#18 - Richard Isaacson, M.D.: Alzheimer's prevention

Foreign. 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@peterattiamd.com. 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 round 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' attending neurologist at New York 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 Comic 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 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.alzletteru.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 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 10 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 going to 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 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 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 1/10 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 OB, 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 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, 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 want to 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 kind of 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, 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, it 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, welcome to my interview with Dr. Richard Isaacson. Richard, thanks so much for coming over, man.

Sure, thanks for having me.

It's not a far walk, is it?

Four minutes.

Very well. What do you think of the coaster I gave you?

I don't know if that was intentional, but we have 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 yeah, amazing guy.

I gave you my Muhammad Ali coaster without even thinking about the implications of that.

Serendipity or synchronicity? Which one is that? Not sure.

Okay, so before we start this, I just learned something about you today that I. I've known you for a while. I thought I knew everything, but as we were just getting ready to record, I was like, oh, by the way, let's just stick our phones on airplane mode and you whip out your iPhone and you put on airplane mode and then you whipped out this white and gold diamond studded thing.

Yeah.

Can you tell our listeners what that thing was?

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.

The word collect implies you have more than just that white thing that describe what it has on it.

Well, it's.

Besides the alligator skin on the back.

Sure. It's white alligator. It came from Africa, then went to Italy and then the skin was then shipped to the uk. I had to get all the passport, I had to get all the paperwork because 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. Its 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 is actually from 2008. The phone was built in 2010. In 2010, this was the fattest phone on the market.

And that's ph.

Fat, phattest for the young people with a ph. Yes. So we have white sapphire keys. We have 18 karat gold trim, white alligator. Of course. Say that a few times surrounding dating.

Anyone at the time you got this.

You're very perceptive. Actually, wait, I didn't talk about the diamonds. It's called a diamond pillow.

Am I allowed to include a picture of this thing in the show notes?

Absolutely.

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 is listening to this right now is thinking, what are these two clowns talking about? But they need to see this thing.

It's called like a diamond pillow. Like that's what they market it as. But anyway, it's on airplane mode, so I can keep it on the table.

No, please keep it on the table because that thing is fantastic. Oh, wait, wait, wait.

Check this out. The ringer 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.

I have to ask, how much did that cost in 2010? Dollars.

In 2010 it was just over 25,000. However, I got it in an auction on ebay. Oh, no. You know what this one actually got. So the company went out of business last year. That's right. And they were liquidated. The company's vertu v E R T U and the company went out of business last July. They had a blowout auction sale, liquidation sale. So I was the highest bidder. Actually, two people beat me, but then they'd never paid the money. So then, long story short, I was the highest bidder. I won the phone In September. I didn't get it till January because of the customs and all the.

Oh, wait, wait. So you didn't actually buy this in 2010?

Oh, couldn't afford it.

Yeah. Okay. Okay. I was gonna say because.

But in 2011, I had a girlfriend. Ex girlfriend was very. That kind of whatever. And I went to Vegas, and I won sixteen hundred dollars in Vegas.

You were a huge slot machine guy, if I recall.

Yes. Although when I first met you, Jay Walker burst my bubble and said, it's all luck and random, and I could have sworn it wasn't. My uncle lived in Vegas. My grandfather lived in Vegas, so he taught me the way of slot machines. And I thought I beat slot machines until Jay Walker, that has, like, 700 slot machine randomization code, passwords or patents, basically said, no, it's all lucky. He burst my bubble. But anyway, I was in Vegas. I like Vegas. I go about every year, every other year, and I won sixteen hundred dollars. I was like, oh, yeah, there's this luxury cell phone store, and I'm gonna go buy the phone to impress the girl that I was hanging out with. So we go and I put the phone. We take it out. It was $8,600, not $1,600. So I actually did buy one sticker price for $8,600. That being said, and just to make.

Sure I understand this, you walked in there with $1,600 in your pocket, ready to give away your winnings because it's free money. The guy whips it out, it's $8,600. You can't back away now because the girl you're trying to impress. You have no idea how many questions I want to ask you, but we will not end up talking about Alzheimer's disease or dementia. So just to Summarize, you blew $8,600 in 2011 on a luxury phone. You have since accumulated six more of them, including a retail $25,000 pimp phone that we're going to include a picture of that you got for hopefully a lot less than that.

You know, it was a problem. It was the shipping and the customs fees and, like, the. All the.

This is a humanitarian crisis. Seriously. Like, I collected old blackberries.

You.

Yeah. Going back to, like, remember the very first one, which was like a wedge. That was a pager. Yeah, yeah, yeah, yeah, yeah. So I just wanted one of every generation of BlackBerry.

Weird.

But I didn't get blinged out ones. Like, I just wanted, like, the regular one. And I also collected Hewlett Packard Calculators, all of the hps. Now I never got some of the originals because those were just too out of my price range. But. And I thought that was weird, but I gotta tell you, this might be a bit weird. Well, not there's anything wrong with that.

Here's the deal though. I've spent less than 12, $13,000 total because of the auctions and the deals and whatever. And I've traded in some. And then they once sent me a loaner and I kept it because they forgot they sent it to me. The company's out of business now, so they won't come after me. But actually.

So you think.

True, good point. So I actually have eight, eighty something thousand dollars of cell phones that I've actually only paid thirteen thousand dollars for. So no rhyme or reason.

You sound like me rationalizing the dumb shit I buy. Like I have X thousands of dollars worth of Y that I only paid Z for. But like Z is still probably. Anyway, I'm not going to judge because I am the last guy that should be judging. But I cannot wait to include a picture of that phone. It's just hard to believe it exists.

It's like it was handmade and the signature was behind the battery. The guy signed it in metal.

I can't believe we have been talking for six minutes and 55 seconds. And we could talk for another hour just about this. That's how many more questions I have to probe your psyche.

The Ferrari one that I have, this is a good one too. The Ferrari one. Actually they stuck a recorder underneath a Ferrari in 2010 to record.

To record the sound.

Ferrari, Ferrari accelerating. And that Ferrari is the ringer. The acceleration sound.

See, that's one I could get into. Yeah, I might have to borrow that one.

It's beautiful. That's like super bling. That's like got a red back hue. Like you can see the red lights and the.

Anyway, I didn't know such a market existed.

Well, the company went out of business.

Needless to say, it doesn't really exist.

Oh, and then there was the one last. Sorry, I'm sorry. Then there was the one where I bought.

This is your show. You can literally talk about whatever you want.

Is a great one. Because I bought. I got such a great deal online, I couldn't figure it out. And I get this phone, I was so excited. And it's all in Chinese. So I would text my friends, family, just in Chinese, just. And they wouldn't know what I was saying. I didn't know what I was saying. That Was a problem.

So when you say text, just randomly type characters.

Yes. And I was hysterical. People were like, what are you talking about? I'm getting Chinese characters. And I would reply in Chinese. And that's a great phone. It's on the shelf still. But that was a nice phone. Very inexpensive.

Oh, God, this is fantastic. We might have to do a dedicated episode just on this stuff.

The phone. I'll bring them all. I can try it on the block.

Okay. Well, onto the Monday, I was reading through something because 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 want to 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 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.

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 took all the money and bought out this other guy, this older guy's old recording studio. So I got like, again, it's all about value. So I spent like three grand, which is 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 Penny Saver. I'm dating myself now. I grew up in Suffolk county in Long island in Comac. And I put an ad in the Penny Saver and people in Queens were my best customers because 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.

Did that help you fund college or anything like that?

No, I was a computer tutor. I had like 400 bucks in cash from computer tutoring for college that I got to use. No, I didn't.

You ended up spending that money. You reinvested it. You reinvested the recording in music equipment.

Random weird guitars shaped the NJ Warlock. Like this weird looking guitar thing. Yes, I like weird.

It's not weird, man. It's beautiful.

Appreciate it.

Embrace it. When you went to med school, did you know that you wanted to be a neurologist?

Sort of, yeah. If you don't think I'm a dork for collecting luxury vintage cell phones, 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 we're heading on down to Nashville. And on the bus I brought, I shouldn't giggle, but neuroanatomy made easy and understandable.

It's like Neuroanatomy for Dummies.

Exactly the same series. Yep, that's exactly what it was. And this is. I was in sixth, seventh grade. My brother was a neurologist.

Your brother's older.

He's older. 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 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 a hundred 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.

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.

Yeah, so my uncle was diagnosed when I was in high school. And I always knew I was gonna be a neurologist. I didn't know exactly which area, which field. I think the brain was interesting. I also 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 8. 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 actually. In some ways the plan was to go to like as best of a residency as I could so I could then one day joined my brother in practice live in Florida. But I wasn't sure about Parkinson's. I liked it. I liked Alzheimer's also. I like cognitive neurology. 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 Gesch was in the conference room. So, long story short, I think cognitive neurology was always challenging and interesting, but I didn't just want to do phenomenology, like, oh, 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. Terrible. 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, like, my Uncle Bob introduced my parents, so it'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 on 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. To this day, I actually avoid water. I hate swimming. I don't go in the ocean. I don't go in baths. I mean, I stay away from water.

You were traumatized by that?

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 all the weddings and whatever. So just to see someone like that become what he became, and then just to see what the toll took on his daughter and son, it's 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.

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 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 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, and then did you come back to New York?

No. So I actually left New York for longer than I was in New York. I graduated at 17. I spent years six 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 have 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 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 history of neurology tour throughout Europe for one of the elective months. So I just got so much medicine exposure. Usually medical students get two years of clinical medicine. I had, like, six years intermittently of clinical medicine. 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 headed back to Miami. My mom was down there, my family's down there, so I headed to back down there, and I was in Miami for eight and a half years.

Was that how you met your fiance?

Yep. You got it in Miami. And my band was playing. She was in the front row.

Wait, what do you play?

I play bass.

Okay, because you grew up playing the cello. That I knew I did.

I grew up playing the cello until I got a fight with my orchestra teacher. I told him to go F himself, and that was the end of that. He had this, like, complex, you know, like, I'm better than you because he was in a Maxwell House commercial. He was the conductor in the Maxwell House commercial. And, like, that's the pinnacle. Exactly. He was the conductor in the Maxwell House commercial. So, like, you know, he was. His crap didn't stink, so I just couldn't take it. And I told him to F you, and I walked out and.

What? How old were you?

I was probably in 10th grade. Yeah, 10th grade. So then I joined a band, actually.

Is it easy to transition from cello to bass?

I didn't practice, didn't take a lot. I took two lessons. That's right. I took two lessons. And I just kind of.

