The Peter Attia Drive - #18 - Richard Isaacson, M.D.： Alzheimer's prevention

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful, top-performing individuals in the world, and this podcast

00:00:23.620 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.000 and other topics at peteratiyahmd.com.

00:00:41.200 Hey everyone, welcome to this week's episode of the Peter Atiyah Drive. This week I have the

00:00:47.560 privilege of interviewing a good friend, a collaborator, and an all-around interesting

00:00:52.740 dude named Richard Isaacson. Richard is a neurologist who specializes in Alzheimer's

00:00:58.920 disease. He is the director of the Alzheimer's Prevention Clinic at Cornell here in New York

00:01:04.480 City. His life has been touched by Alzheimer's disease, and from a very early age, as Richard

00:01:09.380 describes, he felt a calling to go into neurology. It is clearly his life's work. He's an absolute

00:01:14.960 expert in Alzheimer's disease, but specifically has chosen to focus his efforts on the prevention

00:01:20.180 of Alzheimer's disease as opposed to the treatment of Alzheimer's disease. And actually this puts him

00:01:24.900 in the minority of neurologists. Professionally, as I said, he's an associate professor of neurology

00:01:30.960 at Cornell Medical College here in the city. He's also an attending neurologist at New York

00:01:36.060 Presbyterian Hospital. He grew up not too far from here in Long Island or thereabouts, and actually

00:01:41.940 one of my favorite little tidbits I learned about him is he went to a high school called Connick High

00:01:45.820 School. And he was recently named among the most distinguished alumni. So his photo now hangs

00:01:52.700 alongside fellow recipients Rosie O'Donnell and Bob Costas. So that's pretty impressive.

00:01:58.540 He's a little bit of a Doogie Howser, started college at 17, finished medical school at 23. So

00:02:04.220 as I think I point out in the podcast, he finished medical school before I actually started medical

00:02:08.360 school, did his internship in Miami before ultimately doing his training at Beth Israel and Harvard.

00:02:14.300 Ultimately, he has wound his way back to New York. And as we get into great detail in this podcast

00:02:20.100 about what his work is, and I think more importantly, how it can help people listening to this or their

00:02:25.320 loved ones. And also, I think we, I think are very open about the limitations in this space and what

00:02:29.940 we do and don't know. Richard has developed, and I should say Richard and his team, let's be honest,

00:02:35.140 like all great people, they're sort of surrounded by a team of great people. They've developed something

00:02:39.060 called ALZU. So that's www.alzletteru.org, which might be one of the single most important

00:02:47.200 resources for people with Alzheimer's disease or early cognitive impairment and their family

00:02:52.700 members. So we'll obviously link to that very prominently, but I think that's something that

00:02:56.860 will, if you take nothing else from this podcast, other than a sort of visit to ALZU.org, that would be

00:03:02.700 terrific. Richard and I get into a lot of stuff. I think this podcast probably runs about two and a half

00:03:07.180 hours and we talk at the initial part, by the way, we get into something that was not at all planned,

00:03:12.540 but when Richard came over, I don't think in all the time I've known Richard, which has been about

00:03:16.900 three and a half or four years, I didn't notice how much he was into like bling phones. And when he

00:03:21.780 whipped his phone out, I just couldn't stop laughing. So the first like 10 minutes of this podcast are us

00:03:26.820 talking about this ridiculous thing that I hope we have pictures of to link to in the show notes.

00:03:32.660 Obviously the show notes are usually timestamped, so you can skip past the patty cakes and get to

00:03:38.140 the meat of the discussion should you want. But that said, I can't highly enough recommend

00:03:43.060 listening to Richard talk about his slot machine addiction and his funny phones. We talk about the

00:03:50.880 etiology of Alzheimer's to the best of our ability to understand it. We talk about the incidence prevalence

00:03:55.720 and the distinction between those two. We talk quite a bit about the distinction between men and women.

00:04:00.440 As some of you may know, there seems to be a bias towards women getting Alzheimer's disease more

00:04:05.320 commonly than men. And both Richard and I agree that that's probably not just an artifact of women

00:04:10.800 living longer. There must be something else going on there. And we explore that topic.

00:04:14.440 We go into great detail about what we believe the state of the evidence is, which admittedly at this

00:04:20.900 point is still relatively early about what steps people can take to reduce their risk of Alzheimer's

00:04:27.340 disease. And we get really into the semantics of this. What is the difference between risk reduction

00:04:31.240 and prevention? And we talk all about the politics of that and how those have changed.

00:04:36.360 We give, when I say we, meaning I discuss with Richard and Richard gives a great overview and

00:04:42.180 primer on APOE. We've had a lot of questions on APOE and we've deliberately punted those from the AMA

00:04:49.200 because I knew that this discussion with Richard was coming up. So for many of you to have questions

00:04:53.220 about the APOE gene, I think you'll find that interesting. And I'll tell you something that

00:04:57.160 I learned even in this discussion was so much of the subtlety around other genes that are named and

00:05:04.640 unnamed at this point or snips that we know about versus don't know about that also seem to be

00:05:08.420 predisposing to Alzheimer's disease. Unfortunately, this is a disease that is going to touch pretty much

00:05:15.920 everybody who's going to listen to this podcast indirectly or directly. In other words, if you're

00:05:19.980 listening to this, there's a non-trivial chance that you already know somebody who's afflicted

00:05:24.320 with Alzheimer's disease. And tragically, there's an even greater likelihood that at some point you

00:05:28.700 will, whether it be a parent, a loved one, or a friend or something like that. So I'm relatively

00:05:34.140 unabashed in my praise for Richard's work and I'm relatively shameless in my plugging for people to fund

00:05:43.460 this type of research. The type of research that Richard does is relatively unsexy. People don't really

00:05:49.560 know what to do with clinical research that is focused on Alzheimer's prevention and probably

00:05:55.420 somewhere in the vicinity of like 10 basis points worth of resources, meaning like one-tenth of one

00:06:01.280 percent of resources are going into funding this type of work. And after this podcast, Richard and

00:06:05.700 I went out for dinner and we talked about a gift that a patient of mine gave Richard. It was about a

00:06:11.160 $50,000 gift or a $40,000 gift, which is obviously a lot of money, but in the grand scheme of the types

00:06:16.340 of dollars that people are pouring into this research, it's not that much. And Richard was

00:06:19.700 able to walk me through what came of that gift from that particular patient. And I was so blown

00:06:25.120 away that I got, I came home from dinner and I actually emailed him to tell him the impact of his

00:06:30.560 actual dollars. And I will say this, having spent a lot of my time around biomedical research, it is

00:06:35.340 very rare that a $40,000 gift can move the needle. So if anybody's listening to this and they do feel

00:06:41.300 touched and compelled to get involved in this space, whether it just be through the standpoint of

00:06:46.000 education and understanding or through funding research, I think Richard's team at Cornell is

00:06:51.520 doing exceptional work. So finally, I'll just close by saying a couple of housekeeping things.

00:06:56.180 One, there's a weekly email that has grown immensely in popularity. So I want to make sure that people

00:07:01.520 who are interested in receiving such an email know about it. You can sign up for it on the site.

00:07:05.560 Every Sunday morning, I shoot out an email that kind of highlights things that are interesting to

00:07:09.320 me over the course of the week. I promise to do my best to make it not lame such that it's actually

00:07:14.240 an email worth receiving. Remember on the show notes for this podcast and every podcast are always

00:07:19.480 found on our website and we put an unbelievable amount of time into that. In fact, more time goes

00:07:23.900 into that than goes into the podcast. The podcast, you know, two and a half hour discussion, I might

00:07:28.360 spend two hours preparing for it. Bob and Travis, two of our analysts spend double digit hours preparing

00:07:35.020 those show notes and the feedback has been excellent. So for those of you that maybe aren't utilizing

00:07:40.100 those, it might be something to consider. And of course, if you do find this enjoyable, by all

00:07:44.020 means, please go to Apple, leave a nice review on iTunes. And I guess you can leave a review if you

00:07:48.740 don't like it as well, but I won't push you quite as hard. So without further ado, welcome to my

00:07:54.720 interview with Dr. Richard Isaacson.

00:07:59.480 So Richard, thanks so much for coming over, man.

00:08:01.340 Sure. Thanks for having me.

00:08:02.360 It's not a far walk, is it?

00:08:03.580 Four minutes.

00:08:04.620 Very well. What do you think of the coaster I gave you?

00:08:07.120 I don't know if that was intentional, but we have someone with dementia pugilistica on the

00:08:11.920 coaster, Muhammad Ali. And my brother's a Parkinson's specialist, so he would be the

00:08:15.140 right one to talk to. But yeah, amazing guy.

00:08:17.960 I gave you my Muhammad Ali coaster without even thinking about the implications of that.

00:08:23.060 Serendipity or synchronicity? Which one is that? Not sure.

00:08:26.060 Okay. So before we start this, I just learned something about you today that I have known you

00:08:30.940 for a while. I thought I knew everything. But as we were just getting ready to record, I was like,

00:08:35.100 oh, by the way, let's just stick our phones on airplane mode. And you

00:08:37.880 whipped out your iPhone and you put on airplane mode. And then you whipped out this

00:08:41.120 white and gold diamond studded thing. Yeah.

00:08:45.060 Can you tell our listeners what that thing was?

00:08:47.360 Well, I'm a very practical guy. So I collect luxury vintage cell phones. It doesn't connect

00:08:53.220 to the internet. Every 75 text messages, the memory gets full. So I have to delete them all.

00:08:57.920 It's very practical. Yeah. I collect vintage luxury cell phones.

00:09:01.640 The word collect implies you have more than just that white thing that's seven. Yeah.

00:09:06.300 Describe what it has on it. Well, it's besides the alligator skin on the back.

00:09:09.680 Sure. It's white alligator. It came from Africa. It then went to Italy and then skin was then shipped

00:09:14.140 to the UK. I had to get all the passport and all the paperwork because it got stuck in customs for

00:09:19.680 fish and wildlife had that phone in customs for like three or four weeks when I ordered it because

00:09:24.580 they couldn't verify that that wasn't an endangered species. So they found all the paperwork.

00:09:28.800 Then I had to get the paper trail of where the fabric came from. It's a alligator,

00:09:33.520 white alligator. It was actually assembled though. The phone was assembled in the UK

00:09:36.820 and it's got white sapphire keys. It's a pseudo blackberry. It's actually a Nokia.

00:09:41.360 The Nokia is actually from 2008. The phone was built in 2010. In 2010, this was the fattest phone

00:09:47.000 on the market. And that's pH fat.

00:09:48.800 pH.

00:09:49.360 For the young people.

00:09:50.400 With a pH. Yes. So we have white sapphire keys. We have 18 karat gold trim.

00:09:55.740 White alligator, of course, say that a few times.

00:09:57.500 Were you dating anyone at the time you got this?

00:10:00.320 You're very perceptive, actually. Wait, I didn't talk about the diamonds. It's called

00:10:04.320 a diamond pillow.

00:10:05.240 Am I allowed to include a picture of this thing in the show notes?

