my grandmother was diagnosed with Alzheimer's disease when she was 70 years old, and by 80 she was dead." And let's just assume that the patient doesn't know their APOE status or any of these other things. You're not gonna see this patient again. You know, you're at a cocktail party in Los Angeles and you're flying back the next day. [clears throat] What are five things that you would put in the no regret move list that you could say to that person, even at a general level?
- RIDr. Richard Isaacson
I hate to be general, like too general, but one is knowledge is power. Learn about brain health now because brain health incremental changes that you make now at 30, 40, 50, whatever, the earlier the better. But throughout the lifespan, learn about brain health. So I will refer them to this website. Again, it's free, ALZU.org. There's been 1.1 million people that have been on the site. I'll never be able to treat 100,000 people in my clinic, so Go to the site, learn every single thing possible. I can't tell you everything at a cocktail party
- PAPeter Attia
Are there diagnostic tests that people can do f- to get a sense of their own cognitive abilities?
- RIDr. Richard Isaacson
There are. We don't give results at this time. We have, like, one test that gives results, but it's for research purposes, so-
- PAPeter Attia
But it's for tracking.
- RIDr. Richard Isaacson
It's for tracking. Yeah.
- PAPeter Attia
So a patient can say, "I'll take the test on ALZU once a year."
- RIDr. Richard Isaacson
And there's email reminders to, to tell you to take it.
- PAPeter Attia
And, and do they get results if their performance deteriorates, or do you get a result?
- RIDr. Richard Isaacson
No. This is for research purposes only, so everything's decoded. So right now we don't give results, but give us a little more time, and we unfortunately don't have the funding to analyze this one-million-strong cohort because when you get a million points of data, it's very expensive to analyze, and we don't have the right statistical teams.
- PAPeter Attia
So step one is at least go and familiarize yourself with all of this information.
- RIDr. Richard Isaacson
Yeah. And I'm not trying to be like, "Oh, whatever." I'm not trying to like... Everyone wants that like, "What do I do now, Dwight? What pill should I take? How much should I exercise? What's the magic dose?" To me, it's like if you're gonna really get serious about brain health, it's just not that simple. Our intake at the clinic, it's an hour and a half cognitive testing, hour and a half with me, filling out a 45-minute survey, taking courses online. Before you can even get an appointment with me, you have to f- do all this pre-stuff. Alzheimer's prevention is not simple. Take the time. Y- you're gonna be watching YouTube or flipping through Facebook or doing whatever the heck you're doing to waste time on your cell phone late at night. Take the course online. You're gonna learn things, internalize them, make incremental changes. So number one is education.
- PAPeter Attia
Okay.
- RIDr. Richard Isaacson
Nelson Mandela said, "Education is the most powerful tool to change the world," whatever, whatever the quote was that I mangled, but education is number one. Number two is know your numbers. Okay? Um, what do I do about... I... They want me actionable tips. Actionable it. No, take a step back. Know your numbers. What is your blood pressure? What is your pulse? What is your body fat? What is your weight? What is your cholesterol? What is your blood sugar? Know everything about yourself. Your body is a temple. That's the saying. Know everything about... You know, you and I, um, you use the Oura Ring, I believe. I use, uh, the WHOOP Biosensor, nothing to disclose, whatever. I know everything about-
- 2:11:42 – 2:19:50
Incidence vs Prevalence, Cognitive Reserve, and Closing Thoughts
- PAPeter Attia
So, so I guess the reciprocal to this question, we're now no longer at the cocktail party, but we're sitting back here, uh, at the table. Everything that you described to this woman is, quote-unquote, "lifestyle-based," meaning the top five things that you suggested that she would do once she understood her baseline all have to do with modifying how she eats, drinks, exercises, sleeps, and manages stress. What that makes me wonder is when we see the incidence and prevalence of Alzheimer's disease today higher than it was 40 years ago-
- RIDr. Richard Isaacson
Well, the... I'm terrible with inc- I shouldn't admit this on a recorded podcast, but the rate of Alzheimer's cases is actually coming down.
- PAPeter Attia
The incidence is coming down?
- RIDr. Richard Isaacson
Incidence is coming down.
- PAPeter Attia
Right.
- RIDr. Richard Isaacson
But prevalence is going up because of our aging population, right?
- PAPeter Attia
Okay, but the, but the incidence today is still much higher than it was 40 years ago, even though it's less than what it was 10 years ago. And as you said, of course, the prevalence, which is-- I think of the prevalence as the integral, right? It's the area under the curve of what you're accumulating is so much higher. Both of these facts taken together suggest there is something triggering environmentally Alzheimer's disease more today than 40 years ago, which is usually a constellation of these lifestyle factors. So do you believe that the difference in prevalence today from the year we were born is what percent a result of the changes in these environmental factors you just mentioned versus what percent an increase in awareness and diagnostic acumen?