But the fingering is similar.

Yeah, the frets threw me. Actually. The frets were hard. So I actually got a fretless bass, joined a band with some of my friends, and then actually the guitarist and one of the bands I joined has been living on my couch for a year and a half. That's a whole nother story.

But a Lot of stories in your life.

I like that. Keeping it simple, you know. Exactly. So played bass. Always been into music.

So you're the bass playing neurologist hipster in Miami.

Yep. Meet the blonde girl sitting in the club. So yeah, I was wearing my Mexican wrestling mask and shirtless.

Yeah.

My band had this shtick. We were called the Regenerates. Music for the right brain. And our logo was this brain. But we had like this shtick where we played like. Anyway, long story short. But yeah.

So is there any video evidence of this?

Oh.

That we can link to.

It's all over Facebook.

Okay. Very well.

The regenerates. We have 99 likes on Facebook.

So Travis and Bob, in preparing the follow up show notes for this will have a challenge trying to just focus on some of the Alzheimer's stuff we talk about and limiting the bling phones and banned photos and videos to 10% of the total volume of show notes. Exactly.

The phone is called the Virtu Constellation Quest.

Oh, we're going to be taking a picture of that thing after we talk. Don't you. Nothing will be left to the imagination.

I had professional pictures taken of the phone.

God damn.

Because I dropped it like it took like a few years. I dropped it.

No, I can totally. I'm sitting here laughing at you and look on my wall. There's professional photos of watches.

I feel much better. And the BlackBerry collection. I'm redeemed.

I don't even know who I am to judge. So then what got you to New York?

I guess in life one needs to make a decision kind of where one goes and one. What priorities one has. Miami was amazing. I had amazing opportunities. 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 guidelines. And 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, neurologists are just 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 want to do anything and everything as long as it's evidence to based and safe. So I was known for jamming the printer in the neurology department because my Recommendations was like sometimes 10 pages, 15 pages. And I put together 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 a 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 talked about publicly. Next thing I know, I'm selling hundreds of books online and put up a website and all that kind of thing. So why do I tell the 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 have. 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 actually a colleague. I shouldn't really say this, but there's a colleague on the down the hall from me 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. And I just, I don't want to say that someone questioned my integrity or whatever, but I guess someone questioned my integrity and I, I'm not trying to sell something, I 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 New York and Boston. I was about this close to going back to Boston. I had a great offer at Harvard. Would have been a major stepping Stone in my career to be that age and that level, to be an associate professor and director of an Alzheimer's clinic. But they wouldn't let me use the term prevention. Then I came to interview at Cornell and my chair said, oh yeah, Alzheimer's prevention, that's probably going to be something new. Sure. And the dean, as she was signing my letter back in 2012, said, no, no, I gotta meet this guy. So July 4th weekend, 2012, I'm all like, oh, it's about to move to New York, what's happening? And I go meet her and I got a 15 minute meeting, I got a seller on because it's literally the only place in the country that I, that was, I was allowed because I called around and whatever, I wanted to start this Alzheimer's prevention thing. And she interviewed me and she, you know, had written my cv. It was like, I think this was.

The dean of Cornell.

Cornell Medical School.

CEO of medical school.

Exactly. The dean of the medical school 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 our calendar to plead my case. And the first question she had for.

Me, did you bring in a Bling phone?

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?

She doesn't know you're Doogie Howser, man.

She was expecting the traditional bearded, bow tie, older, 50s, whatever, 60s, neurologist type. And I look like that. So we talked about my age and my training and the 23 thing, which.

By the way, today is probably not even legal.

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 over promising. 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 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 that's it. 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. And Weill Cornell and New York Presbyterian has been the saying for New York 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 have been able to do this.

So you mentioned 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 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?

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 going to 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 that 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 and activities of daily living. People can still take care of themselves, they can still 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.

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?

No, that's true. I've heard his wife, she was honored at the American Academy of Neurology last year, and she talked about this, and he. I didn't treat him. I don't diagnose. I 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.

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?

Yeah. So, you know, by far, Alzheimer's disease.

Which I've been told, by the way, can only be diagnosed in an autopsy.

Yeah, I mean, I'm a clinical diagnostician, so it's a new era. It's a new 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 still always defer to the clinical impression. But in 20, 18, 19, 20, etcetera, 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 other cognitive changes, it's probably Alzheimer's until proven otherwise. The key thing is that we want to 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 want to rule out reversible causes. We always have to do some brain imaging. Either a CAT scan. Got to rule out a tumor, or a mri. Now, the American Academy of Neurology states you can do any brain imaging. In my clinical practice, we always recommend an MRI.

What phase of MRI?

Just a regular MRI. No contrast.

I just want to make the T2. Which image you looking at, the T1 or the T2?

Well, I. I want to look at everything. Is there A vascular burden, could this be vascular cognitive impairment by itself, could this be vascular and Alzheimer's? Because about 35% of the time you have Alzheimer's and vascular cognitive impairment. So you just want to get a sense of what it looks like. 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 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. Even soon we'll be able to do tau scans. Tau protein is another amyloid pathologic protein that gets built up in the brain of a person with Alzheimer's. 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 going to 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 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.

This was later found with a scan or on autopsies.

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.

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?

So when I think about the brain, I think about different areas. And I don't want to 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 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 because my phone's from 2010, but when my nephew is texting at the.

Which you could text in Chinese though, if you had the other one.

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 asked my Nephew a question 20 minutes later. It's not like they forgot.

They never assimilated.

Exactly. Never encoded it. It never got into the memory. So we always want to make sure. Is this an attentional thing? Because, for example, common things happen commonly dementia common, but depression is also very common in a pseudo dementia 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 pseudo dementia 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.

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 Pelachar, who is 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 going to do the best blood testing imaginable. We're going to do the best. This, the best, this, the best. This, the best cognitive testing. Well, that turned out to be a fool's errand 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, look at this stuff. And I mean, my take on the sort of commercially available ones, because 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 going to do those tests because, like, we don't have the skill to do it and we're not going to invest the time to do that because we don't have the patient volume. Like, we're not in Alzheimer's clinic, right? So 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. 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 six guys that 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 in the cognitive test at that point I was like, okay, we are not going to 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. Like we're going to send our high risk patients to you guys because this is way too much work. It's really complicated.

Oh, this has been complicated for decades. And just to tell a quick story, I mean, first of all, our battery, the cognitive test we do is we do about a little more than half on computer because 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. 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 a greatest hits, that tries to look at people that are, you know, in the normal slash very early phases of Alzheimer's. The problem is that most of the cognitive tests out there have really been scaled or used and validated and meant for people with dementia.

So they're not sensitive to pick up people with early cognitive decline who do not have dementia.

Exactly. And the newer tests just don't have the robust validation 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, any, some are better than others for sure. We just don't have the perfect solution. 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, there's six centers like this like ours now. We were the first in 2013. Where are the other five in 2014? The Alzheimer's risk Assessment and Early Intervention Program in University of Alabama at Birmingham opened in 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 Gelbacher. Then actually we opened a satellite clinic in Puerto Rico, the Alzheimer's Prevention Clinic and Research center in Puerto Rico. Doing amazing. Everything was great. And then, then the hurricane. 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 and 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 North Shore Hospital in Chicago in Evanston, Illinois, and that's been running.

I'll be there next week.

Oh, cool. Yeah, good, good people over there, they have a very heavily focused on electronic medical records to try to track these things. Newest center is actually two One's in Boca Raton, Florida. At a 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 that 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. And then the newest center is opening at the Pacific John Wayne Cancer Institute, but it's Providence St. 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 because honestly, I don't know what the right measures are. We're trying to create an additional, 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. So we built six versions of something called the face Name Associative Memory Test. We worked with Doreen Rentz 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 is then we then created all this.

Do you remember how predictive it was?

Don't quote me on that kind of stuff, but 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. 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 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 new day and a new era. For example, even the 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, you know, 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 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 and 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. Okay, great. It's 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 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 because 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.

I had a different experience several years ago ago that has given me 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 risk reduction of breast cancer. And so I gave this long talk about all of these topics. And one of the implications of my talk was that if metformin could be effective in reducing the 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 had to ask like 12 questions to get at the layer of the hostility. But it became very clear to me what 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 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, 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.

Things are much better now. Things are totally different.

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 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 any of these RO1s.

Yeah, one we have one part of a program project one R01 we're looking at. But the program project looks at women between the ages of 40 to 65.

Looking at very early onset.

Well, well.

And perimenopause.

Yeah, well, not actually. It's funny you say 40s early. I say we need to start at 30. But no, 40 to 65 I think is a good sweet spot. And we're looking at women between the ages of 40 to 65. That's the program project. Then we just got. Lisa Moscone is the PI on the men's brain imaging. So we're looking at menopause transition as the window of opportunity. Like, when do we need to intervene and how. And then the RO1 we got was the men's brain imaging study, which is basically the male menopause transition, which is andropause. So we're looking at. It's a small, small number. Only 15 men a year for four years. But it's better than nothing between 40 and 65. We then just got an administrative supplement to now image women not just at baseline, but also at 18 months. So we just got that today, actually. And then, I mean, that's pretty, pretty good.

Yeah. No, that's a huge improvement. And so much of what you just said now makes me want to take a step forward. 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?

Anyone with a brain is at risk for Alzheimer's disease.

Well, let's take a step further back than that. What is the prevalence of Alzheimer's disease in the United States today?

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 posted all over.

So why don't we have those data the way we do for cancer, for example?

Alzheimer's is confusing. I mean, there's Alzheimer's, dementia, and probably around 4 or 5 million people have it. But the best numbers were recently published. The most updated was that 47 million Americans have preclinical Alzheimer's disease. Meaning Alzheimer's in the brain but no symptoms.

Sorry. Meaning based on something you would see on an imaging study or a lumbar puncture or. Because 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.

Yep. So 5ish million people have dementia due to Alzheimer's. 47 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 going to get it yet. And then there's a kind of 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. 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.

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 reach 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, within that constellation of diseases, the one that people fear most is Alzheimer's disease. But 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?

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 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 and that.

UTI becomes pyelonephritis, which becomes sepsis, which can kill them very quickly.

Exactly. So some people will put Alzheimer's on their death certificate.

And other some will say urosepsis.

Yeah. So there's never going to be great numbers. Alzheimer's is the impetus to death in most patients for sure. They can't report their pain. Close. Call him a friend, but he's a patient in the clinic also. Good guy. I've seen his mom, and his mom was just diagnosed with cancer and she was complaining of abdominal pain. Something non specific. She saw a doctor. Doctor said, oh, she's got dementia, has 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 or 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 the caregiving has to happen for them.