00:10:08.500 Absolutely.

00:10:09.120 I'm looking at it as you're describing it and I can't freaking believe everything you're

00:10:13.520 saying except that I'm looking at it. So I know that whoever is listening to this right now

00:10:17.140 is thinking, what are these two clowns talking about? But they need to see this thing.

00:10:21.620 It's called like a diamond pillow. Like that's what they marketed it as.

00:10:24.220 But anyway, it's on airplane mode so I can keep it on the table.

00:10:28.240 No, please keep it on the table because that thing is fantastic.

00:10:31.140 Oh, wait, wait, wait. Check this out. The ringer is no joke. I mean, I'm being recorded

00:10:34.920 so you can like verify this. But the ringer for these phones was recorded by the London

00:10:39.040 Symphony Orchestra specifically for this phone line.

00:10:42.260 I have to ask, how much did that cost in 2010 dollars?

00:10:45.120 In 2010, it was just over 25,000. However, I got it in an auction on eBay. Oh, no, you

00:10:52.120 know what? This one I actually got. So the company went out of business last year. That's

00:10:55.860 right. And they were liquidated. The company's Virtu, V-E-R-T-U. And the company went out

00:10:59.320 of business last July. They had a blowout auction sale, liquidation sale. So I was the

00:11:04.700 highest bidder. Actually, two people beat me, but then they'd never paid the money. So

00:11:09.200 then long story short, I was the highest bidder. I won the phone in September. I didn't get

00:11:13.000 it till January because of the customs and all the...

00:11:15.800 Oh, wait, wait. So you didn't actually buy this in 2010.

00:11:17.940 Oh, couldn't afford it. Yeah. Okay. Okay. I was going to say because...

00:11:20.680 But in 2011, I had a ex-girlfriend who was very that kind of whatever. And I went to

00:11:26.320 Vegas and I won $1,600 in Vegas.

00:11:29.040 You were a huge slot machine guy, if I recall.

00:11:31.340 Yes. Although when I first met you, Jay Walker burst my bubble and said, it's all luck

00:11:36.000 and random. And I could have sworn it wasn't. My uncle lives in Vegas. My grandfather

00:11:39.160 lives in Vegas. So he taught me the way of slot machines. And I thought I beat slot

00:11:42.920 machines until Jay Walker that has 700 slot machine randomization code passwords or patents

00:11:48.420 basically said, no, it's all luck. He burst my bubble. But anyway, I was in Vegas. I like

00:11:52.660 Vegas. I go about every year, every other year. And I won $1,600. So I was like, oh,

00:11:57.280 yeah, there's this luxury cell phone store. And I'm going to go buy the phone to impress

00:12:02.720 the girl that I was hanging out with. So we go and I put the phone, we take it out. It

00:12:07.660 was $8,600, not $1,600. So I actually did buy one sticker price for $8,600. That being

00:12:14.500 said, I have... And just to make sure I understand this, you walked in there with

00:12:17.520 $1,600 in your pocket, ready to give away your winnings because it's free money. The

00:12:22.480 guy whips it out. It's $8,600. You can't back away now because the girl you're trying

00:12:26.520 to impress. You have no idea how many questions I want to ask you, but we will not end up talking

00:12:31.480 about Alzheimer's disease or dementia. So just to summarize, you blew $8,600 in 2011 on a luxury

00:12:38.100 phone. You have since accumulated six more of them, including a retail $25,000 pimp phone that

00:12:44.240 we're going to include a picture of that you got for hopefully a lot less than that.

00:12:48.260 You know what was the problem? It was the shipping and the customs fees and all the...

00:12:52.420 This is a humanitarian crisis. Seriously. I collected old BlackBerrys.

00:12:58.480 You?

00:12:58.700 Yeah. Going back to like... Remember the very first one, which was like a wedge that was

00:13:02.060 a pager?

00:13:02.680 Oh, yeah, yeah, yeah.

00:13:03.220 Yeah, yeah, yeah. So I just wanted one of every generation of BlackBerry.

00:13:06.680 Weird.

00:13:07.280 But I didn't get blinged out ones. I just wanted the regular one. And I also collected Hewlett-Packard

00:13:12.060 calculators, all of the HPs. Now, I never got some of the originals because those were just

00:13:18.080 too out of my price range. And I thought that was weird. But I got to tell you, this might be

00:13:23.500 a bit weird. No, there's anything wrong with that.

00:13:25.120 Here's the deal, though. I've spent less than $12,000, $13,000 total because of the auctions

00:13:30.360 and the deals and whatever. And I've traded in some. And then they once sent me a loaner

00:13:33.980 and I kept it because they forgot they sent it to me. The company is out of business now,

00:13:36.940 so they won't come after me.

00:13:38.440 But actually...

00:13:38.920 So you think.

00:13:39.620 True. Good point. So I actually have $80,000-something of cell phones that I've actually

00:13:45.540 only paid $13,000 for. So, no rhyme or reason to that.

00:13:50.340 You sound like me rationalizing the dumb shit I buy. Like, I have X thousands of dollars worth

00:13:56.780 of Y that I only paid Z for. But like Z is still probably... Anyway, I'm not going to judge

00:14:02.480 because I am the last guy that should be judging. But I cannot wait to include a picture of that

00:14:07.780 phone. It's just hard to believe it exists.

00:14:09.980 It's like it was handmade and the signature was behind the battery. The guy signed it in metal.

00:14:16.380 I can't believe we have been talking for six minutes and 55 seconds and we could talk for

00:14:21.680 another hour just about this. That's how many more questions I have to probe your psyche.

00:14:26.280 The Ferrari one that I have. This is a good one, too. The Ferrari one, actually,

00:14:30.280 they stuck a recorder underneath the Ferrari in 2010 to record the sound.

00:14:35.440 Ferrari accelerating. And that Ferrari is the ringer, the acceleration sound.

00:14:39.980 See, that's one I could get into. I might have to borrow that one.

00:14:43.300 It's beautiful. That's like super blinged. It's like got a red back hue. Like you can

00:14:46.380 see the red lights and the... Anyway.

00:14:49.140 I didn't know such a market existed.

00:14:51.400 Well, the company went out of business.

00:14:53.400 Needless to say, it doesn't really exist.

00:14:55.480 Oh, and then there was the one last... Sorry, I'm sorry. Then there was the one

00:14:58.460 where I bought it...

00:14:59.460 This is your show. You can literally talk about whatever you want.

00:15:02.020 This is a great one because I bought... I got such a great deal online. I couldn't figure it out.

00:15:05.620 And I get this phone. I was so excited. And it's all in Chinese.

00:15:09.000 So I would text my friends, family, just in Chinese, just... And they wouldn't know what

00:15:14.500 I was saying. I didn't know what I was saying. That was a problem.

00:15:17.340 So when you say text, just randomly type characters.

00:15:19.860 Yes. And I was hysterical. People were like, what are you talking about? I'm getting Chinese

00:15:25.020 characters. And I would reply in Chinese. And that's a great phone. It's on the shelf still,

00:15:29.240 but that was a nice phone. Very inexpensive.

00:15:31.180 Oh God, this is fantastic. We might have to do a dedicated episode just on this stuff.

00:15:36.700 I'll bring them all. It's right down the block.

00:15:38.760 Okay. Well, onto the mundane. I was reading through something because we've known each

00:15:44.080 other for several years now, but there are a bunch of things you just don't know about a

00:15:47.080 person until you realize, oh, I'm going to sit down with Richard and talk to them. I want to learn

00:15:50.080 at least five things about him that tell me a little bit about how he got to where he got.

00:15:54.640 And so I'm reading through this. And the two things that I learned, well, now three,

00:15:59.360 given this bling phone thing. But the two things that I learned about you were,

00:16:03.120 you had finished medical school before I had started medical school. You finished med school

00:16:07.060 at 23. The other thing I learned about you is you were a rip roaring DJ.

00:16:12.060 DJ and recording producer. My name was DJ Rush. I had a recording studio in my basement growing up

00:16:17.540 with my bar mitzvah money. Actually, I took all the money and bought out this other guy,

00:16:23.000 this older guy's old recording studio. So I got like, again, it's all about value. So I spent like

00:16:28.340 three grand, which is a lot back then, huge amount of money, but it was all of my bar mitzvah money,

00:16:32.200 all the presents. And I got like 12, $15,000 of recording equipment. And magically I set up a

00:16:37.760 recording studio and I actually put an ad in the penny saver. I'm dating myself now. I grew up in

00:16:41.920 Suffolk County in Long Island and Comac. And I put an ad in the penny saver and people in Queens

00:16:47.480 were my best customers because people in Queens would usually go to the city and pay all this money

00:16:51.880 for recording, but then they would come out East to Suffolk County. And that's how I made money in high

00:16:56.800 school. Did that help you fund college or anything like that?

00:16:59.540 No, I was a computer tutor. I had like 400 bucks in cash from computer tutoring for college that I

00:17:04.860 got to use. No, I didn't. You ended up spending that money. You reinvested it. You reinvested the

00:17:11.080 recording in music equipment, random, weird guitars shaped the NJ warlock, like this weird looking

00:17:17.160 guitar thing. Yes. I like weird. It's not weird, man. It's beautiful. Appreciate it. Embrace it.

00:17:22.980 When you went to med school, did you know that you wanted to be a neurologist?

00:17:25.660 You sort of, yeah. If you don't think I'm a dork for collecting luxury vintage cell phones,

00:17:30.300 this is even more ridiculous. But I was in summer camp in sixth, seventh grade and it was teen travel

00:17:36.120 and we would go to like, I think we're on a trip to Tennessee actually. And we're heading on down to

00:17:41.740 Nashville and on the bus I brought, I shouldn't giggle, but neuroanatomy made easy and understandable.

00:17:49.600 It's like neuroanatomy for dummies.

00:17:51.360 Exactly.

00:17:51.600 Part of the same series.

00:17:52.520 Yep. That's exactly what it was. And this is, I was in sixth, seventh grade. My brother was a

00:17:57.020 neurologist.

00:17:57.780 Your brother's older?

00:17:58.680 He's older. He's 13 years older than me. So he was finishing med school also at 23. He did a six

00:18:03.240 year program also. I was 10. So I got his hand-me-down books. He would leave them in the room and I

00:18:09.000 would, I guess, read them. So I think I was interested in the brain, but I could never, even though I had

00:18:13.680 this book, I would read this book a hundred times. I have no conception of neuroanatomy. I just like,

00:18:18.160 it's just like way over my head, even though I started studying it when I was 11.

00:18:22.540 So you guys are from an underachieving family. You also had an uncle, I believe, that was diagnosed

00:18:27.840 with Alzheimer's disease when you were quite young.

00:18:29.540 Yeah. So my uncle was diagnosed when I was in high school and I always knew I was going to be

00:18:32.960 a neurologist. I didn't know exactly which area or which field. I think the brain was interesting.

00:18:37.360 I also kind of chose neurology because it was the most challenging. I wanted to be challenged for my

00:18:41.420 career. But honestly, when I was in residency, I guess I just felt a connection to older people.