- RIDr. Richard Isaacson
I've written on this, and my answer is I don't know.
- PAPeter Attia
But it's some combination of both.
- RIDr. Richard Isaacson
It's both. It's both. Yeah. I mean, you know, Alzheimer's is a huge stigma and shame, right? Now people are coming out of the shadows and talking about it more, and there's, like, young people that are talking about it. You know, Seth Rogen has his charity, Hilarity for Charity, and they're raising money for Alzheimer's education in young people. I mean, they're talking about Alzheimer's in high school students and college students-
- PAPeter Attia
Wow
- RIDr. Richard Isaacson
... and medical students. I mean, like, the conversation is not only, like, getting better, but you have, like, people that are speaking up on its behalf and kind of adding a, a new, new flavor to it. So, so there's much less stigma, much more attention to it. Doctors are talking about it. Not just senility or that's normal with age. We now have biomarkers. So sure, sure, we have all that. But we-- it-- this is definitely lifestyle component, too. You know, sitting all day, there's, like, sitting is the new smoking, I think. You know, I've heard whatever about that. That's, like, really bad for the brain. It's not just bad for the... The bigger the belly, as the belly gets larger, the memory center in the brain, the hippocampus, gets smaller. So, you know, m- metabolic conditions and, and lack of activity and sedentary lifestyles, like, it doesn't just affect the belly and the body. It affects the brain 'cause they're all connected.
- PAPeter Attia
So that reminds me of another question that I have, which is how much does mental activity ward this off? You know, we hear so often the anecdote of Bernie was working his little tail away, beavering away at, and then when he retired to play golf, it all went to hell in a handbasket. And then the other one you often hear anecdotally is once so-and-so's spouse passed away, oh my God, the remaining spouse just regressed completely and seemed to have this accelerated case of Alzheimer's dementia. So the, the idea here being once that person retired and they weren't cognitively engaged, and they were, not to say golf is cognitively bankrupt, but presumably it's less cognitively engaging than whatever that person was doing before, or once the sense of purpose, the social support vanishes, again, anecdotally, this seems overwhelmingly the case. Is there any data to support that?
- RIDr. Richard Isaacson
So yes, but it's complicated. The cognitive reserve-
- PAPeter Attia
Can't one thing just be freaking simple here?
- RIDr. Richard Isaacson
No. Alzheimer's prevention? No.
- PAPeter Attia
[laughs]
- RIDr. Richard Isaacson
No, man, this is, this is tricky.
- PAPeter Attia
You sound like me, man.
- RIDr. Richard Isaacson
Yeah, I know.
- PAPeter Attia
Everything's complicated.
- RIDr. Richard Isaacson
Everything's complicated. I wish I could give you a concise bullet point sta- you know, like a m-
- PAPeter Attia
I want a bumper sticker.
- RIDr. Richard Isaacson
Yeah, yeah. Live TV, you gotta give them like a quick snapshot. N- not on this topic. So early life risk factors for Alzheimer's are different than midlife and late life, and early life risk can be mitigated most so by long-term educational attainment. That's the best evidence we have. We also have evi-
- PAPeter Attia
And to be clear, has that been normalized for socioeconomic status? It strikes me as almost impossible to normalize that for socioeconomic status.
- RIDr. Richard Isaacson
Mm, above my pay grade. Don't know the literature as well as I need.
- PAPeter Attia
The point here being, like, people who go on to get secondary and tertiary education are gonna have lower risk. Is it because of the things that enable them to do that, perhaps having more resources, lead to them doing other healthy lifestyle things that go beyond the education as the-
- RIDr. Richard Isaacson
I hope the studies have controlled for that, but I know it's impossible to control for everything. But that being said, I think early life educational attainment, for example, m- musical experience, midlife and, midlife musical experience as well as early life absolutely can give, build up greater cognitive reserve so that when you get Alzheimer's, you're more resilient. You have this resiliency. The other aspect is-
- PAPeter Attia
And, and I don't know enough about music, but when you were the cello-playing to bass guitar-playing guy, what part of the brain is getting exercise when you do that?
- RIDr. Richard Isaacson
Well, it's very multimodal. It's the parietal lobe is the music side, maybe on the right side. The, uh, you know, reading music notes is kind of like language, so it'll be the left side of the brain, and that's visual. It's, it's basically, um, association cortices. Basically, the, the whole brain's talking to each other. So I think music is a great way to recruit different parts of the brain to work together, and the stronger those pathways get, the better the person does.
Episode duration: 2:24:31
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Transcript of episode Vq_hAXQsB78