So you see a lot of these aspiration pneumonias. You see, you know, my closest friend, 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. 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 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.

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 each phase of life, Alzheimer's is a confusing, difficult disease to manage. 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, which we're going to talk about a lot, commonly researched gene, start off with a smaller brain.

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 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.

Yeah. You know, you asked me before, what's your high risk patient? What does that look like? And 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.

Not everyone, technically, I have some counterfactual.

Not talking politics, not going there. How did you know?

That's why I was. I wasn't even gonna. Yeah, go there.

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 2 years, 3 years, 5 years, 6 years? Have some hot off the press data I sent you right before I arrived to send you some new results. So we're trying to hone in on the can we delay it and for how long? But honestly, other people will do everything right and absolutely still get Alzheimer's disease. And I think I understand why now, because there's a tug of war going on 100% of the time. It's a tug of war between you and your genes, environment and genes. And when it comes to Alzheimer's, the mnemonic I use is age. A G E A stands for age because age is the number one risk factor for Alzheimer's. G is genetics and E is environment. So epigenetics, your interaction between the environment and your genome is going to put you on the path or try to knock you off of the path towards Alzheimer's. And some people can do everything right, but because of their APOE4 gene plus another gene, or because of their X gene or because of their whatever, they're going to get Alzheimer's disease. Other people can modify their environment, modify the impact of that gene on their outcomes. And I believe that it's very reasonable to expect that one out of three cases of Alzheimer's can be prevented. Because if you can delay Alzheimer's by 2, 5 or 7 or 10 years by doing everything right in that subset, they're going to probably die from something else.

Yeah, and the other thing that I always talk about in the prevention space, I mean, as you know, I take such a hard liner on cardiovascular disease because it is the leading cause of death. And I believe of the major pillars, atherosclerotic disease, cancer and neurodegenerative disease, it's the most preventable. We understand the pathology of that disease so much better than the other two. And we have more tools that seem to have efficacy at preventing that, if nothing else. I say it's optionality. Time is optionality. And so similarly, if you take somebody who, for whom, maybe it is a fait accompli that they are going to get Alzheimer's disease, but you say, you know what Instead of getting it at 69, we could make it 78. Well, a lot can happen in nine years. It's not just that you could die of something else, which is maybe better, maybe not, depending on what that something else is. But more importantly, maybe you and your peers have nine extra years to come up with something else. Let's talk about apoe, because everybody, you know, I was actually doing an Ask me anything yesterday, the AMAs, and there was a great question about APOE 4, and I just punted it because 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. It exists mostly in three types, though I'm told there are actually a couple of others. But for the large part, there's an Apoe 2, an Apoe 3 and an Apoe 4.

Yep. You get one from mom and one from dad. And that way everyone either has a 2, 3 or a 3, 3 or a 3, 4 or 4, 4 or whatever.

There are six combinations. The approximate prevalence, the three threes represent probably what, about 55, 60%?

Yep, you got it. Neutral risk.

So we call that unity risk. Right. Those are the single risks. The two twos are very rare. I've actually never seen a two two.

I've seen one.

Okay. They're reported at less than 1% of the population, maybe two.

I think I've seen two.

And they come with a risk reduction, I believe, of about 20%. At the far end of the spectrum you have the 4 4. 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.

You know, in our 600% person cohort we have 37.

But you're selecting for high risk. Yeah, I don't select for high risk, but I still feel like it's about 4%.

Yeah, yeah. In our cohort it's like 6.

Now this is interesting. The very first time I started paying attention to APOE gene, which was about 2011, 2012, the literature said the 4:4 patients relative to the 3:3 patients have a 25 fold increase. Today we see that number, I think, continually being downward revised. So for my four, four, four patients, the good news that 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 mean you and I, I think offline would agree. Unofficially it might be closer to 4 to 6x.

I don't even think, are you even, are you optimistic? Well, I'm just going to be frank. Alzheimer's and APOE is confusing and having two copies before does absolutely not mean you're going to get the disease. And it's a, a polygenic risk when it comes to the disease. You know, you can have two copies of E4 but never have a family member and never get the disease. I don't believe it's medically correct. You know, split hairs or whatever. 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 genes are.

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 going to talk about. But the point here is that's a heck of a lot better than a 20 to 25 fold risk. Then you have the three fours now they represent quite a bit of people. That's like 20 to 25% of the population.

It's all 25.

Yeah.

In our cohort it's about 40.

Okay. Which again makes sense. You're over representing again. They used to be represented as about a 3 to 4x. I mean, I think today we're saying maybe a 2x again, notwithstanding your caveat.

Yeah. So polygenic risk. We'll talk about precision medicine and kind of what the future of Alzheimer's disease is. And I actually think the future future of Alzheimer's disease prevention is now. I don't even think it's the future anymore. I think the future is artificial intelligence. But we can talk about that some other time. The person that walks in with an E3, E4, I am actually more optimistic when they come in and less freaked out about the four because at least I know what I'm up against. Okay. If that person.

Because you have so many three fours in your cohort now.

Easy, easy, easy. I know lifestyle interventions work. I am confident that when I do XYZ, ABC, the 27 things that I'll tell them to do based on precision medicine, based on their metabolic risk factors, their cholesterol, their individual risks, I can predict that they will have a response of this. And this is satisfying to me. The problem is when someone comes in with a. I'm like, oh, meaning for.

A 33 to show up in your clinic, by definition, there's a reason. Either their family member had premature Alzheimer's disease and. Or they're potentially even showing early signs of cognitive impairment that are subtle or. No, no.

I mean, you know, we were a prevention clinic, so to get into our clinic, you have to have normal cognitive function with a family history of Alzheimer's. So we focus on the normals. Now, a 33 could mean you did not get the 4 from mom or dad, and life is beautiful. Maybe the risk is lower. But if you have a 33 and mom and dad were a 3 3, and they didn't have the 4, guess what? They probably have another gene. And I don't know what that gene is, and I don't know what I'm up against.

Do you test the parents in that situation?

Well, it's tricky. I know a lot of. I would say when I first started the program, most of our prevention patients, I would say 60% of our prevention patients came from. From the patient with dementia I was treating. I then saw their kids and their cousins and whatever else. There's families I see with five, six, seven members. And that's the best to see because you can really understand the genotype and phenotypes and see the patterns.

I do the same thing with LP, actually, in the cardiovascular front, which is very helpful. It's to be able to say, let's track where this disease is coming from and see how much of it we can attribute to the genetic influence. So. So if a patient comes in and they're 3:3, and mom got Alzheimer's disease at 57, and you know that mom is 3:4, you feel a heck of a lot better than if mom is 3.3.

Totally. Absolutely. And, you know, we're trying to simplify things, and with polygenic risk, there's dozens of Alzheimer's genes, and the goal is to. Now it's hard because we don't have a neurogeneticist, and as I mentioned, Holly before, a nurse practitioner and myself, we don't have the team it would take to spend hours and hours and hours and days to decode someone's genome. But in the future, hopefully we'll be able to do this in an automated way. But the goal is to understand, okay, if they have a four, we're going to do A, B and C. If they don't have a four. We're going to do X, Y and Z.

And I want to come to the study that allowed you to talk about that. Before we go there, we'll round this out. You have two threes and two fours. Two fours are pretty rare about neutral risk.

My cousin's a two four.

I've seen two cases, but it's pretty rare. Do we think that the two fours are at increased risk? Decreased risk because of the 2. Increased risk because of the 4.

All things equal. Similar ish to 3 3, but a little worse.

Yeah, that's sort of my thinking. And then the two threes get a benefit. Not as much as the two twos. Looks like it's about 11, 10 to 15%.

Yeah, I like two threes. Two threes I can really sink my teeth into.

But you must not see many of these people.

No, no, I see two 3s all the time.

Why? They still have risk. They're still coming to you because of family history.

Oh yeah, but it's a different gene. There's a different gene lurking in there.

And we don't know what it is yet.

Yeah, but their polygenic risk is lower because they don't have a 4 to amplify the gene. I have a whole family where they came in and they said, oh no, we have early onset Alzheimer's in the family. And I said, no you don't. Doesn't sound like it. And we did all the stuff and mom had E44, uncle had E4 4. Well that's pretty weird, but okay. Grandparents, I'm sure they had four. Four. There must have been a lot of fours going on. And then when we look at the kids, they have a three, four. Well, we do the three, four. But wait, why did they get early disease? What's going on? And we found another gene, a TNF alpha gene.

Yes.

So when you take TNF alpha and you add to a four, well you're gonna have a six fold risk. That's polygenic risk. That's why they had early on.

Tell me what the TNF alpha gene does. What's the phenotype when they have this?

Well, you have an inflammatory cascade.

It's a pro. Inflammatory.

Sure. So that's like fast forwarding to Alzheimer's. Now when you have a 44 and a TNF alpha, that's when you start getting symptoms in your late 40s or 50s. It's not early onset Alzheimer's disease.

What's the gene that is Almost a guarantee?

Presenilin 1. Presenilin 2 and amyloid precursor protein gene mutation. These are three genes that cause true early onset Alzheimer's. Meaning you have the gene and you get the disease in your 40s or 50s.

Yeah. Meaning this is one of the only deterministic genes for AD.

Correct. It's exceedingly rare, less than 1%. As an example, I have a 27 year old woman, great gal. She has a precinelin 1 gene.

How old was she when her mom or dad was diagnosed?

Well, her mom's in her early 50s and acting weird now and kind of in denial. Her family members range from 50s to.

Early 60s at the time that they were diagnosed.

Yep. But then you take a deep dive into pre senilin one and she actually has a good one from Belgium where they actually have later early onset, meaning like 60s, 6, 0. And she's the first person I'd ever seen in the prevention clinic who had an early onset gene. And I could not say that she was going to get Alzheimer's. I said no, I don't know that you will. I think we can do something. We have so much time in the next 20 years for you. I'm not even like worried. Sure will take care of this. So even, and this is super controversial, but I don't even think one person can say even having an Alzheimer's gene where you're going to get the disease means you're going to get the disease. Because the field is changing.

Is the field of genetics considering that a deterministic gene? Yes, they do. There's only about 75 to 100 genes, so there's 20. Just for the listener, there's about 20,000 genes in the human genome. Directionally, only 100 are deterministic. Polygenic Single gene leads to problems. So you have the mutation for cystic fibrosis, you are getting cystic fibrosis, you have the gene for this glycogen storage disease. You are getting it. Virtually every disease that we think of commonly, of course, does not have a deterministic genome. Certain cancers do, but very few. Virtually all cancers, of course, are somatic mutations and not acquired germline mutations. That's a ballsy thing to say. Right? You're saying, look, 1% of Alzheimer's comes from a deterministic gene. I'm not even convinced that's deterministic. It might be an artifact of our GWAs.