00:18:46.480 I didn't exactly have grandparents. I only had a grandfather who passed away when I was eight.

00:18:49.520 I didn't meet any of my other grandparents. They passed away before I was born.

00:18:53.180 And I don't know, I just felt a connection to older people. So that was part of it. I guess I

00:18:57.000 could have seen myself doing Parkinson's disease. Actually, in some ways, the plan was to go to like

00:19:00.900 as best of a residency as I could. So I could then one day join my brother in practice, live in

00:19:05.960 Florida. But I wasn't sure about Parkinson's. I liked it. I liked Alzheimer's also. I like cognitive

00:19:11.440 neurology. I actually trained in Beth Israel Deaconess Medical Center in Boston where

00:19:15.560 cognitive neurology really was born. It's the first place in the United States.

00:19:19.840 A picture of Norman Gesh was in the conference room. So long story short, I think cognitive

00:19:24.660 neurology was always challenging and interesting. But I didn't just want to do phenomenology like,

00:19:29.340 oh, look at this aphasia or look at this whatever. I wanted to treat patients. And I think because I

00:19:35.540 understood what it was like, you know, Alzheimer's terrible, just like a terrible, terrible,

00:19:40.840 horrible disease. I don't want to get like, you know, emotional and upset. But it's just terrible.

00:19:45.560 And like my Uncle Bob introduced my parents. So that's number one. So that's why I'm here today.

00:19:50.480 And this is a completely true story. I was three. My Uncle Bob was in the Navy. And I was at my Aunt

00:19:54.520 Carol's house, also in Long Island. And I jumped into the pool. I sank to the bottom. And everyone was

00:20:00.400 inside. And my Uncle Bob ran out, jumped in and saved me. To this day, I actually avoid water. I hate

00:20:06.700 swimming. I hate, I don't go in the ocean. I don't go in baths. I mean, I stay away from water.

00:20:10.780 You were traumatized by that. Oh, yeah. Oh, yeah. I can't even, I don't want to go near a pool.

00:20:15.800 I don't go in pools. I don't like the feeling of water. My Uncle Bob, obviously, was a special guy.

00:20:21.060 But just to see, like, he was the life of the party. That was like that relative where

00:20:24.620 he had a saying, what a party, like at all the weddings and whatever. So just to see someone like

00:20:31.100 that become what he became. And then just to see what the toll took on his daughter and sons,

00:20:37.560 just, it was just a terrible, horrible disease. So I think I empathized with it. I understood it.

00:20:42.260 And that's really where I chose to forge the career path.

00:20:45.740 I think it's so interesting how many people in medicine have a story about a moment that,

00:20:51.560 either a moment or an interaction or relationship that became so pointed in their decision to enter

00:20:57.120 medicine. I don't think that's absolutely necessary. I mean, I think many people enter

00:21:01.120 medicine for sort of less specific or less tangible reasons. But I'm always amazed by these stories. So

00:21:08.180 I appreciate you sharing that. Let's fast forward a little bit and talk about, you finished residency

00:21:13.120 in Boston. And then did you come back to New York? No. So I actually left New York for longer than I

00:21:18.440 was in New York. I graduated at 17. I spent six years in Kansas City. This is a six-year medical

00:21:22.840 program. And so I finished early. This is how the way most other countries do it in Europe and

00:21:27.080 in Asia. But actually, the unique part about our program was medical school from day one. So

00:21:31.880 I'm 17 years old, University of Missouri in Kansas City. I have my lab coat. And literally Tuesday

00:21:36.560 and Thursday, I was in the hospital. And Monday, Wednesday, Friday, I was in college. And it was

00:21:41.640 a very unique, blended program. And I couldn't ask for anything more. I had literally six years of

00:21:47.240 medical experience. I was doing tons of medicine. I was doing electives throughout the country,

00:21:51.540 throughout the world. I did a history of neurology tour throughout Europe for one of the elective

00:21:56.200 months. So I just got so much medicine exposure. Usually, medical students get two years of

00:22:00.500 clinical medicine. I had like six years intermittently of clinical medicine. So I did

00:22:04.720 that. Then I popped over to Miami for a year to do medicine training and then to Boston for three

00:22:08.160 years. And then I headed back to Miami. My mom was down there. My family's down there. So I headed

00:22:12.700 back down there. And I was in Miami for eight and a half years.

00:22:16.900 Oh, was that how you met your fiance?

00:22:18.320 Yep. You got it in Miami. And my band was playing. She was in the front row.

00:22:21.720 Wait, what do you play?

00:22:22.460 I play bass.

00:22:22.940 Okay. Because you grew up playing the cello. That I knew.

00:22:25.440 I did. I grew up playing the cello until I got in a fight with my orchestra teacher. I told him to

00:22:30.580 go F himself. And that was the end of that. He had this complex. He was like, I'm better than you,

00:22:37.100 because he was in a Maxwell House commercial. He was the conductor in the Maxwell House commercial.

00:22:41.300 That's the pinnacle.

00:22:42.380 Exactly. He was the conductor in the Maxwell House commercial. So his crap didn't stink. So I just

00:22:48.260 couldn't take it. And I told him to F you. And I walked out.

00:22:50.700 How old were you?

00:22:52.180 I was probably in 10th grade. Yeah, 10th grade. So then I joined a band, actually.

00:22:56.500 Is it easy to transition from cello to bass?

00:22:58.700 I didn't practice. I took two lessons. That's right. I took two lessons. And I just kind of...

00:23:03.500 But the fingering is similar?

00:23:04.700 Yeah. The frets threw me, actually. The frets were hard. So I actually got a fretless bass,

00:23:09.100 joined a band with some of my friends. And then actually the guitarist. And one of the bands I

00:23:12.960 joined has been living on my couch for a year and a half. That's a whole nother story.

00:23:16.460 There's a lot of stories in your life.

00:23:18.080 Yeah. Keeping it simple. Exactly. So I played bass, always been into music.

00:23:23.800 So you're the bass-playing neurologist hipster in Miami.

00:23:27.520 Yep. Meet the blonde girls sitting in the club. So yeah. I was wearing my Mexican wrestling mask

00:23:34.180 and shirtless. Yeah. My band had this schtick. We were called the Regenerates,

00:23:38.700 music for the right brain. And our logo was this brain, but we had this schtick where we played

00:23:44.280 like... Anyway, long story short. But yeah. Is there any video evidence of this?

00:23:48.240 Oh, it's all over Facebook.

00:23:50.160 Okay. Very well.

00:23:50.800 The Regenerates. We have 99 likes on Facebook.

00:23:54.380 So Travis and Bob, in preparing the follow-up show notes for this, will have a challenge trying

00:24:00.840 to just focus on some of the Alzheimer's stuff we talk about and limiting the bling phones and

00:24:06.600 band photos and videos to 10% of the total volume of show notes.

00:24:11.260 Exactly. The phone is called the Virtue Constellation Quest.

00:24:14.240 Oh, we're going to be taking a picture of that thing after we talk. Don't you worry.

00:24:17.220 Okay, cool.

00:24:17.620 Nothing will be left of the imagination.

00:24:19.220 I had professional pictures taken of the phone.

00:24:23.820 Goddamn.

00:24:24.600 Because I dropped it. It took like a few years. I dropped it.

00:24:27.180 No, I can totally... I'm sitting here laughing at you. And look, on my wall, there's professional

00:24:31.160 photos of watches.

00:24:32.260 I feel much better. And the Blackberry collection, I'm redeemed.

00:24:36.220 I don't even know who I am to judge. So then what got you to New York?

00:24:39.260 I guess in life, one needs to make a decision kind of where one goes and what priorities

00:24:44.440 one has. Miami was amazing. I had amazing opportunities. I wrote a book back in 2010,

00:24:49.760 and then it came out like first week in 2011, called Alzheimer's Treatment, Alzheimer's Prevention,

00:24:53.660 A Patient and Family Guide. And I put together in this book this plan about what I do for my

00:24:58.420 patients. I was known in Miami for spending a lot of time with patients. And when patients

00:25:03.380 would leave, they would always have like 10 things to do or 15 things to do. And that was

00:25:07.540 very unique because most people, neurologists, there's a saying, it's called diagnose and

00:25:11.660 adios. And neurologists don't treat disease. We admire it. Well, not me. I'm going to because

00:25:17.260 of my family history, because of whatever, one thing leads to another. And I want to do anything

00:25:21.280 and everything as long as it's evidence-based and safe. So I was known for jamming the printer

00:25:25.900 in the neurology department because my recommendations was like sometimes 10 pages, 15 pages. And I put

00:25:31.760 together a nutrition little pamphlet and this. And it got to the point where I was jamming

00:25:35.680 the printer so much that I went to Kinko's. I had it bound. It was more expensive to bind

00:25:39.260 it. So I wrote this book and I would give the book to the patient. It was like printed

00:25:42.840 out like $2 to print out the book. So I would give the book to the patients. And then magically

00:25:47.080 the Today Show called one day needing an expert about like music and Alzheimer's disease, which

00:25:51.520 I talked about publicly. Next thing I know, I'm selling hundreds of books online and put

00:25:56.360 up a website and all that kind of thing. So why do I tell the story? I tell the story

00:25:59.800 not to sell books. I don't care about selling books. But when I wrote the book, I got a lot

00:26:03.600 of flack because in the title I wrote Alzheimer's Treatment, Alzheimer's Prevention, this plan,

00:26:08.540 what is this plan that you're telling people to do? Show me the evidence. You know, there's

00:26:12.120 FDA approved drugs that may work marginally, but what is all this other stuff you're doing?

00:26:16.040 It's crap. So, you know, I talked to the Alzheimer's Association on the phone and they

00:26:19.520 said, no, you can't say this. And I talked to the, actually a colleague, I shouldn't really

00:26:22.860 say this, but there's a colleague on the down the hall for me and my academic appointment.

00:26:27.420 I knew his wife did this. I shouldn't be saying this again. It's being recorded, but whatever.

00:26:30.720 His wife wrote a really negative scathing review about my book. It was actually probably him writing

00:26:35.420 the review. And I said to myself, but I really believe in this. I'm not trying to sell books.

00:26:40.280 I don't give a crap about books. I made the book large print and it costs more money to print and

00:26:45.520 I make less money per book and I don't care. I want better quality pages. And I just, I don't want

00:26:50.580 to say that someone questioned my integrity or whatever, but I guess someone questioned my integrity

00:26:54.360 and I'm not trying to sell something. I believed in it. And the only way to prove in a rigorous

00:26:59.780 way that multimodal interventions work, whether it's patient education, lifestyle interventions,

00:27:05.520 pharmacologic management, everything. The only way to prove that that works,

00:27:10.600 the only way to do that as in a large academic medical center. And I basically interviewed in

00:27:14.620 New York and Boston. I was about this close to going back to Boston. I had a great offer at Harvard.

00:27:19.160 Would have been a major stepping stone in my career to be that age and that level to be an associate

00:27:24.080 professor and, you know, director of an Alzheimer's clinic, but they wouldn't let me use the term

00:27:28.420 prevention. So then I came to interview at Cornell and my chair said, Oh yeah, Alzheimer's prevention.

00:27:33.260 That's probably going to be something new. Sure. And the Dean, as she was signing my letter back in

00:27:37.820 2012 said, no, I got to meet this guy. So July 4th weekend, 2012, I'm all like, Oh, it's about to move

00:27:44.760 to New York. What's happening. And I go meet her and I got a 15 minute meeting. I had a seller on

00:27:49.040 because it's literally the only place in the country that I was, I was allowed because I called

00:27:53.140 around and whatever. I wanted to start this Alzheimer's prevention thing. And she interviewed

00:27:57.700 me and she, you know, had written my CV. It was like, I think this was the Dean of Cornell Medical

00:28:02.060 School. The CEO of the medical school. Exactly. The Dean of the medical school says, no, I'm not

00:28:05.880 signing this guy's letter. We're not starting an Alzheimer's prevention clinic. That's crazy. I have

00:28:09.360 to meet him. And I was given 15 minutes on my, on our calendar to plead my case. And the first

00:28:14.140 question she had for me. Did you bring in a bling phone? No, but I was so prepared. I had like a

00:28:18.320 collated folder and I had a USB with all the evidence and I was ready to go. And I walk

00:28:23.440 in and she looks at me. She looks down at my CV and she looks at me and she says, how old

00:28:30.220 are you? She doesn't know your Doogie Howser, man. She was expecting the traditional bearded

00:28:35.580 bow tie, older fifties, whatever, sixties neurologist type. And I look like that. So we talked about

00:28:43.960 my age and my training and the 23 thing, which by the way, today is probably not even legal.

00:28:48.320 Probably. Exactly. And then in the last two minutes of after talking about the age and

00:28:54.620 how the CV got so long, I basically said, listen, I'm serious. This is my plan. I'm not over

00:29:00.540 promising. Alzheimer's starts in the brain decades before the first symptom. People don't know

00:29:05.200 that. I don't even think she realized that when someone's diagnosed with dementia, it didn't

00:29:09.960 start that day. It started decades before I explained this to her. The new criteria had just

00:29:14.400 came out. The new diagnostic criteria had come out like that summer. And she said, okay,

00:29:18.320 I'll let you do this prevention thing. And that's it. The only place that I could have gone in the

00:29:22.980 country, possibly the world who knows to do what I have tried to do and what I've actually been able

00:29:28.240 to accomplish in the last five and a half years is New York city. It's just a, and while Cornell and

00:29:32.760 New York Presbyterian has been the saying for New York Presbyterian is amazing things are happening

00:29:37.640 here. And I'm not trying to give a commercial, but there's just no other place that I would have

00:29:41.620 been able to do this. So you mentioned the diagnostic criteria. So let's start from the beginning

00:29:45.500 because at least once a week, I get a call from a friend or a patient saying, I think my mom or my

00:29:50.520 dad is in the early stages of Alzheimer's disease. And I say, well, tell me why, tell me a bit more.

00:29:55.000 And they're like, well, you know, my mom's just having a harder time remembering things. She's

00:29:59.640 repeating herself or my dad is, you know, having a hard time fill in the blank. Right. So how is the

00:30:06.140 diagnosis of Alzheimer's disease made and how does it differ from other types of dementia?

00:30:10.200 Alzheimer's disease has traditionally been a clinical diagnosis, meaning you talk to a patient

00:30:15.380 like you were doing, you get a history of progressive short-term memory loss. And when

00:30:20.420 that memory loss and other cognitive changes and sometimes sleep trouble and behavior changes,

00:30:26.300 depression, agitation, whatever. So cognition, sleep, psychiatric comorbidities, when all of these

00:30:33.920 cognitive brain symptoms cause activities of daily living to be no longer able to be done by that

00:30:41.840 person, then that person has something called probable Alzheimer's disease dementia. So in the

00:30:47.140 past, the clinical way was to talk to the patient, progressive short-term memory loss, common things

00:30:52.000 happen commonly. It's probably going to be Alzheimer's disease. Now it's about 60, 70% of the time

00:30:57.240 when people get older, sometimes they forget things. They lose their keys. You have a word on the tip of

00:31:03.380 your tongue, but you remember that later, you find your keys later. That can be non-pathological

00:31:09.140 changes associated with age. So there's something called age-related cognitive change or cognitive

00:31:14.120 aging is even the more appropriate term. Cognitive aging is separate from Alzheimer's disease, but it

00:31:18.680 doesn't lead to a pathological diagnosis in the brain. And it doesn't lead to alterations and

00:31:24.480 activities of daily living. People can still take care of themselves. They can still pay bills and

00:31:28.580 function independently. So Alzheimer's disease is the most common form of dementia, but there's

00:31:35.400 different forms of dementia. Also, there's frontotemporal dementia, which is more of a

00:31:39.300 behavioral problem. There's dementia with Lewy bodies, and that's similar to Parkinson's disease

00:31:44.360 symptoms along with dementia.

00:31:46.600 It was reported that after Robin Williams' death, that he had Lewy body dementia superimposed on whatever

00:31:52.120 else people had speculated was going on. Is that true, or is that just a rumor?

00:31:55.560 No, that's true. I've heard his wife, she was honored at the American Academy of Neurology last

00:31:59.900 year, and she talked about this. And I didn't treat him. I don't diagnose. I can say only from

00:32:04.420 a periphery, but it seems from what I've heard, some of the paranoia, the hallucinations, the slowed

00:32:10.180 movements, the vivid dreams, acting out dreams, it seemed pretty consistent.

00:32:15.520 And would those be different from a patient presenting with the more typical Alzheimer's disease? In other

00:32:20.340 words, are those slightly more unique to Lewy body dementia?

00:32:22.960 Yeah. So, you know, by far, Alzheimer's disease...

00:32:25.320 Which I've been told, by the way, can only be diagnosed in an autopsy.

00:32:27.900 Yeah. I mean, I'm a clinical diagnostician, so it's a new era. It's a new world. So when your

00:32:34.120 friends or your patients call you and say, does my mom have Alzheimer's disease, you listen to the

00:32:38.300 story. Neurologic diagnosis should be made based on the history 80 to 90% of the time. So I still

00:32:44.940 always defer to the clinical impression. But in 2018, 19, 20, etc., it's just a different

00:32:51.280 world. We can do biomarkers. So we can do scans. And does the person have amyloid in the brain?

00:32:56.280 Well, that's Alzheimer's. But then again, people with Lewy body dementia also have amyloid. So

00:33:00.380 it's confusing. But long story short, when people have progressive short-term memory loss and other

00:33:06.760 cognitive changes, it's probably Alzheimer's until proven otherwise. The key thing is that we want to

00:33:11.180 rule out reversible causes. So make sure they don't have thyroid trouble or B12 deficiency,

00:33:16.160 things like that. Pretty uncommon, 5% of the time, 8% of the time, whatever it is. And a lot of times

00:33:21.240 people have a thyroid problem or B12 deficiency, you'll fix it. And maybe the symptoms will get a

00:33:26.100 little better, but they may have Alzheimer's anyway. So we want to rule out reversible causes.

00:33:30.520 We always have to do some brain imaging, either a CAT scan, got to rule out a tumor or a MRI. Now,

00:33:36.220 the American Academy of Neurology states you can do any brain imaging. In my clinical practice,

00:33:40.900 we always recommend an MRI.

00:33:43.100 What phase of MRI?

00:33:44.520 Just a regular MRI, no contrast.

00:33:46.760 T2? Which image are you looking at, the T1 or the T2?

00:33:49.280 Well, I want to look at everything. Is there a vascular burden? Could this be vascular cognitive

00:33:53.060 impairment by itself? Could this be vascular and Alzheimer's? Because about 35% of the time,

00:33:58.120 you have Alzheimer's and vascular cognitive impairment. So you just want to get a sense of

00:34:01.620 what it looks like. But to me, when I look at an MRI, I look for atrophy, shrinkage of the brain.

00:34:06.440 And if the frontal lobes, which is the planning, processing, higher order thinking part of the brain,

00:34:10.900 and the temporal lobes, which is the memory center of the brain, especially the part of the brain

00:34:15.320 called the hippocampus. Hippocampus, I think in Latin means seahorse, basically looks like a little

00:34:19.460 seahorse thing when it's cut. And if there's a hole in the hippocampus, you know, where the big space

00:34:24.220 of shrinkage, even without all the fancy biomarkers, which we'll talk about, progressive

00:34:28.900 short-term memory loss and atrophy in the brain in certain Alzheimer's specific areas, especially the

00:34:34.800 hippocampus, is Alzheimer's still proven otherwise? Now, again, it's a new era. We can check for

00:34:40.020 amyloid in the brain. We can look for amyloid and tau in the spinal fluid. You know, even soon,

00:34:44.780 we'll be able to do tau scans. Tau protein is another like amyloid pathologic protein that gets

00:34:49.960 built up in the brain of a person with Alzheimer's. And you can look at these biomarkers to make a

00:34:55.680 definitive diagnosis, does this person have Alzheimer's? The only main reason to do that is

00:35:00.580 if we're going to think about a clinical trial, because if you get into a clinical trial, the only way

00:35:05.140 to do that is to have Alzheimer's in the brain. And in the past, and we'll talk about why have

00:35:10.060 so many Alzheimer's drugs failed, why have studies left and right failure, failure, failure. There

00:35:15.160 was one study that, you know, this was only like five or six years ago, before the era of biomarkers,

00:35:20.260 there was one study where 40% of the people with a clinical diagnosis of Alzheimer's disease

00:35:25.080 in the study did not have amyloid in the brain, but they were getting anti-amyloid treatments.

00:35:31.360 This was later found with a scan or on autopsies?

00:35:34.820 Different studies have done it different ways. So the take-home point here is that

00:35:38.300 Alzheimer's is a little confusing. You can make a clinical diagnosis, but the clinical diagnosis

00:35:43.080 isn't always correct. So that's why we need to think about biomarkers in certain situations.

00:35:47.740 You talked a lot about short-term memory. Where do you see changes? When do you see changes

00:35:51.840 in other parameters of cognition, such as executive function or processing speed?

00:35:57.480 So when I think about the brain, I think about different areas, and I don't want to say

00:36:00.740 like pin the tail on donkey, but it's like, you know, pin the tail on the part of the brain

00:36:04.560 that's manifesting a change in cognition. So, you know, memory, there's short-term memory,

00:36:10.000 there's long-term memory. In able to have a memory, someone needs to be able to pay attention

00:36:15.380 to something. So another area of the brain in terms of cognitive function is processing speed

00:36:20.580 or attention, and they're pretty similar. Then there's executive function, which is higher

00:36:24.460 order processing, judgment, planning, things like that. There's other things. Language

00:36:28.900 is important. Learning is important. If you can't learn something, how can you remember

00:36:32.980 it? So what we do is we try to really hone in on exactly what the cognitive domain or cognitive

00:36:40.180 area is deficient. So for example, when you have someone call you and say, oh, my memory

00:36:44.940 is terrible. Well, is it really memory? That's what cognitive assessments do. When my nephew

00:36:50.580 was texting, I can't say when I'm texting because my phone's from 2010, but when my nephew is texting

00:36:55.840 at the dinner. Which you could text in Chinese though, if you had the other one. Oh, the other

00:36:59.420 one. Oh, that's a great phone. Next podcast, I'll bring that. Someone's texting and not paying

00:37:03.940 attention. And then I asked my nephew a question 20 minutes later. It's not like they forgot.