Well, no, no, no, no.

It's meaning our GWAs has basically never tried an intervention.

Correct. Since it's a late. Well, early means 40s and 50s. But since we have now 30 and 40 years to figure it out, especially in her case who's 27. And if she doesn't get symptoms for 25 years, I'm loading her up with curcumin. I mean I got X, Y and Z. We're going to be putting her in whatever amyloid drug that comes out in the next five to seven years. I mean, I cannot say that she's going to get it. So deterministic genes from birth, well, that's a different story. Cystic fibrosis, terrible disease. You get it and you have it. Early onset Alzheimer's genes, It's a pretty.

No, that's my point. Yeah, I think that when I say artifact of gwas, I mean the GWAS is only so genome wide association studies, which for the listener is how we link genes to diseases. It's basically epidemiology of genes. If you study something where a potential treatment for a disease that could have played a role was never introduced, you can actually be misled.

Yes.

Yeah. So the other thing I tell my patients, so correct me if I have this right or wrong, is that about 2/3 of patients in the US who present with Alzheimer's disease have at least one copy of E4 and about one third of patients do not have a copy of E4. Is that directionally about right?

That's probably pretty close. I've always said 60, 40, so I guess that's right around the same.

I'm trust you more than I trust.

Me, but I don't know what's the latest? It depends on populations.

And so the point you want to make is, look, about a quarter of the population has an E4 gene, one or two copies, and that quarter of the population makes up 2/3 to 60% of the disease. So for my patients who have E4, I say the good news is this doesn't mean that your E4 means you're gonna get the disease. To my E3 and E2 patients who are busy high fiving at this point, I say, by the way, the bad news is not having E4 doesn't mean you are not susceptible to this disease. So you still need to pay attention.

I think that individual risk needs to be calculated individually. I said before, oh, three, three. I'm worried. Well, well, you know, I don't want people who are listening to say, oh wait, I thought three, three was good. Yes, for the grand vast majority of people, 3, 3 is good. But I need to know what your other genes are and I take a stupid amount of time doing this through looking at their SNPs and this is a, you know, research clinical, complicated, takes eight hours of Holly's time, four hours of my time, and then a whole lot of like cerebral.

You guys looking at Tom 40.

Tom 40, 40 has. We don't have a commercial test that we can test for it. There is a way to do it if we send it somewhere, but we really never went there.

We pull it out of Prometheus. Do you guys do that?

I may be getting this wrong, but I don't think all it depends on.

Where the genetic test was done. And you won't be able to do this out of 23andMe anymore, unfortunately.

Work through Prometheus.

Yeah, you can no longer take 23andMe data into Prometheus and get this degree of fidelity anymore, which thanks fda, if you're listening way.

So my understanding was that the 23andMe no longer has an API or like a way to transmit the data, but you can still download the data from 23andMe and then re upload it to Prometheus and still get the same report.

Okay, if that's true, that makes me feel better. We'll confirm that. I hope that's the case.

Yeah. We've only done this once for citizen scientists out there. I talk to your doctor and don't do this at home, but one back of the napkin way to Google Google your genome is to do 23andMe, download the data file, upload it to a service like Prometheus, and then basically filter, filter and filter.

I mean we've been working with you and we've come up with basically the SNPs for everything that we see in the literature that is of high risk. And then we run like kind of an AD panel. You know, it's interesting. We only do this for patients who are E4. I guess we should be doing this for every patient.

Family history of ad.

Yeah, yeah, yeah, exactly. That's good point. But it's interesting, you know, it speaks to another controversy that we won't get into, which is like information, you know, I mean, I've been scolded by physicians for measuring APOE 4 and telling a patient that they have an APOE 4. I won't go into that. So what is it about Apoe 4 that's so special? Why is it getting all this attention? I mean, aside from the epidemiology which we've just discussed, what is it doing or not doing that is increasing risk?

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.

So you just brought up something interesting, which was the question of females. 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. Do you. I mean this. I think I know what my answer is, but I'm. I don't want to. What's the term? I want to lead the witness. What is your view for why you think women are at a higher risk than men? All things equal?

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 having lots of children versus less children that can impact the two. And there's a whole variety of things, more stress, 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 I believe that Alzheimer's disease is a mitochondrial based disease. The mitochondria, the battery of the cell, the mitochondria can cause all sorts of bad diseases from Parkinson's to ALS to whatever, Huntington's possibly. Actually that 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're going to get sick. But the upstream effect is mitochondrial dysfunction. And there's something about the mitochondrial bioenergetic pathways. So I'll just talk in generalities because 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?

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 is amyloid and tau?

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. 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, 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. We're not at color and we're not at height deaf. 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.

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 a vascular path.

Two or three. I think there's like 12 or 16.

I mean, 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 I 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 described, which to me strikes me as the Occam's razor explanation for why women would disproportionately have this difference from men.

There's this great paper about this by Schelke and Atiya. I've read it. It's great.

You know, there was an interesting paper, Richard, about three years ago. It was a very small paper. I don't even remember how many women were in it, but I remember it was 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. Improve cognitive performance? 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?

Yeah, this is a tricky one. You know, I know what I know and I know what I don't know. And I have a very specific score scope of practice. I've never 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 tacit suggestions and I'll use Omega 3s and that kind of thing with cholesterol. Same thing with hormones. I would never prescribe.

Do you have physicians that you that are willing to work alongside you in these areas?

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 reproductive endocrinologist in Texas 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 said apoe4 may have something to do with. I also think metabolic status is something to do with this. Roberta Brinton has looked at women with vascular risk. So high cholesterol, diabetes, high blood sugar, whatever, that maybe those patients are the one that respond preferentially to hormone replacement therapy. 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, harmonization, hormone replacement may be a good idea. I just. It 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 may geared towards the latter, but I actually just don't know. There's a study with allopregnanolone which I think is going to be very interesting.

So I just, I have strong feelings about this. So we're going to go have dinner after this. We're going to talk for probably two hours just about this topic. 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 answer. And no, I don't want to get into. I don't want to jump on my soapbox about this because I want to come back to talking about this. 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 I'm talking about the matrix ofmthfr by ApoE biomarker versus cognitive thing. Is that submitted yet published?

We literally have. So let's 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 our ducks in a row with getting the cognitive assessments and the IRB approved and whatever. So since March of 2015, last three and a half years and change, we've been recruiting patients into a registry where we basically follow patients across primary prevention, secondary prevention and training, 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, over a thousand pages of results, data tables, graphs, and I've only scratched the surface.

So let's explain the intervention. Taking a step back, you're saying, look, we're going to stratify patients by four things. One, genetics. And the genes you looked at were APOE and mthfr. Can you say a little bit about MTHFR for the listener?

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.

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. I'm like, no, actually it's methyl tetrah.

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, you can take different roads to Alzheimer's. It's one of those roads.

It's a metabolic road through homocysteine. I mean, is that what your hypothesis is?

Exactly. And basically methylation, detoxification, you know, whatever word you want to use. I don't love using these words because 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 downstream cascade of biochemistry. Homocysteine goes up and it's a margin marker for something not working efficiently and well and detoxifying. Whatever you want to 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 biological biology is necessary because if you don't have high homocysteine, you probably don't need this stuff. You probably don't need B complex vitamins. So 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. 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 is 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 in different forms and different companies that make it. Actually, the company that I use for my practice you told me about, because literally, reliably, I send that little bottle and the yellow bottle, it always works. It always works. It absolutely always works. So you can do the prescription version, and that actually probably always works too, which is a little more expensive, but it definitely always works. So I'm going around the block to get across the street because 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 methylpholbic, whatever, folate, folic acid, methyltouch or hydrofolate, 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 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?

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. 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 going to be able to show that table here that's not yet published, right?

Oh, no, no. I mean, that's on page 700 to 900. Yeah. So, you know, the first paper that we got accept.

I show that to patients all the time.

But I mean, that poster is great. Yeah, that's a poster we presented last year. But you have to put the cart before the horse or whatever that saying is. But first you have to get the methods paper published. And this is pretty amazing that we got this published in the Alzheimer's and dementia journal, Journal of the Alzheimer's Association. And this is currently available, just recently published.

Yeah, we'll link to anything and everything that you. You let us.

My primary care doctor, who you got to meet in Miami, this guy, Dr. Wolfe. You guys are like two peas in a pod. He basically said, oh, this is your manifesto. Like, that's not my manifesto. It's just, you know, whatever. But he called it the manifesto. It's 11,000 words of everything you need to know about how to manage a patient for Alzheimer's prevention. And we've created a free will be.

Accepted in one journal article.

It's 3,000 words, 3,500 words in the main thing. And then we have all the rest in the appendices. Yep. And I can't believe it, but it was all accepted and it took seven months. But basically we've actually, since this is is hard to read, an 11,000 word article, we've actually created a free online CME course for physicians, basically using this.

Will that be ready by November?

Yes. So alzu.org so we'll make sure we.

Absolutely link to that. Is there value in there for patients as well?

So alzu.org is a free site that is for the public. So for the lay public, if you want to learn everything about what is and what is not in our control about Alzheimer's disease, Alzu is a completely free site to learn about everything. Then there's the healthcare provider page. If you go to the little healthcare provider tab and you type in your information, you can then enroll in the healthcare provider course and actually receive CME credit for it.

So there's actually a valuable CME course out there. Like, are they not the most useless idiotic things on the face of the earth?

Okay, not the one.

I mean, once in a while you find a gem like this. Every time I do a CME course on nutrition, I like have to deliberately answer the questions incorrectly to pass the test.

Right? Yeah. CME is one of those things. We've tried to really use CME to RFA because no one knows about this stuff. Doctors just don't know.

Well, that's great.

You know, we're trying to get the word out. We got the methods paper out that's done explaining the intervention.

Let's explain it sort of at a high level. The intervention is a lifestyle intervention. That is multimodal patients are stratified, as I said, by genetics. So you have an MTHFR apoe. You have. You also have a anthropometric.