00:37:08.340 They never assimilated. Exactly. They never encoded it. It never got into the memory. So we always want

00:37:13.080 to make sure, is this an attentional thing? Because for example, common things happen commonly.

00:37:17.380 Dementia, common, but depression is also very common. And a pseudo-dementia of depression

00:37:24.440 is very common. So if someone says, oh, I can't remember, but if they're depressed,

00:37:29.540 whether it's a serotonin issue, whether it's whatever, and you do the testing,

00:37:33.160 they're not able to be attentive during the exam. So they're not remembering.

00:37:37.000 If you treat the depression, for example, serotonin drugs or whatever else,

00:37:41.720 well, then the attention gets boosted and then the memory comes back. So it's not

00:37:46.080 a dementia due to a neurodegenerative condition. It's a pseudo-dementia due to depression. So

00:37:52.260 there's a lot of things out there. And that's why getting to the root of the which area of the

00:37:57.300 brain is truly not working is key. Short-term memory, long-term memory, processing speed,

00:38:01.780 attention, that kind of thing. It was about three or four years ago when I realized I wanted to start

00:38:07.200 including cognitive testing in our assessments in our practice. And so Dan Pelachar, who was one of

00:38:15.160 our analysts at the time, I said, I tasked Dan with this problem. I said, Dan, I want you to go out

00:38:19.260 there and I want you to learn everything about cognitive testing so that we can get the best in

00:38:24.020 class. You know, we're going to do the best blood testing imaginable. We're going to do the best this,

00:38:27.420 the best this, the best this, the best cognitive testing. Well, that turned out to be a fool's errand

00:38:30.900 because he came back with, I don't know, 27 different tests that one could do. Some of these

00:38:38.760 were clinical tests, like the NIH had a toolkit with all of its tests within it. But then there

00:38:43.860 were a bunch of commercial tests you could do online and, you know, look at this stuff. And I

00:38:48.220 mean, my take on the sort of commercially available ones, because there was one problem that immediately

00:38:52.720 became obvious to me, which is it took a great deal of skill to administer a subset of these tests.

00:38:58.960 So immediately said, we're not going to do those tests because like, we don't have the skill to do

00:39:02.920 it. And we're not going to invest the time to do that because we don't have the patient volume.

00:39:06.960 Like we're not an Alzheimer's clinic. Right. So we figured we have to use an off the shelf

00:39:11.380 thing. And I was like, these all strike me as like kind of bullshit. But I was like, look,

00:39:17.240 here's the definitive assessment we're going to do. And I had Dan, maybe I shouldn't be saying this

00:39:21.440 story online, but it's probably legal. If not, let's bleep this part out, please. Bob,

00:39:25.600 I basically had Dan and a bunch of his buddies, like get together one night at their place.

00:39:30.200 They're all over 21, by the way, and take the test. Each of them took the test. Like there was

00:39:34.640 like six guys that each took the test and then do a shot. I provided the alcohol and then redo the

00:39:40.060 test and then do a shot and then redo the test and then do a shot. And I think they did this for six

00:39:44.540 rounds. And my question was, if the test is truly a measure of cognitive capacity that cannot be

00:39:53.100 learned, their performance should deteriorate. If you can learn the test, then their performance

00:39:59.620 should stay flat or even get a little bit better as they become inebriated. And of course their

00:40:04.400 performance was flat. So like six hours later, you know, whatever, they're eight drinks into this

00:40:09.900 thing. They're hammered. They're doing just as well in the cognitive test. At that point, I was like,

00:40:14.140 okay, we are not going to solve this problem using over-the-counter commercial tests. And that's when,

00:40:19.560 you know, you and I already knew each other, but that's when I was like, all right, Richard,

00:40:21.840 what is going on with this cognitive testing thing? And then I came into the clinic. I met you,

00:40:26.560 I met Holly, I met the team. And I was like, oh yeah, we're never doing this. Like we're going to

00:40:30.920 send our high risk patients to you guys because this is way too much work. It's really complicated.

00:40:37.180 Oh, this has been complicated for decades. And you know, just to tell a quick story. I mean,

00:40:40.380 first of all, our battery, the cognitive tests we do is we do about a little more than half on

00:40:44.560 computer because, you know, we use the NIH toolbox. We also use odor identification, which is important.

00:40:49.240 And that's hard to have a practice effect on. Some tests are less practice-effectible. Other

00:40:54.380 tests are common to expect that. We use pen and paper tests. So what we've done is we've put

00:40:58.860 together an hour and 20, 30 minute battery that kind of is a greatest hits that tries to look at

00:41:04.500 people that are, you know, in the normal slash very early phases of Alzheimer's. The problem is,

00:41:08.880 is that most of the cognitive tests out there have really been scaled or used and validated and meant

00:41:14.340 for people with dementia. So they're not sensitive to pick up people with early cognitive decline who

00:41:19.140 do not have dementia. Exactly. And the newer tests just don't have the robust validation in people who

00:41:24.600 are normal versus normal, no amyloid in the brain versus normal with amyloid in the brain. And until

00:41:29.940 we have thousands of people that do that, any off the shelf or any, some are better than others for

00:41:35.100 sure. We just don't have the perfect solution. This actually is a great time to talk about this,

00:41:39.000 but this past weekend we had the first ever Alzheimer's Prevention Clinic and Brain Health

00:41:42.960 Clinic Symposium where all of us, there's six centers like this, like ours now. We were the

00:41:48.000 first in 2003. Where are the other five? In 2014, the Alzheimer's Risk Assessment and Early

00:41:52.860 Intervention Program in University of Alabama at Birmingham opened in 2014. Very different model

00:41:57.640 than us. It's a two-visit model sort of thing. They get an MRI and they do, it's just a different way

00:42:01.420 to do it. Great person down there, David Gelbacher. Then actually we opened a satellite clinic in

00:42:05.880 Puerto Rico, Alzheimer's Prevention Clinic and Research Center in Puerto Rico, doing amazing.

00:42:11.420 Everything was great. And then, oh boy, she didn't have power for six months. She's picking up the

00:42:16.940 pieces, you know, patients coming for prevention. Patients just need to come to like get electricity

00:42:22.460 and get psychological counseling for the PTSD after the storm. She's calling it PTSD in Pueblo. I think

00:42:28.240 that's what she calls it. So that was a tough time, but we're still running. We have the Brain Health

00:42:32.980 Center at North Shore Hospital in Chicago, in Evanston, Illinois. And that's been running strong.

00:42:37.640 I'll be there next week.

00:42:38.360 Oh, cool. Yeah. Good, good people over there. They have a very heavily focused on electronic

00:42:42.400 medical record to try to track these things. Newest center is actually two. One's in Boca Raton,

00:42:47.760 Florida at Florida Atlantic University in Boca Raton. The Dementia Prevention Initiative,

00:42:52.060 Jim Galvin is like, if you think we do a deep dive, Jim Galvin does the deepest dive. I mean,

00:42:58.360 we're talking to like the magma of the earth that he does from bone density to metabolomics and

00:43:04.400 proteomics to EEG. I mean, if there's an outcome measure, he does it, but that's his expertise and

00:43:10.080 he's super great at that. And then the newest center is opening at the Pacific John Wayne Cancer

00:43:15.180 Institute, but it's Providence St. John's and it's called the Pacific Brain Health Center in Santa

00:43:21.680 Monica, California. Really great people that were recruited from UCLA. David Merrill is one of them.

00:43:25.740 And we're all for the first time trying to collaborate and trying to harmonize these

00:43:30.100 measures because honestly, I don't know what the right measures are. We're trying to create an

00:43:34.120 additional free cognitive assessment that can be done online, but the toolbox can only be done on

00:43:39.740 computer and iPad. The versions that we built were actually on the phone. So we built six versions of

00:43:45.020 something called the face name associative memory test. We worked with Doreen Rents to help us with

00:43:49.540 this. She's amazing. She validated this where if you do poorly on a face name associative memory,

00:43:55.300 that predicts amyloid in the brain. So what we've done is then we then created all these.

00:43:59.180 Do you remember how predictive it was?

00:44:00.560 Don't quote me on that kind of stuff, but it's pretty predictive. It worked pretty well. I don't

00:44:04.560 remember from the paper, but we created these tests and it was not the NIH per se. It was a different

00:44:09.300 reputable organization because the words Alzheimer's and prevention was in our name. They didn't want to

00:44:14.720 use our tools or really be associated with our program. So we've been getting tomatoes thrown at us for

00:44:21.080 quite some time. And for example, this symposium we had this weekend, we had all these brain health

00:44:24.840 centers. We all get criticism and you know, we all get criticism because for example, we don't even

00:44:30.460 know what are the right tools to use, which are the best cognitive tests, which is this, which is

00:44:34.080 that. So we've been getting criticism for a long time. However, thankfully the tide is turning and

00:44:40.140 it's kind of a new day in a new era. For example, even the, you know, last year, the Alzheimer's

00:44:44.740 Association put out 10 tips for brain health to preserve cognitive health. That's amazing. This year at

00:44:51.840 the Alzheimer's Association meeting in Chicago, the amount of the words prevention that were used

00:44:57.680 was, I couldn't believe it. Prevention this, prevention that. Now, now, you know, there's a

00:45:02.500 big, big, big debate on, you know, Alzheimer's prevention or Alzheimer's risk reduction, which is

00:45:06.720 the most accurate term. We just got our foundational methods paper accepted and the paper as we titled

00:45:12.300 it was the clinical practice of Alzheimer's prevention, a precision medicine approach, went through

00:45:17.040 the review process. Now this is the journal Alzheimer's and dementia, the journal of the Alzheimer's

00:45:21.120 Association. It's the number one journal of all Alzheimer's journals. It's the number four

00:45:25.600 ranked clinical journal in neurology. Okay, great. It's impact factor 12.75, whatever it

00:45:31.700 is. This is the first time they've ever published anything from us. So that's good news. But one

00:45:37.280 of the six reviewers said, no, you can't use prevention in the title. You have to change it

00:45:41.240 to risk reduction. That then led us to write another paper, which I hopefully will be submitting

00:45:45.440 soon called Alzheimer's prevention versus Alzheimer's risk reduction, transcending semantics

00:45:50.520 for clinical practice, because there's a big difference in my mind about prevention versus

00:45:54.900 risk reduction. There's also implications because when you say prevention, the patient sitting

00:45:59.340 in front of you gets that. When you say risk reduction, what kind of message is that to

00:46:03.220 the public? It's confusing. So there's this whole semantic argument. We went through this

00:46:07.060 with our paper.

00:46:07.740 I had a different experience several years ago that has given me a window into understanding

00:46:12.860 where this resistance comes from. So it was probably four years ago and I was asked to give

00:46:18.640 a grand rounds and discuss breast cancer, but specifically to discuss the use of metformin

00:46:24.920 in the risk reduction of breast cancer. And so I gave this long talk about, you know, all

00:46:30.160 of these topics. And one of the implications of my talk was that if metformin could be effective

00:46:36.880 in reducing the risk of breast cancer, the question then became, could dietary choices also impact

00:46:44.700 breast cancer. And so one of the questions was posed, if a woman has breast cancer, is she

00:46:49.780 better off eating ice cream or not eating ice cream? And I said, look, all things equal. My

00:46:53.820 intuition is she's better off not eating ice cream, given that most breast cancers are quite

00:46:58.040 insulin sensitive. They're very sensitive to IGF and a number of other growth factors. This

00:47:02.820 one person in the room who is very senior, quite an opinionated individual who I'm not overly

00:47:07.520 fond of, basically leapt up and down and said, you know, this is complete bullshit. The moment

00:47:12.360 you start suggesting, and I had to ask like 12 questions to get at the layer of the hostility,

00:47:18.140 but it became very clear to me what the hostility stemmed from, which was an understandable

00:47:20.940 opposition. It was, if you start talking about breast cancer prevention, if you start suggesting

00:47:27.720 that a person with breast cancer can change the way they eat to reduce their risk of death from this

00:47:33.180 disease, you are implying that the patient brought this disease on themselves. Now, again, I think that's

00:47:37.980 an error. I think there's a logical fallacy there, but I believe that that logic exists in Alzheimer's

00:47:43.120 disease as well. I think that when we talk about Alzheimer's prevention, somehow it is being turned

00:47:49.940 into, well, then you're saying patients are bringing this on themselves. It's their fault. There could be

00:47:53.860 something done to prevent this. Therefore, you know, and we don't like that message. So that's what my

00:47:58.500 intuition tells me is this opposition. And unfortunately, I think that type of third grade JV poor

00:48:06.200 understanding of logic and risk is basically slowing down progress in this space immensely as evidenced

00:48:12.760 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

00:48:16.100 true today. Things are much better now. Things are totally different. But there was a day when you

00:48:19.000 could not get a grant to study Alzheimer's prevention. If you had the word prevention in

00:48:23.180 the grant title. Zero. We have three NIH grants now. Actually, I just got a, like a fourth little part.

00:48:28.480 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

00:48:34.980 program project. One RO1. We're looking at the program project looks at women between the ages

00:48:40.180 of 40 to 65. Oh, wow. Very early onset. And perimenopausal transitions. Yeah. Well, not.

00:48:46.100 Actually, it's funny. You say 40 is early. I say we need to start at 30. But no, 40 to 65,

00:48:50.500 I think is a good sweet spot. And we're looking at women between the ages of 40 to 65. That's the

00:48:54.720 program project. Then we just got Lisa Moscone is the PI on the men's brain imaging. So we're looking at

00:49:00.500 menopause transition as the window of opportunity. Like when do we need to intervene and how?

00:49:06.300 And then the RO1 we got was the men's brain imaging study, which is basically the male menopause

00:49:12.000 transition, which is andropause. So we're looking at, it's a small, small number, only 15 men a year

00:49:16.820 for four years, but it's better than nothing. Between 40 and 65. We then just got an administrative

00:49:21.660 supplement to now image women, not just at baseline, but also at 18 months. So we just got that today,

00:49:27.940 actually. And then, I mean, that's pretty, pretty good.

00:49:31.120 Yeah, no, that's a huge improvement. And so much of what you just said now makes me want to take a

00:49:35.620 step forward. So let's start with the following. How do you define in your clinic, what a high risk

00:49:42.200 patient means? What is the definition of a high risk patient?

00:49:45.000 Anyone with a brain is at risk for Alzheimer's disease.

00:49:47.540 Well, let's take a step further back than that. What is the prevalence of Alzheimer's disease in the

00:49:51.840 United States today?

00:49:52.540 No one knows. You'll see 5.1 million Americans, 5.3 million Americans, 5.7 million Americans.

00:49:59.140 This is all estimations based on like one county in Illinois from like years ago. And then it's

00:50:04.480 been extrapolated and posted all over.

00:50:06.200 So why don't we have those data the way we do for cancer, for example?

00:50:09.500 Alzheimer's is confusing. I mean, there's Alzheimer's dementia and probably around four or

00:50:13.900 five million people have it. But the best numbers were recently published. The most updated was that

00:50:19.280 47 million Americans have preclinical Alzheimer's disease, meaning Alzheimer's in the brain, but no

00:50:25.820 symptoms.

00:50:26.380 Sorry. Meaning based on something you would see on an imaging study or a lumbar puncture or

00:50:33.680 because those would be basically the only two ways you could see something in the brain today.

00:50:37.780 47 million people would have that finding. That also must be an estimate, but do not yet have

00:50:43.800 cognitive impairment.

00:50:44.740 Yep. So five ish million people have dementia due to Alzheimer's. 47 million Americans have

00:50:51.620 Alzheimer's in their brain, but no symptoms yet. There's people before that with no Alzheimer's in

00:50:57.040 their brain and no symptoms. And we don't know if they're going to get it yet. And then there's a

00:51:00.240 kind of gray area in between called mild cognitive impairment due to Alzheimer's disease. And we don't

00:51:05.620 exactly have the best numbers on that, but it's somewhere between the transition phase between

00:51:10.040 preclinical, pre-symptomatic Alzheimer's and dementia due to Alzheimer's. It's stage one,

00:51:14.160 stage two, and stage three.

00:51:15.380 When I talk to my patients about death, which if you're trying to practice longevity, you have to

00:51:22.700 be able to talk about death. I share with them the obvious, which is once you reach about the age of

00:51:28.460 40, assuming you're not a smoker, your probability of dying from cerebrovascular disease, cardiovascular

00:51:33.520 disease, cancer, or Alzheimer's disease is north of 75%. And almost without exception, within that

00:51:40.640 constellation of disease is the one that people fear most is Alzheimer's disease. But a very few

00:51:47.080 patients actually understand what it means to die from Alzheimer's disease. And this becomes a bit

00:51:51.820 challenging when one starts to look at death certificates. And maybe this is part of the problem in

00:51:56.540 coming up with an accurate estimate of that. How do people actually die when they have Alzheimer's

00:52:03.500 dementia? Yeah. So Alzheimer's disease is a indirect cause of death. You know, for example, when someone

00:52:10.660 gets a urinary tract infection, that urinary tract infection may be treated by antibiotics because

00:52:16.260 the patient will say, Oh, it hurts. I'm going more frequently, test my urine and give me an antibiotic.

00:52:22.220 But when someone has Alzheimer's dementia, they're not able to convey this.

00:52:25.940 And that UTI becomes pyelonephritis, which becomes sepsis, which can kill them very quickly.

00:52:31.740 Exactly. So some people will put Alzheimer's on their death certificate and other people say

00:52:37.060 urosepsis. Yeah. So there's never going to be great numbers. Alzheimer's is the impetus to death

00:52:44.400 in most patients for sure. They can't report their pain close, uh, call him a friend, but he's a patient

00:52:49.960 in the clinic. Also good guy. I've seen his mom and his mom was just diagnosed with cancer.

00:52:56.460 And, um, she was complaining of abdominal pain, something nonspecific. She saw a doctor,

00:53:01.500 doctor said, Oh, you know, it's got dementia. It's got some belly pain. You probably constipated

00:53:06.000 here. Take some constipation meds. Didn't get better. Didn't get better. Didn't get better.

00:53:10.560 Turns out she may have pancreatic cancer and she had a gallbladder or something. And now she had to

00:53:14.660 put a stent in, right? Only when she turned yellow, did they figure out what the cancer was. So

00:53:18.600 Alzheimer's disease, dementia causes a person not be able to express themselves and not be able to care for

00:53:25.560 themselves in certain ways. And the caregiving has to happen for them. And so you see a lot of

00:53:30.100 these aspiration pneumonias. You see, you know, my closest friend, uh, one of my closest friends,

00:53:34.780 my roommate in medical school, I just went back to his father's funeral two weeks ago. His father

00:53:39.600 just passed away. He had Alzheimer's disease, but it was very sudden onset. And within the course of

00:53:44.660 eight months, his health deteriorated so quickly. And ultimately he died from cellulitis, obviously,

00:53:51.160 but you can see that this is someone who probably at the very end was at risk for these things because

00:53:57.480 of all these other changes. So, and I've also seen people die from just failure to thrive. They

00:54:03.480 have Alzheimer's disease and they just can't eat it. They don't want to eat. They completely lose

00:54:06.640 their appetite. They become anorexic and they be sort of almost drift into a vegetative state where

00:54:12.080 unless you would force feed them, they will die relatively quickly. But this also strikes me as part

00:54:17.000 of the challenge of trying to get a handle on a disease that has such a ubiquitous face at the

00:54:24.800 end. You know, Alzheimer's disease is a life course disease. At every moment, someone is either

00:54:30.080 potentially having silent pathology building up. Alzheimer's is a life course disease. And at each

00:54:36.700 phase of life, Alzheimer's is a confusing, difficult disease to manage. You know, end of life, it's more

00:54:42.600 obvious, but towards even the beginning of life, you know, people that are born with the

00:54:46.200 APOE4 gene, for example, it's the most commonly researched gene, um, start off with a smaller

00:54:52.320 brain. So you think of Alzheimer's disease the way I think of cardiovascular disease, which is this

00:54:56.360 disease begins at birth. Everybody's on a different plane based on a number of hereditary or acquired

00:55:02.440 risk factors. Your path is not set on that slide. You get to determine it, but your track might be a bit

00:55:09.880 set. Yeah. You know, you asked me before, uh, what's your high risk patient? What does that look like?

00:55:13.600 And I said, I didn't mean to be glib. I meant, I just was honest. If someone has a brain,

00:55:18.300 they're at risk for Alzheimer's. Okay. Well, everyone has a brain. So go deeper.

00:55:22.340 Not, not everyone. Technically I have some counterfactual, not talking politics, not going

00:55:26.600 there. Uh, I wasn't even going to go there. Excellent. So moving right along at every point

00:55:33.620 in the life course, a person's risk may change. So early life, midlife and late life, there's different

00:55:39.760 risk factors for Alzheimer's. And, you know, I agree with you that some people can do everything

00:55:45.460 right and still get Alzheimer's. However, based on population attributable risk models being

00:55:52.780 conservative, one out of every three cases of Alzheimer's disease may be preventable if that

00:55:58.360 person does everything right. Now the other two out of three cases, well, Hmm, it may not be

00:56:03.460 preventable. Maybe we can delay it. Could we delay it by two years, three years, five years,

00:56:08.180 six years. I have some hot off the press data. I sent you right before I arrived to send you some

00:56:13.100 new results. So we're trying to hone in on the, can we delay it and for how long, but honestly,

00:56:18.460 other people will do everything right and absolutely still get Alzheimer's disease. And,

00:56:22.880 and I think I understand why now, because there's a tug of war going on a hundred percent of the time.