We try to keep it simple. So the ABCs of Alzheimer's, prevention management. It sounds kitschy, but I really think ABCs actually fit. So A is anthropometric. We look at body fat, we look at lean mass. We look at. Is it visceral fat? Where is the fat? You know, I learned a lot of this stuff. We really take a deep dive. It's not just about weight and bmi, like that's just like the worst. No, it's about body fat. Where is the fat? Metabolically active, yada, yada. Then the B is for biomarkers, but blood based biomarkers, specifically cholesterol markers, especially the deeper dive.

I just want to take my hat off to you, Richard. You do more detailed lipid profiling than most cardiologists do. I remember the first time I sat down with You. I was fully expecting you to just whip out, like, the ldl, hdl, triglycerides, or this. And you went deep. I mean, you had apob, you had ldlp, you had particle subtype. You really got into it. And I was like, why is the neurologist knowing all of this stuff when every cardiologist seems to, like, still be in the dark ages on this?

That drives me crazy. You know, it's interesting. We have four cardiologists now in the practice. Actually, one who listens to the podcast. Give him a shout out. Probably shouldn't say his name.

Yeah, let's not say his name.

What's up? Really great guy, actually. He's been a great. He's a patient, but he's been a mentor and a teacher to me too. And, you know, we have cardiologists in the practice, and one is. Was like, totally anti. Like, what are you ordering? And he's still anti all that stuff. But he really wants to know his numbers and he really wants me to interpret it. But. But for his patients, you know, it's like, I don't use this stuff.

What are some of the other biomarkers you focus on?

So the four main categories are cholesterol, but deep dive cholesterol, inflammation. However, there's just four inflammation labs, and they're just not great. But it's just in our panel.

So what are you looking at? Besides CRP and fibrinogen, what do you look at? IL1 or IL6TNF.

Yeah, I wish did. Baby steps. It's myeloperoxidase and LP, PLA2, which I don't exactly know what to do with, but yeah, fibrinogen. Interesting. And high sensitivity crp. Now that I see all the results in our outcomes, HSCRP is probably the most informative. But, you know, something like myeloperoxidase is a risk factor for vascular cognitive impairment later. That's a new study. So I don't exactly know what to do with the inflammatory markers, but we're checking the.

And what stands in the way of adding some interleukins to that?

Some of the money. Benjamin's. I would love to get better nutritional biomarkers, which we'll talk about. We do it in the serum. We'd absolutely need to do it in the red blood cell, but we'd need to send it to a different place in a different FedEx account.

This is the thing. Can I just. I'm just gonna get back on my soapbox. God damn it. 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 a hundred thousand dollars 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 immediately. $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.

And it's funny, like, if I would have had $75,000 more three years ago, I would have had the right biomarkers. So I could definitively say about which omega three, which, this. Which that I could have for $75,000. You know, we've gone through $8 million in five years.

Okay.

It'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 because I couldn't afford the right test. 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 going to 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 CD 50s and I wish we could.

Yeah. 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? Because right now that portfolio is about 99 to 1. $99.9 are going into treatment, $0.1 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.

Oh yeah. And if, when you do this precision medicine approach where you look at their cholesterol and 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 ABs and Cs. 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 going to keep doing it. I have people that say, I haven't been able to lose weight my whole life. Are you doing the wrong thing? You run elliptical for 20 minutes three times a week. That's not going to 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 1 do everything and everything based on your individual biology and genetics, then that's when a person can have the most success. When they have success. It's positive reinforcement.

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.

They love it.

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 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, 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.

Yeah. When I'm sleeping without any pr, without anything, just because the way the Internet works, when I 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 want to help people and educate people. I'm sleeping. You're right. I see seven patients in a day, sometimes five because it takes a lot of time. But when I'm sleeping, over a thousand patients are on that free education website with two hours of, of interactive Educational content about Alzheimer's prevention. That's how we impact lives.

So I'm hoping that we can increase that from 1,000 to 8,600 patients while you're sleeping.

I would get the reference.

The listener will get the reference to that.

So does my pocketbook. Absolutely. So. And everything's free and we don't charge for any of this stuff. But that was an inside joke. So I guess as we go back to the A, Bs and Cs. So the other blood biomarkers that we could probably wax poetic and talk about for another several hours is metallic metabolism. Because I believe Alzheimer's disease is a metabolic disease in the vast majority of cases. And we look at again, if we could talk about this for now.

Is it 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.

What? The amyloidocentric people and the Taoists. The amyloid and tau people.

The Taoists. I mean, that's a sweet title.

That is cool, right?

I would like to be a Taoist.

Yeah, I call it amyloidocentric, but other people say the Baptist. Baptist means bapinuzumab, which is an anti amyloid drug. Anyway, the Baptist Taoist, whatever. I'm a mitochondrialist 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.

Soapbox rant number two coming up now. This would be a good time to hit forward by two minutes if you don't want to 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 want to 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. And what you just said is staggering to me, actually. I would not have guessed that when.

I found out this one person had no clinical training and basically did some radiology trash. I don't want to talk about specifics, but. And the other person. Like a related kind of 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 you say, oh, hey, nice to meet you. And they say, I heard about you. You give me the scowl. They give me that scowl. At least they're saying now because you're.

Such a low life neurologist who's, like, on the ground actually touching these patients.

Yeah, like, I heard about you. You're that guy. Prevention. 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.

All right, we'll take. That's progress.

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, and.

For a guy who doesn't cook, this is a highly inefficient use of tomatoes. Like, if someone threw a bunch of tomatoes at me, I could make some nice sauce.

Yeah, I've turned on my oven once, and that was in 2001.

Before you started storing your textbooks.

My textbooks are. That was in 2001. I started putting my textbooks in there because I had no room in Boston. I actually. I've put my textbooks and other things in my oven for a long time. I live in a tiny apartment. I have two dogs, two cats. A guy on the couch is a problem. Guy's got venting. I talked to my therapist.

Are you trying to figure out why your fiance hasn't moved to New York yet?

I wonder why.

Yeah, I have no insight into why.

And the guy's got long hair. Oh, no, she's in California.

Oh, she's in California.

She's in California. Yeah, one of those things. We have a bicoastal dog, cat, whatever. Guy on the couch. Definitely gotta go by the time she comes back.

Is he listening to this?

No, he's not a podcast listener, so.

There'S no risk that he's gonna be offended by the fact that you said he's gotta go. No, no, I don't have to cut that part out.

No, no. He's got long hair. The hair's everywhere. It's just like. It's all messy. Anyway, back to metabolism. Metabolism?

What are you measuring metabolism? Do you do oral glucose tolerance test?

Well, Dr. Peter Attia has schooled me on this more than one time, and I would love to, however, we can only. Do you don't have the budget we can do. Yeah. And the time and the trickiness. But sure, I'm not doing everything as precise as I need to. And, you know, you're the one that's taught me about how, you know, you can have fluctuations in sugar up and down, but then the average hemoglobin A1c is normal, but you're missing those other things. So we do it better than maybe the average Joe. But we look at hemoglobin A1C, we look at homa IR, we look at fasting insulin, we look at fasting blood glucose, which I really like, even though it's imprecise, it just does give me a good snapshot. We look at adiponectin, which is confusing sometimes. So, you know, these are some of the main. We used to look at more things, and then it was expensive. So we do the best we can, but then we triangulate. So the key here in the abc.

Are there any other classes of biomarkers?

Oh, sorry. Nutrition. Nutrition, yes.

And what do you look at there specifically?

This is our problem because we look at saturated fat, monounsaturated fat, dha, epa, ala, you know, all this sorts of.

Stuff based on what, food frequency questionnaires?

No, no, in the blood.

Oh, you're measuring RBC levels of all of these?

No, that's the problem. We're measuring serum levels. It's a problem.

Oh, yeah, that's a problem.

I know.

We'll add that to our discussion.

That's. Hence my $75,000, whatever, that got sucked away back in 2013. That was 2015. We had money for this. And then things happen sometimes. So what's the C? The C is as important as the A and the B. And I never would have said this five years ago or even thought that I would be talking about something this ridiculous, but C is cognitive function.

It doesn't sound ridiculous.

Well. Well, using cognitive function to personalize or individualize a person's care from a biological perspective, that sounded ridiculous to me five years ago. But we look at processing speed, attention, memory, executive function, all of these different cognitive domains. When I see lipids, I now see executive function. When I see vitamin D and homocysteine, I say, could that be processing speed? When I see metabolism problems and high visceral body fat, that's screaming memory. Metabolism and memory and what we do.

So this is news to me. Like, I didn't.

Me, too.

Yeah. So are you seeing this as. Is this just. Basically a blind squirrel has found some nuts. Like you're just digging through Your data. And these patterns are emerging.

No, not data. No, this is clinical. This is clinical observations.

That's what I mean though, because it's still generating clinical data.

Yeah, this is pre data analysis. And you know, some of the data analysis doesn't even hold up with maybe my clinical observations because people are different. And when you lump Bob and Jim and whoever else together all in a bunch.

So these are just very loose sort of observations that are becoming now testable hypotheses.

Right. And the testable hypotheses are tricky here because what we do is more traditional statistics. We do your means and averages and you know, all the fancy least squares means and whatever, Bayesian yada, yada. But we probably need to be doing N of one studies. And N of one is a way to.

Which brings us back to AI. Yeah, I mean, until you have the AI engine to do.

Totally. And I was a computer dork in a past lifetime and I was would do artificial intelligence with my life. If I had a billion dollars tomorrow, I would fund my research and get the right people on the bus to do all the things I want to do. And I would focus professionally on programming and artificial intelligence because that's how we can really beat this stuff. That's another. See, I'm getting on my rant. Or that was my soapbox time. But long story short is N of one people, where you can make these associations and you average it all together in the cohort and it gets too hazy. But metabolism and memory, metabolism and learning and memory specifically. And what we do here, and this is the key, triangulating the A's, the B's and the C's. So never say, oh, your blood sugar fasting is 97. You need to do X, Y or Z differently. No, no, no, no. 97, that's above 95. And that's my cutoff of normal for brain health, memory and cognitive function, which is less than the 100 cutoff, which in med school it was 125 and then 170, 16 in residency, and now it's 100 and hopefully in five years it'll be 95. I don't know what you think a fasting blood sugar is appropriate in terms of a reference range, but for brain health I think it's 95, based on some work from Germany. So what we do is we take the A's, the B's and the C's, we triangulate the information. Only then do you make a clinical decision. And you can't just treat based on one. You have to interpolate everything. And when you do that, that's when, when you can come up with the clinical precision medicine plan.

So what cutoffs are you using on your lipids these days? Let's just go with LDL particle.