00:56:29.100 And it's a tug of war between you and your genes, environment and genes. And when it comes to

00:56:34.180 Alzheimer's, the mnemonic I use is age, A-G-E-A stands for age because age is the number one

00:56:40.460 risk factor for Alzheimer's. G is genetics and E is environment. So epigenetics, your interaction

00:56:46.280 between the environment and your genome is going to put you on the path or try to knock you off of

00:56:51.680 the path towards Alzheimer's. And some people can do everything right, but because of their APOE4 gene

00:56:57.020 plus another gene, or because of their X gene, or because of their whatever, they're going to get

00:57:01.900 Alzheimer's disease. Other people can modify their environment, modify the impact of that gene

00:57:09.760 on their outcomes. And I believe that it's very reasonable to expect that one out of three cases

00:57:17.280 of Alzheimer's can be prevented because if you can delay Alzheimer's by two, five or seven or 10 years

00:57:22.200 by doing everything right in that subset, they're going to probably die from something else.

00:57:26.380 Yeah. And the other thing that I always talk about in the prevention space, I mean, we,

00:57:29.200 as you know, I take such a hard liner on cardiovascular disease because it is the leading

00:57:33.440 cause of death. And I believe of the major pillars, atherosclerotic disease, cancer,

00:57:38.940 and neurodegenerative disease, it's the most preventable. We understand the pathology of that

00:57:43.160 disease so much better than the other two. And we have more tools that seem to have efficacy

00:57:48.020 at preventing that if nothing else, I say it's, it's optionality. Time is optionality.

00:57:53.520 And so similarly, if you take somebody who, for whom maybe it is a fait accompli that they are

00:57:58.960 going to get Alzheimer's disease, but you say, you know what, instead of getting it at 69,

00:58:03.820 we can make it 78. Well, a lot can happen in nine years. It's not just that you could die of something

00:58:09.200 else, which is maybe better, maybe not, depending on what that something else is. But more importantly,

00:58:14.880 maybe you and your peers have nine extra years to come up with something else.

00:58:20.860 Let's talk about ApoE because everybody, you know, I was actually doing an Ask Me Anything

00:58:25.560 yesterday. Well, this is the AMAs. And, um, there was a great question about ApoE4 and I just punted

00:58:31.740 it because I knew you and I were talking today. So I was like, ah, I love the speed round when I can

00:58:36.180 say next. ApoE is a gene. It exists mostly in three types, though I told there were actually a couple

00:58:44.480 of others, but for the large part, there's an ApoE2, an ApoE3, and an ApoE4.

00:58:49.700 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

00:58:55.500 or a 4-4. There's six combinations. The approximate prevalence, the 3-3s represent probably what,

00:59:02.000 about 55, 60%? Yep. You got it. Neutral risk. So we call that unity risk, right? Those are the

00:59:07.200 single risk. The 2-2s are very rare. I've actually never seen a 2-2. I've seen one. Okay. They're

00:59:13.140 reported at less than 1% of the population. Maybe two. I think I've seen two. And they come with a risk

00:59:18.320 reduction, I believe, of about 20%. At the far end of the spectrum, you have the 4-4. Now that used

00:59:25.440 to be reported as 1% of the population, but I see that so often that I think that's closer to 3% or

00:59:29.760 4% of the population. You know, in our 600-person cohort, we have 37. But you're selecting for high

00:59:37.060 risk. Yeah. I don't select for high risk, but I still feel like it's about 4%. Yeah. Yeah. In our

00:59:41.980 cohort, it's like six. Now this is interesting. The very first time I started paying attention to ApoE

00:59:46.460 gene, which was about 2011, 2012, the literature said the 4-4 patients relative to the 3-3 patients

00:59:53.620 have a 25-fold increase. Today, we see that number, I think, continually being downward revised. So for

01:00:00.420 my 4-4 patients, the good news that I have three patients in my practice who are 4-4. The good news

01:00:06.460 for those patients is, look, these numbers are getting better and better. I mean, you and I, I think,

01:00:10.680 offline would agree unofficially it might be closer to 4-6x. I don't even think you can know.

01:00:15.580 Are you even more optimistic?

01:00:16.740 Well, I'm just going to be frank. Alzheimer's and ApoE is confusing. And having two copies

01:00:22.740 of E4 does absolutely not mean you're going to get the disease. And it's a polygenic risk when

01:00:28.040 it comes to the disease. You know, you can have two copies of E4, but never have a family member and

01:00:33.520 never get the disease. I don't believe it's medically correct. You know, it's hard to, you know,

01:00:40.720 split hairs or whatever. I don't even think you can say it's 2% or 5% or 20% or whatever percent

01:00:46.400 higher or how many fold, whatever, because you can't know until you know what the other person's

01:00:52.380 genes are.

01:00:53.000 Yeah, it's very hard to do. And I think the best that people are doing in these large population-based

01:00:58.140 studies is saying, acknowledging the heterogeneity of those other risk factors, all things equal.

01:01:04.520 The last, you know, paper I read basically said 8 to 10x. So again, maybe that's still an

01:01:09.920 overestimate. I believe it is an overestimate. And I think it's certainly an overestimate with all of

01:01:13.640 the interventions we're going to talk about. But the point here is that's a heck of a lot better

01:01:17.980 than a 20 to 25 fold risk. Then you have the three fours. Now they represent quite a bit of people.

01:01:23.680 That's like 20 to 25% of the population.

01:01:25.540 It's all 25. Yeah. In our cohort, it's about 40.

01:01:27.680 Okay. Which again, makes sense. You're over-representing.

01:01:29.760 Again, they used to be represented as about a three to four X. I mean, I think today we're

01:01:35.020 saying maybe a two X again, not withstanding your cat. Yeah. So polygenic risk that, you know,

01:01:39.700 we'll talk about precision medicine and kind of why, what the future of Alzheimer's disease is.

01:01:44.680 And I actually think the future of Alzheimer's disease prevention is now, I don't even think

01:01:48.200 it's the future anymore. I think the future is artificial intelligence, but we can talk about

01:01:51.760 that some other time. The person that walks in with an E3, E4, I am actually

01:01:58.380 more optimistic when they come in and less freaked out about the four because at least I know what

01:02:05.740 I'm up against. Okay. If that person- Because you have so many three fours in your cohort now.

01:02:10.080 Easy. Easy. I know lifestyle interventions work. I am confident that when I do X, Y, Z,

01:02:17.780 A, B, C, the 27 things that I'll tell them to do based on precision medicine, based on their

01:02:22.400 metabolic risk factors, their cholesterol, their individual risks, I can predict that they will

01:02:30.320 have a response of this. And this is satisfying to me. The problem is, is when someone comes in

01:02:36.660 with a three, three, I'm like, Oh, meaning for a three, three to show up in your clinic, by definition,

01:02:41.200 there's a reason either their family member had premature Alzheimer's disease and, or they're

01:02:46.680 potentially even showing early signs of cognitive impairment that are subtle or no? No, I mean,

01:02:51.860 you know, we were a prevention clinic. So to get into our clinic, you have to have normal

01:02:56.000 cognitive function with a family history of Alzheimer's. So, so we focus on the normals.

01:03:00.940 Now a three, three could mean you did not get the four for mom or dad and life is beautiful. Maybe the

01:03:07.120 risk is lower, but if you have a three, three and mom and dad were a three, three and they didn't have

01:03:12.420 the four, guess what? They probably have another gene and I don't know what that gene is. And I

01:03:17.480 don't know what I'm up against. Do you test the parents in that situation? Well, it's tricky. I

01:03:21.280 know a lot of, uh, I would say when I first started the program, most of our prevention patients, so I

01:03:25.820 would say 60% of our prevention patients came from the patient with dementia I was treating. I then saw

01:03:31.920 their kids and their cousins and whatever else. So, and you know, there's families I see with five,

01:03:36.580 six, seven members, and that's like the best to see. Cause you can really understand the

01:03:41.040 genotype and phenotypes and see the pattern. I do the same thing with LP little a actually

01:03:45.220 in the cardiovascular front, which is very helpful, right? It's to be able to say,

01:03:48.880 let's track where this disease is coming from and see how much of it we can attribute to the

01:03:53.560 genetic influence. So, so if a patient comes in and they're three, three and mom got Alzheimer's

01:03:59.420 disease at 57 and you know that mom is three, four, you feel a heck of a lot better than if mom is

01:04:04.820 three, three. Totally. Absolutely. And, and you know, um, we're trying to simplify things and

01:04:09.280 there's, there's polygenic risk. There's dozens of Alzheimer's genes. And the goal is, is to now

01:04:16.160 it's hard because we don't have a neurogeneticist. And as mentioned Holly before and as practitioner

01:04:19.620 and myself, we don't have the team it would take to spend hours and hours and hours and days to

01:04:25.500 decode someone's genome. But in the future, hopefully we'll be able to do this in an automated

01:04:30.180 way. But the goal is, is to understand, okay, if they have a four, we're going to do a, b, and c.

01:04:35.000 If they don't have a four, we're going to do x, y, and z.

01:04:36.860 And I want to come to the study that allowed you to talk about that. Before we go there,

01:04:42.180 we'll round this out. You have two threes and two fours. Two fours are pretty rare about neutral risk.

01:04:48.840 My cousin's a two four. I've seen two cases, but it's pretty rare. Do we think that the two fours

01:04:53.600 are at increased risk, decreased risk because of the two increased risk because of the four?

01:04:57.300 All things equal, um, similar ish to three, three, but a little worse.

01:05:01.780 Yeah. That's sort of my thinking. And then the two threes get a benefit, not as much as the two twos.

01:05:06.160 Looks like it's about 11, 10 to 15%. Yeah. I like two threes, two threes. I can really

01:05:11.320 sink my teeth into and, but you must not see many of these people. No, no. I see two threes all the

01:05:15.680 time. Why? They still have risk. They're still coming to you because of family history. Oh yeah,

01:05:19.780 but it's a different gene. There's a different gene in that lurking in there, but we don't know

01:05:23.400 what it is yet. Yeah. But their polygenic risk is lower because they don't have a four to amplify

01:05:27.560 the gene. I have a whole family where they came in and they said, Oh no, we have early onset Alzheimer's in

01:05:31.640 the family. And I said, no, you don't. It doesn't sound like it. And we did all the stuff and mom

01:05:36.980 had E4, four uncle had E4, four. Well, that's pretty weird, but okay. Grandparents for I'm sure

01:05:43.700 they had four, four. There must've been a lot of fours going on. And then when we look at the kids,

01:05:47.800 they have a three, four. Well, we do the three, four, but wait, why did they get early disease?