Oh, gosh, this is confusing because I don't want to talk about bimodal curves and maybe people with too high HDLs can be bad. And I mean, there's a lot of complexity here. And it's an individual and this is a phenotype thing like I just ctep, cetp, cholesterol ester transfer, whatever. I don't know what that gene is called, but I can see that the person has, has the gene because I can feel it in my gut. And I can look at the labs and I can just, I can see.

Based on their HDL cholesterol, you mean? Or the combination of their HDL particle and their HDL cholesterol in size, it's.

Really hard for me to give generalities because there are certain people where the rules don't apply or the rules apply backwards. So LDL cutoff. Sure, absolutely. Below 100. I'd love below 70.

What about in the particle?

Sub 1000? But 600, 500? Better than 8 or 900 maybe, but I don't really know for sure.

And are you concerned that statin use, even though at the population level statin use is always associated with a lower risk of dementia, that in certain individuals it can exacerbate it?

I hate to say this, but yes. And five years ago I would have said, heck no, statin should be in the drinking water. I'm very pro statin, period. Just like you said, population based. I'm very pro statin because of this clinical observation where you see, see patient after patient after patient and you see genotype and then phenotype and whatever. I do believe that different statins work differently in different people. I think there's a gender difference. I think when in doubt, low dose is better. I think people with ApoE4 genes, especially two ApoE4 genes, holy cow. You have to be careful. I think you were the one that taught me about Livalo. And then I learned more about Crestor and high potency and low potency and lipophilic and blah, blah, blah, and how atorvastatin showed to, to be beneficial in men with slowing hippocampal atrophy, but not in women. And you know, and I've just seen men change from one cholesterol drug to another because, hey, their numbers look great. But now Their memory got worse. High potency statin, APOE 4. Maybe we need to come down a little bit. So I am pro statin, period, and I think I'm pro statin. Let me just say that. But I'm anti. One size fits all.

Yeah. I mean, I think this is one of those things in medicine that. That I think is very hard for people to understand, which is how can something like a statin potentially be good and potentially be bad? And the reality of it is it can be very positive from a vascular standpoint, can be positive from an inflammatory standpoint, it could be negative from a cholesterol biosynthesis standpoint in a susceptible individual. And so, I mean, like you, I consider myself pro everything under the right conditions. I'm pro hammers when I have a nail and a piece of wood, but I'm pro Phillips screwdriver when I have a Phillips screw and a piece of drywall.

Perfect. Yeah, that's a great point. So then there's plant sterols and Zeti and this and that and omega 3s, and I'd like omega 3s to get down.

And you mentioned earlier on the omega 3 front, I mean, I think in the last year and a half, actually, during the time when we were writing that manuscript, I think it became a little bit more clear that it might even be the DHA.

And it works better in E4 as well. But it just takes years to work to have the most robust. Takes two and a half years, I think, to recycle the amount of DHA in a person's brain. So when you study it for six months and you're only getting 20. I'm sorry, it drives me.

Rant number three, soapbox again. When someone says such and such an agent was studied and it had no effect. Should you immediately dismiss the intervention? Only if you can be confident that it was. That it was studied correctly and that the time course of the disease and the intervention were appropriately matched. And it's that latter point that almost always seems to be the missing link. And that's a great example of that. Frankly, half the primary prevention studies in disease, I think, miss the mark because they don't understand the time course of the disease that's being studied.

And the other part about this is, you know, if you do this one size fits all and you give, say, omega 3s to everybody, but people with high omega 3s maybe don't need it, but then they lump the results together, well, guess what? The study is going to be negative. Maybe you should have just given the Omega 3s to people that actually needed it, and that would have been your enrollment criteria, then your outcome would have been different. So precision medicine and this whole one size fits all thing is just very dichotomous. So yeah, we take these ABCs and we generate evidence based and safe from patient education. Two hours more online interactive education online for free patient counseling with me and Holly. And then we really type out a whole plan. And this is four pages, five pages sometimes.

So in which patients. Not to get too tactical, but I know that a lot of people listening to this are probably chomping at the bit to know some of the things. I mean, we've alluded to a number of these things. Now another one that's really come on my radar in the last two years is a specific type of curcumin called theracumin. Can you talk a little bit about what that is, how it works and why?

Sure. And I have nothing to disclose. I did a medication escape piece on Thera Kerman and man, I got tomatoes thrown at me in the comments section. This one ER doctor in Kansas, hopefully he's not listening to this actually call.

Hopefully he is listening.

Yeah, well, I actually called him to discuss and the, the secretary in the ER said, all right, we don't give your or whatever out, but you know, I have nothing to disclose and I don't sell supplements.

You don't have a supplement company on the side?

No, I wish. I have hundreds of thousands of student loans. My fiance has 450,000 student loans.

A recommendation. If you could start monetizing your bling phones, there might be a way to start putting a dent in those.

This is a very unique audience is interested in these though, so I'd have to spend money to find that person. If you know any oligarchs, that's what usually if you can find a Chinese billionaire. I have a Chinese billionaire.

You have that Chinese phone and then this white alligator skin one.

So I want to part with this.

So you wrote this thing in Medscape about Theracumans.

Yeah, and I got. And he's trying to sell things. Listen, just for disclosure, I wish, but I've made a conscious decision not to. I live in a one bedroom apartment with two dogs, two cats and a guy on the couch. It's. My bathroom is the size of a closet. I live in New York City. I have tons of loans. I am negative when it comes to my net worth since moving to New York five years ago. I don't need a sob story. I have a Roof over my head. I'm very fortunate, whatever, But I am not trying to make money, I'm not trying to sell stuff. So although I probably should. I'm not selling my phone though. So when it comes to theracurmin, it is a specific type that comes from Japan. And this Japanese company, from my understanding, basically made this nanoparticle small particle version. Now there are versions of curcumin that may be optimized for absorption and blah blah, blah. But in the Alzheimer's study by John Ringman and colleagues, when they did a randomized study on curcumin for mild to moderate Alzheimer's, the study was negative. But when they did the blood samples, the curcumin was being swallowed and not being absorbed in the blood. So I wonder why curcumin didn't work. So this basically led to this Japanese company putting together this theracurmin version, nanoparticles, whatever it is. And a study by Gary Small and colleagues basically showed that after 18 months of using it, when you look at PET scans, there was less amyloid in the group that got the real optimum.

So does that mean we should be using theracumin even in our non high risk AD patients that we would otherwise be giving curcumin to?

Well, precision medicine. No one size fits all. So sorry to, you know, get back on that soapbox. But no, not everyone I don't think needs curcumin. I think it depends on what their ABCs are. You know, if they have some inflammatory stuff. Well, I'm not checking the right inflammatory stuff, so I can't use that as a biomarker. If they have some memory stuff. Well, maybe if they at higher risk and they have an APOE4 gene, maybe.

What was the dose if they're accumulating that small study? Well, small meaning the author, not the size.

Yeah, it's two pills a day. It was like 500, 600 maybe. I just. It's two pills a day. Read the label, read the study. I'm forgetting, but it's one pill a day for a week.

And there are several companies that sell theracumin now or just one.

Several companies, yeah. So again, I'm not vouching for any brand, but as you said earlier, Peter, you know, you, you taught me which methyl yada yada to use, use and it works every time. And it's like finally we have a good version.

I do vouch for sure for the listener. The brand that we've switched to across the board is jarrows. They have a combined lozenge that's methylfolate and methyl B12.

Yeah, the yellow bottle.

But yeah, a little yellow bottle with the pink lozenge.

So you know, we choose specific supplements because we know that they work and they're verified and you know, we've used them and we can see it jumping in the blood so we know it works. Theracumin is. Theracumin. I'm even know how to pronounce it. I don't think everyone needs to be on it, but I do think if you're going to be on it and you have amyloid in your brain, you better be on the right stuff. So that's important. Should someone take more? I have no idea. I've never told someone to take more. But I have this family, two multiple, actually two families, three that have the APOE4 gene and the TNF alpha gene. Well, how does curcumin work? They're on the TNF Alpha pathway. What we've been doing is then we can add additional, additional labs that cost money. But you got to do what you got to do sometimes. And we look at CD50 and other inflammatory markers and TNF. And while TNF isn't really changing, for example, in multiple patients that we put on this Theracurmin, the CD50 is increasing. So I don't exactly know what that means, but I do know that their memory is not getting worse and maybe hopefully over time we'll get better.

So has anybody commented on this rise in CD50?

I've never really talked about it before.

I mean you've sent me this, these data, but is there anything in the literature about CD50?

I'm not aware my brain can only hold so many things. I'm a one third preventative cardiologist when I shouldn't be. And I have a great guy, Randy Cohen, bless his heart, he's just been. I email him and he emails you back in 48 hours. I have this phone, a friend list of people that are way smarter than me, but I'm 1/3 preventative cardiologist, make believe one. I'm 1/3 neurologist and 1/3 primary care doctor. And I just can't internalize all this stuff. So I email you and I have this like group of like 12 to 15 minches that just help me for free. And it's amazing. So don't know what to say.

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.

I sell carpet or sofa beds. That's what my dad did. That's a great answer.

I'm either a shepherd or. Or a race car driver.

You look like a race car driver.

I thought you were gonna say I look like a shepherd.

No. Well, you have that sheep thing in the corner over there. Yeah, yeah, the sheep herding stick. Race car driver is a great.

It's just a great way to not.

Have to talk about Formula one. Yeah, I like that.

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 going to see this patient again. You know, you're at a cocktail party in Los Angeles and you're flying back the next day. 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, 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 a hundred thousand people in my clinic. So go to the site, learn every single thing possible. I can't tell you everything.

Are there diagnostic tests that people can do to get a sense of their own cognitive abilities?

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 it's for tracking.

It's for tracking.

So a patient can say, I'll take the test on Alzu once A year.

There's email reminders to tell you to take.

And do they get results if they're performing deteriorates or do you get a result?

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 1 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 team.

So step one is at least go and familiarize yourself with all of this information.

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? What pills should I take? How much should I exercise? What's the magic dose? To me it's like, if you're going to 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 do all this pre stuff. Alzheimer's prevention is not simple. Take the time you're going to 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 going to learn things, internalize them, make incremental changes. Number one is education. Nelson Mandela said, education is the most powerful tool to change the world. Whatever the quote was that I mangled. But education is number one. Number two is know your numbers. Okay, what do I do about. They want me actionable tips. Actionable that. 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 use the Oura ring. I believe I use the whoop biosensor. Nothing to disclose. Whatever. I know everything.

I do have something to disclose, which I disclose publicly. I have invested in Aura and I advise them. So please make sure everybody knows.

Yeah, of course. So I want to know everything about my physiology, about my sleep, how many hours when I go to sleep, when I whatever, how much my exercise is, what my strain is, what my output is, what my average heart rate is, my. My resting pulse. I want to know I'm A data junkie.

Right now, the person's ready to spill their drink on you. They're like, I got it. I'm going to memorize the site. I'm going to learn everything about me, but I want to know, is there anything that I should be doing more or less of with respect to exercise? Food, sleep, meditation, yoga, supplements? Are there any. No regret moves?

So exercise is the number one thing any person can do. The only thing a person can do right now if they have amyloid in their brain to reduce it or slow the accumulation, is exercise on a regular basis.

Yeah. When we were writing up what our white paper that eventually became the basis for the paper we collaborated on, I remember when Dan first presented to me, just internally, like, all of his findings. I guess I should take a step back and explain why we did this, because I think it provides an example of how we started working together. But I remember he said that he was like, peter, you're not going to like this answer, but there's literally only one thing in the literature that suggests that you have any hope of mitigating Alzheimer's disease. And I was like, oh, let me see if I can guess. And I came up with, like, 10 guesses, and they were all wrong. And he goes, no, it's exercise. And I was like, okay. I mean, I get that exercise is important, but are you telling me that in the literature, exercise is the only. Only thing that meets level one evidence for the treatment of Alzheimer's disease? And look, I mean, that's an important thing to know.

I would say risk reduction.

Yeah, risk reduction. So again, we could wax philosophically on why. By the way, the reason we ended up doing this is we read a review article by Dale Bredesen, who many of the listeners will probably recognize. I don't know Dale. I've never met him. I don't even think we've exchanged emails. But we read a paper that was a pretty exhaustive paper based on his recommendations for Alzheimer's prevention. And we just wanted to start from first principles. And there were 200 or so references in the paper. And poor, I don't know, Dan or Bob or one or two analysts got the task of, please go and get every one of those references and make sure the references line up with what's being said. And I don't think this is deliberate. I think this is just the nature of what happens when people are writing papers. But, like, we couldn't verify a third of these references. For example, there was one reference that said, take resveratrol and we went to that paper. And that paper, while it was about resveratrol, had nothing to do with resveratrol and Alzheimer's revenge. So that's when we decided we just wanted to do this from first principles. We wanted to go and take a first principles approach. And we had an unusual methodology, as you recall, which was start from an intervention, look at an intermediary and understand a mechanistic pathway and then how does it lead to the convergence of a final common pathway? And so in many ways, Dale's work was helpful to get us started. But we felt that we wanted to do better. Could we do better if we were able to abandon everything that had been done? So exercise. Let's go back to the woman at the cocktail party. She wants to exercise. Is there a type of exercise? Do we have any belief that you talked about high intensity training? Do we believe that that's better than sitting on the elliptical for 30 minutes or going for a run or lifting weights?

Here I go again. Not one size fits all. But know your numbers. What is your body fat? What is your muscle mass? Men body fat is less important, potentially. Muscle mass is probably more protective on brain health. Women body fat is.

Why do we think that is?

Smart people smarter than me have told me this mechanistically.

What is it? Glucose disposal? Is it other circulating factors? IGF seems to be somewhat protective.

That's not over my pay grade or whatever that saying is. Yeah, I'm not 100% sure, but I can tell you that mixing it up is important. Important. The vast majority of evidence out there is aerobic exercise. Minimum of 150 to 180 minutes a week, for example. And that's mixing it up. Most people would say, based on the preponderance of evidence, two thirds cardio, one third strength training. But someone's going to have to personalize it based on themselves. You know, for me, I spun this morning. I. I do spin class. I was never a spin person. Like. And this is not. I don't want to get. I go to flywheel. I love flywheel and peloton. Why do I like those two? Because I know my numbers. I can see my. It's actually competitive because I can, I can race against people in the class. But it tells me what my torque is, what my average output is, and that way I can know, I can see well. What is my pulse, what is my strain?

What is my. So just to be clear, when you talk about. I think anybody can dog it, but if you're doing A peloton class. Right. You're working up a sweat. I mean, it's. That's a very different experience than I'm going to go on the elliptical and watch the news while I'm raising my pulse from 80 to 90. That doesn't seem to count as exercise.

Oh, no. And it's like I talked about the patients all the time. They say, oh, I go to the Olympic three times a week. I do 45 minutes. I'm like, really? Well, yeah, I don't mind it. I talk to my friends. I text them, bleh. Did I watch TV in my spin class? I can't talk. I can grunt. That's about it. I can grunt. And then I am a absolute mess. And the amount of, you know, my average pulse rate during a class is over 150. 150, you know, 155 ish. Sometimes higher, sometimes lower. And my max is going to be say, 180, you know, give or take. I know these numbers. So high intensity interval training is important, but you got to be careful because if you do too much, you're going to burn muscle. So I have to.

You can hurt yourself.

Yeah, exactly. And you know, I started off very low weight when I was getting back into exercise several years ago. And I, you know, now I'm at higher weights, but I do weights at least once a week. I hate weight training, but I should probably do it twice a week. I probably, I only do it on average once, maybe once and a half.

You definitely need to be doing it two or three times a year.

It's a big problem. I completely understand you and my primary care doctor who is like a clone of you and son in a different way.

If you want no other proof point, just look at Oliver Sacks. Do you know, like, what a beast that guy was? Guy was like a powerlifting champion in medical school and residency. When he passed away, there were some really, really remarkable tributes to this man who not only is I didn't have the luxury of knowing him. Did you?

He lectured at a seminar. I talked to him for about 10 seconds.

Oh, wow. Yeah. I'd never had the luxury of knowing this remarkable human being, but I was amazed after his passing to learn so much about him that I didn't know because, you know, you always saw him and he looked like a fit, strong guy. In photos as an older guy, but then to see pictures of this guy in his 20s and 30s, I was like, my God.

Neurologist, power lifter.

You're the neurologist dj. He can be the neurologist.

Power lifter. Indeed. So muscle strength.

So she's loosening her grip on the glass now. You've actually given her that. That leads to my next question. Should she be drinking alcohol or more to the point, should she think about moderating her alcohol?

Sure.

So.

So alcohol wouldn't go in my top five because there's a lot of other meaning.

Moderation of alcohol would not be.

Not in, like, my five, like, most important things. You know, Nefse and Collins in 2011 or so came out with a paper that basically, basically said one to two drinks a day in men and one drink a day in women is probably protective. Then you have all these new UK studies that show actually, if you do zero, that's better. So the data is a little bit all over the place. I kind of hedge my bets and I say women four drinks a week, men seven to 10. And other people that are really smart that I work with says less.

I'm sorry, is the distinction you make in women to be lower because the risk is higher, or do you think it's related more to body mass or muscle mass?

The ladder. Body mass, muscle mass. And the data. And the data, what the data shows, I'm not sure.

Those data kind of suspect. I think there's so much healthy user bias in those data that I. But again, I think one also has to balance. You know, I sort of think of alcohol like I think of Tylenol. There is no dose of Tylenol that isn't taxing your liver. Right. So if you are asking the question as a hepatocyte, the smallest cell within a liver, how much Tylenol is too much? It's like any amount becomes too much, any amount becomes taxing. So the question is, if you take a hepatocentric view of Tylenol, you should never, ever, ever consume it. But the reality of it is we're not just walking livers, we're walking people. And sometimes we have fevers and sometimes we have pain and things for which Tylenol is a remarkable drug. So we have to balance that. And so similarly, I would say alcohol is a known hepatotoxin. There is no dose of ethanol that isn't, on some level, chronically toxic to the liver. The question is, we're not walking livers, Therefore, are there benefits of alcohol that may, in the early stages of administration, offset some of the downside? And I think the answer for some people probably is yes. I mean, I have patients who, if they don't Sit there and sip their cognac at night, it's very difficult for them to unwind. And while I could sit there and lecture them about how they need to pick, pick a different unwinding practice. In the end, if you can monitor a bunch of things, you know, you sort of take the view that says, look, it's, there's no measurable harm that's being done by this. Your liver function tests are incredibly low, your coagulation factors are low. It's not producing other adverse harm. Maybe there's benefit. But it'll be interesting to see how that story shakes out in Alzheimer's disease because you could certainly come up with plausible hypothesis on either side of that.

Yeah, I have much stronger evidence on other things. So since the evidence is murky, I always hedge my bets. Like you say, sometimes and less is more, but I'm not sure a little bit.

So where are the things where you feel stronger?

So nutrition has to come after exercise. But again, education, know your numbers because nutrition is a close second. Probably, I mean honestly, vascular risk factor modification is probably after exercise. So I should probably put nutrition next. But vascular risk factor modification, cholesterol, diabetes, blood pressure control. The Sprint Mind study, just if you haven't heard about the study, it's like a major, major, major important study in the field that needs to be on like every.

Yeah, it's really modified the way I think about blood pressure management.

Yeah. And this was a five year study. It was the sprint study which is trying to figure out, do people, you know, because lowering blood pressure less than 140 has always been a little bit unclear, like does it improve outcomes? So the study in cardiovascular disease was, and I may be paraphrasing but, but is 140 is better or is 120 better systolic? And there's always been this dogma where, oh, you gotta be careful, you can't lower blood pressure too much in someone who's older because then they're over 70. Oh, they're going to pass out and they're going to have bad outcomes and fall. So in the Sprint Mind study they ended the study early because the outcomes were so much better in the 120s that actually there were no side effects either. So they stopped the study early. Well, the Sprint Mind study then looked at outcomes several, several years later in mind study, this is just like a several years in follow up, like not like 10 or 20, just even after a few years. And this intervention was not that long, actually showed a reduction in the people that had Blood pressure more tightly controlled to a systolic of 120, actually had a reduction in development of MCI mild cognitive impairment by 19%. Like, that is huge.

Over how many years? Two years.

I think it was like, after three and a half, ish, four years of treatment of lower. And then they stopped the study at five years or whatever. And then three years later or something like that. I'm mangling it. But long story short, I mean, 19% risk reduction of MCI. And then you add in the exercise and the blueberries and the low carbs and the this and the precision medicine. I mean, we're talking tangible, like, real, real stuff.

Let's go to nutrition. Why blueberries?

Anthocyanins. I'm mangling how to pronounce that too. Robert Krikorian, pioneer, I believe, in the field of nutrition research and Alzheimer's disease.

So the antioxidants you think provide benefit.

He would be the person to ask about this, but I know he has a paper that he's been trying to figure out. Is the blueberry. Is it the anthocyanin? Is it the whole fruit? Can you just take out the compound? I don't know that I'm 100% sure. I think it may just be the compound. I'm going to.

I actually got an email about this in my news. You know, we get those newsletters every day about Alzheimer's disease. And I think they mentioned this in today's newsletter, which was. Yeah, just the idea was, could this be one of the more potent antioxidants that could be studied in clinical trials?

Because, you know, Dr. Krikorian is looking at, you know, not just blueberry intake, but is it wild blueberries? Is it non wild? And we say, okay, well, what about blueberry powder? Can we just take the blueberry powder? Well, then can we go even deeper? Can we just take the active ingredient? So nutrition. Nutrition research people say, well, first of all, nutrition research is hard to study, but there's a science to nutrition research. And, you know, just randomizing 100 people to one diet versus another. People aren't mice. You can't just, like, make sure that they eat that diet. People go to McDonald's and, like, do other things that they shouldn't do. So nutrition research is inherently bad.

McDonald's is bad. I'm just taking notes here for the girl at the coffee right now.

McDonald's is not. My cousin Stacy caught me at McDonald's once and got pictures. It was a problem. But, you know, everything in moderation. Everything in moderation. I have had two McFlurries Oreo McFlurries in the last year, like once in a while.

I'm not judging by the way. I'm just craving one myself.

Oh, Oreo McFlurries, man, like, forget it. Anyway, long story. You don't, you don't even have sugar in your house. I had put xylitol in my coffee. Killing me, man. So nutrition would be, you know, lower carbs. Good carbs versus bad carbs. Green leafy vegetables. So, so, so important.

Any role of fasting? Any early data on intermittent fasting or caloric restriction?

Well, I don't have data in my practice just yet, but we recommend our diploma diet is looking at 12 hours versus 16 hours and the differential effects. Unfortunately, I have looked at that data. Not written up, non published. There's a lot of noise. I think 16 is better. Five times a week better than 12. I don't know that 12 works. The error bars in our data are so wide.

I think your sample size is too small and there's too much variability at this point. You sent me some of those data a couple weeks ago.

Yeah, I think I did, yeah. That's why we need to take all these different clinics and all these different programs and get a uniform data set.

So that's a pretty good list. I think you've given her five things.

Yeah. And you know, stress reduction is important. And you know, whether it's meditation or blah, blah, blah, do whatever you need to do to de. Stress. Deep breaths. Sleep is super important. Get getting adequate sleep. You don't lose fat and you don't get healthy if you're not sleeping well. And it's the same thing. You age terribly when you're not sleeping well. So there's a lot of components. Sleep, stress.

So I guess the reciprocal to this question, we're now no longer at the cocktail party, but we're sitting back here 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 or 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.

Well, the. I'm terrible with. I shouldn't admit this on a recorded podcast, but the rate of Alzheimer's cases actually coming down.

The incidence is coming down, incidence coming.

Down, but prevalence is going up because of our aging population.

Okay. But. 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 in increase in awareness and diagnostic acumen?

I've written on this, and my answer is I don't know.

But it's some combination of both.

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 more. There's, like, young people that are talking about, you know, Seth Rogen has his charity, Hilarity for Charity, and they're raising money for Alzheimer's education and young people, I mean, they're talking about Alzheimer's in high school students and college students 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 new flavor to it. So there's much less stigma, much more attention to it. Doctors are talking about it. Not just senility. Oh, that's normal with age. We now have biomarkers, so, sure, sure, we have all that. But 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, metabolic conditions and lack of. Of activity and sedentary lifestyles, like, it doesn't just affect the belly and the body, it affects the brain because they're all connected.

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, and then when he retired to play golf, it all went to hell in a handbasket. It. 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?

So yes, but it's complicated. The cognitive reserve.

Can't one thing just be freaking simple here?

No Alzheimer's prevention. No, no, man. This is.

You sound like me, man. Yeah, everything's complicated.

Everything's complicated. I wish I could give you a concise bullet point state, you know, like I'm bumper sticker. Yeah, live tv. You got to give them like a quick snapshot. 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 to be clear, has that been normalized for socioeconomic status? It strikes me as almost impossible to normalize that for socioeconomic status above my pay grade.

Don't know the literature as well as I need.

The point here being like people who go on to get secondary and tertiary education are going to 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?

I hope the studies have controlled for that, but I know it's important, impossible to control for everything. But that being said, I think early life educational attainment, for example, musical experience, midlife and midlife musical experience as well as early life absolutely can give build up greater cognitive reserves that when you get Alzheimer's, you're more resilient, you have this resiliency. The other aspect is, and I don't.

Know enough about music, but when you were the cello playing, two bass, guitar playing guy, what part of the brain is getting exercise when you do that?

It's very multimodal. It's the parietal lobe. It's the music side. Maybe on the right side, the, 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 basically association cortices. Basically 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.

And again, teleologically, that makes so much sense. I guess it begs the question, I would argue we will never know the answer to this question because if we're going to have to rely on very loose epidemiology, which can never be fully controlled and suffers from all of the usual problems that epidemiology suffers from, the question ought to be, is there any harm in believing that the epidemiology is right? Attaining a higher level of education, staying more mentally engaged, sustaining more loving, social, supporting relationships, having a greater sense of purpose, learning to play a musical instrument. I mean, is there a chance that doing those things increases your risk?

Well, I don't think that there's been any evidence that to suggest that it increases risk. But then there's this whole, you know, the naysayers will say, well, what is the cost? What are the trade offs?

What is the opportunity, opportunity cost?

What's also the, how much does it like music lessons? You're going to pay money to do music lessons or buy a guitar, but shouldn't you be like buying healthy food? So there's a lot of confusion and there's. When we get reviewers of our papers, this comes up all the time. So I'm not sure. All I can say is when you build a better backup pathway in the brain, and there's a saying, if you don't use it, you lose it. Well, someone that has Alzheimer's and is very cognitively engaged and has a good backup pathway, they're not going to decline as quickly. That being said, once the disease takes hold and maybe they stop working or they stop, they lose their sense of purpose, you can have a much more sharper decline. So people with high cognitive reserve, high cognitive backup systems are resistant to the effects of the amyloid. But there's a time that comes when, when they decline and those people decline much more sharply than others because they had like this emergency backup system. But sometimes when the parachute fails, the person goes down.

And Alzheimer's disease, that's a subtle, that's a nuance I wouldn't have predicted. It makes sense. The mechanism that you postulate makes sense.

And you know, you gave the other example of the woman whose husband passed away and then she just went downhill. Because when you have a collaborative relationship and you know, when one person's brain isn't working well, but you have another person to cover for you and do the dishes and feed you. And then that person is gone. Aside from depression, serotonin. And you have all that. Oh, I see this all the time. Like, I knew she had it. But then the husband and you know, caregivers of Alzheimer's patients have terribly higher medical illnesses. And when a husband dies and he was the primary caregiver and the wife has all Alzheimer's, that person will decline absolutely exponentially. I saw this in a high school teacher of mine. I mean, I see this all the time.

You know, Richard, your passion for this is palpable. And I mean, I feel like we could talk a lot more about other things, including, I think some of the stories of your patients are some of the most remarkable stories. Both the successes and the failures. Truthfully, the failures are what keep you doing what you're doing. And you are probably the hardest working neurologist. What's the expression? The hardest working man.

Show business.

Hardest working man. Show business. You are the hardest working in neurologist and show business. I know you personally, so I can say this from a close perspective. Your drive to help patients is a beautiful thing. And I know that the patients that you get to work with directly are blessed. And more importantly, I think your work will have a tremendous impact on people that you will not have the luxury or privilege of laying hands on. Because there's only one Richard. But there are lots of neurologists like you who I think want to be able to do more. And I think, I think it's really special that you have built the team around you that you have that. I didn't actually know the story about the dean of the medical center at Cornell taking this big chance on you. I mean, I knew it was obscure to have an Alzheimer's prevention clinic. Of course, you now have the largest Alzheimer's prevention clinic in the United States. It's a really heartwarming story to know that a big name medical center would take a risk on a young, up and coming neurologist and sort of give him the keys to that kingdom. And, and I hope that if one person listening to this is sort of thinking, you know what, that's the way I want to deploy my philanthropic dollars in Alzheimer's disease. Maybe I'll hedge on the side of prevention. Hopefully this discussion will have been worth.

It for you and I appreciate that. I never asked for a single dollar until the bottom dropped out about a year ago. And you, Peter, helped. And I've never asked for money. I've never asked for a single dollar.

It's the worst feeling in the world.

Oh, man, I can't stand asking for it, but it's like so little can go so far. You know, I sent you, on the way over here, an abstract, like the hot off the press, literally. We finished it at 4:32pm and I forwarded to you when I got here at 5, and I forwarded this to you. And like, you read the final statement. And you know, this hasn't been published yet, so I can't exactly read it out loud or whatever. And you read that statement, you're like, whoa, if this is the abstract and if I'm about to read this paper, and this paper holds water, this statement, wow, we're so close and, you know, we're. Every day we're moving closer. But that being said, we have thousands of pages of already collected data that we can't really jump into. So I appreciate your call to action. And I can tell you that our. Our philanthropic funds that have come in, we use immediately, and the ROI on.

Those dollars is remarkable. You know, there are a lot of people who say, look, I mean, maybe I can only part with 25, $50,000, which in new York philanthropic circles is nothing. Right? You don't get your name on a bench for that much. What a difference it can make in your clinic.

Oh, several thousand dollars is helpful, but, yeah, 50, 25. I could just do so much tomorrow. But I'm not asking for money because that's just not how I was raised.

Yeah, yeah, no, screw it. I'm asking for money for it. Well, with that said, Indian or Persian or Turkish tonight for dinner?

Oh, there's a neurology resident happy hour that I may need to stop by for a second, so maybe somewhere near there.

Okay.

Okay.

Figure it out.

That's like a few blocks away. But, yeah, I'm. I prefer food with no taste, so. And I don't do onions, garlic, shallots, scallions.

Oh, for heaven's sake.

I don't do allies.

I'm going to go have dinner by myself.

You can go to Cilantro, but. No, no, no. But I like. I like plain Jane. We'll. We'll find something to talk about glucose and metabolism.

Very well. All right, thanks so much, Richard.

Thanks, Peter. Appreciate it.

You can find all of this information and more@peterattiamd.com podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd safari@peterattiamd.com what's a nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social you can find me on Twitter, Instagram and Facebook, all with the ID Peter Atia md but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice and note no doctor patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please visit peteratiamd. Com About.