01:05:53.360 What's going on? And we found another gene, a TNF alpha gene. So when you take TNF alpha and you add to

01:05:58.360 a four, well, you're going to have a six fold risk. That's polygenic risk. That's why they

01:06:02.940 had early onset disease. And tell me what the TNF alpha gene does. What's the phenotype when they

01:06:06.460 have this? Well, you have an inflammatory cascade. It's a pro-inflammatory. Sure. So that's like

01:06:11.200 fast forwarding to Alzheimer's. Now, when you have a four, four and a TNF alpha, that's when you start

01:06:17.040 getting symptoms in your late forties or fifties. It's not early onset Alzheimer's disease. What's the

01:06:20.680 gene that is almost a guarantee? Presenilin one, presenilin two, an amyloid precursor protein gene

01:06:26.160 mutation. These are three genes that cause true early onset Alzheimer's, meaning you have the gene

01:06:31.620 and you get the disease in your forties or fifties. Yeah. Meaning this is one of the only

01:06:35.280 deterministic genes for AD. Correct. It's exceedingly rare, less than 1%. As an example, I have a 27 year

01:06:41.740 old woman, great gal. She has a presenilin one gene. How old was she when her mom or dad was diagnosed?

01:06:48.540 Well, her mom's in her early fifties and acting weird now and kind of in denial. Her family members

01:06:54.100 range from fifties to early sixties at the time that they were diagnosed. Yep. But then you take

01:06:58.400 a deep dive into presenilin one and she actually has a good one from Belgium where they actually

01:07:02.200 have later early onset, meaning like sixties, six zero. And she's the first person I'd ever seen

01:07:08.100 in the prevention clinic who had an early onset gene. And I could not say that she was going to

01:07:13.540 get Alzheimer's. I said, no, I don't know that you will. I think we can do something. We have so much

01:07:18.140 time in the next 20 years for you. I'm not even like worry. Sure. We'll take care of this. So

01:07:24.640 even, and this is super controversial, but I don't even think one person can say even having an

01:07:29.740 Alzheimer's gene where you're going to get the disease means you're going to get the disease

01:07:33.240 because the field is changing. Is the field of genetics considering that a deterministic gene?

01:07:38.800 Yes, they do. There's only about 75 to a hundred genes. So there's 20, just for the listener,

01:07:43.540 there's about 23,000 genes in the human genome directionally only 100 are deterministic

01:07:49.000 polygenic single gene leads to problems. So you have the mutation for cystic fibrosis. You are

01:07:55.600 getting cystic fibrosis. You have the gene for this glycogen storage disease. You are getting it

01:08:00.040 virtually every disease that we think of commonly, of course, does not have a deterministic genome.

01:08:06.460 Certain cancers do, but very few, virtually all cancers of course are somatic mutations and not

01:08:12.280 acquired germline mutations. That's a ballsy thing to say, right? You're saying, look,

01:08:16.900 1% of Alzheimer's comes from a deterministic gene. I'm not even convinced that's deterministic.

01:08:21.340 It's might be an artifact of our GWAS. Well, no, no, no, no. It's meaning our GWAS has basically

01:08:26.840 never tried an intervention. Correct. Since it's a late, well, it's, it's early means forties and fifties,

01:08:32.480 but since we have now 30 and 40 years to figure it out, especially in her case, who's 27.

01:08:37.900 And if she doesn't get symptoms for 25 years, I'm loading her up with curcumin. I mean, I got X,

01:08:43.580 Y, and Z. We're going to be putting her in whatever amyloid drug that comes out in the next

01:08:47.760 five to seven years. I mean, I cannot say that she's going to get it. So deterministic genes from

01:08:53.000 birth, well, that's a different story. Cystic fibrosis, terrible disease. You get it and you have

01:08:58.460 it. Early onset Alzheimer's genes, it's a pretty, you know. No, that's my point. Yeah. I think that when I

01:09:04.100 say artifact of GWAS, I mean the GWAS is only, so genome-wide association studies, which for the

01:09:10.000 listener is how we link genes to diseases. It's basically epidemiology of genes. If you study

01:09:16.020 something where a potential treatment for a disease that could have played a role was never introduced,

01:09:21.380 you can actually be misled. Yeah. I see. Yeah. So the other thing I tell my patients,

01:09:26.740 and so correct me if I have this right or wrong, is that about two thirds of patients in the US who

01:09:34.040 present with Alzheimer's disease have at least one copy of E4 and about one third of patients do not

01:09:39.880 have a copy of E4. Is that directionally about right? That's probably pretty close. I've always

01:09:45.020 said 60-40. So I guess that's right around the same. I'm going to trust you more than I trust me.

01:09:48.740 But I don't know what's latest. It depends on populations. And so the point you want to make

01:09:52.400 is, look, about a quarter of the population has an E4 gene, one or two copies, and that quarter of

01:09:59.840 the population makes up two thirds to 60% of the disease. So for my patients who have E4, I say,

01:10:06.320 the good news is this doesn't mean that your E4 means you're going to get the disease. To my E3 and

01:10:11.960 E2 patients who are busy high-fiving at this point, I say, by the way, the bad news is not having E4

01:10:18.580 doesn't mean you are not susceptible to this disease. So you still need to pay attention.

01:10:22.800 I think that individual risk needs to be calculated individually. I said before, oh,

01:10:29.060 3-3, I'm worried. Well, you know, I don't want people who are listening to say, oh, wait,

01:10:32.540 I thought 3-3 was good. Yes, for the grand, vast majority of people, 3-3 is good. But I need to know

01:10:38.500 what your other genes are. And I take a stupid amount of time doing this through looking at their

01:10:44.340 SNPs. And this is a, you know, research clinical, complicated, takes eight hours of Holly's time,

01:10:50.420 four hours of my time, and then a whole lot of like cerebral, whatever.

01:10:53.740 Are you guys looking at TOM40?

01:10:55.600 TOM40 has, we don't have a commercial test that we can test for it. There is a way to do it if we

01:11:00.740 send it somewhere, but we really never went there.

01:11:02.840 We pull it out of Prometheus. Do you guys do that?

01:11:05.060 I may be getting this wrong, but I don't think all...

01:11:07.160 It depends on where the genetic test was done.

01:11:08.880 And you won't be able to do this out of 23 and me anymore, unfortunately.

01:11:13.040 What, through Prometheus?

01:11:14.340 Yeah, you can no longer take 23 and me data into Prometheus and get this degree of fidelity

01:11:18.600 anymore, which thanks FDA if you're listening.

01:11:21.720 Wait, so my understanding was that the 23 and me no longer has an API or like a way to transmit

01:11:28.580 the data, but you can still download the data from 23 and me and then re-upload it to Prometheus

01:11:34.140 and still get the same report.

01:11:35.420 Okay, if that's true, that makes me feel better. We'll confirm that. I hope that's the case.

01:11:39.180 Yeah, we've only done this once. For citizen scientists out there,

01:11:42.540 all right, talk to your doctor and don't do this at home. But one back of the napkin way

01:11:46.320 to Google your genome is to do 23 and me, download the data file, upload it to a service like

01:11:51.720 Prometheus, and then basically filter, filter, and filter.

01:11:55.160 Yeah, I mean, we've been working with you and we've come up with basically the SNPs for

01:11:59.420 everything that we see in the literature that is a high risk. And then we run like kind of

01:12:04.340 an AD panel. You know, it's interesting. We only do this for patients who are E4. I guess

01:12:08.920 we should be doing this for every patient. Family history of AD, yeah.

01:12:11.520 Yeah, yeah, exactly. That's a good point. But it's interesting. You know, it speaks to

01:12:14.840 another controversy that we won't get into, which is like information. You know, I mean,

01:12:19.020 I've been scolded by physicians for measuring APOE4 and telling a patient that they have an APOE4.

01:12:27.080 I won't go into that. So what is it about APOE4 that's so special? Why is it getting all

01:12:31.480 this attention? I mean, aside from the epidemiology, which we've just discussed,

01:12:34.640 what is it doing or not doing that is increasing risk?

01:12:39.420 So APOE plus age, higher likelihood of amyloid. Then you add in gender, women plus APOE plus 65 and

01:12:47.460 over, much higher likelihood of amyloid. So again, it's a poly, not just a polygenic, but a poly risk,

01:12:54.000 whatever. It amplifies or increases the likelihood of amyloid deposition.

01:12:58.040 So you just brought up something interesting, which was the question of females. I've always found it hard

01:13:03.640 to believe that the increased risk women see is explained only by their age, meaning their survival

01:13:09.500 advantage over men. Do you, I mean, I think I know what my answer is, but I'm, I don't know what's

01:13:14.840 the term. I want to lead the witness. What is your view for why you think women are at a higher risk

01:13:19.360 than men, all things equal?

01:13:20.640 Well, you know, you can take different roads to Alzheimer's disease. Diabetes will put you in the

01:13:25.180 fast lane and this and that. Women are definitely in the express lane. And why are they in the express

01:13:29.900 lane? I think it has something to do with, and sure, there's, you know, something about life

01:13:33.540 of course. And, you know, having lots of children versus less children that can impact the two. And

01:13:37.840 there's a whole variety of things, you know, more stress, you know, whatever du jour study you want

01:13:43.000 to read to attribute this. But my feeling is the perimenopause transition has bioenergetic

01:13:50.000 impacts on the brain. And, you know, I believe that Alzheimer's disease is a mitochondrial-based

01:13:57.000 disease, but the mitochondria, the battery of the cell, the mitochondria can cause all sorts of

01:14:02.080 bad diseases from Parkinson's to ALS to whatever. Huntington's, I possibly actually, that that's

01:14:07.760 something separate. So long story short, people think of Alzheimer's as amyloid and tau. I think

01:14:13.700 amyloid is the garbage that accumulates. And if you don't take the garbage out, you're going to get

01:14:18.040 sick. But the upstream effect is mitochondrial dysfunction. And there's something about the

01:14:22.460 mitochondrial bioenergetic pathways. I'll just talk in generalities because I'm not an expert at this.

01:14:28.220 But I think there's something about the perimenopause transition, the bioenergetic

01:14:32.440 shifts in the brain that are fast forwarding a woman to Alzheimer's disease. So I think it's

01:14:39.380 hormonal. How do we intervene? Meaning you believe that it's the withdrawal of sex hormones that is

01:14:47.000 accelerating the process of either mitochondrial decline or something that is leading to the

01:14:55.220 accumulation of waste product being manifested as amyloid and tau? Yeah, it's brain aging accelerator

01:15:00.780 due to the menopause transition. And that's why I think that the, where we're going with our research

01:15:06.400 and we have a whole sub research program to look at this is what is the critical window of opportunity

01:15:11.880 to intervene? Now, how do we intervene? And when are the key questions? You intervene before menopause,

01:15:17.300 perimenopause, when do you intervene? What do you do? What progesterone, estrogen,

01:15:21.700 should you use a pill or a cream or a patch? Do you use it for two years, five years, seven years?

01:15:26.640 Do you have to balance the decision based on breast cancer and other things,

01:15:30.140 blood clots and smoking? So I go by my gut in almost all things medical and can say that my

01:15:36.780 understanding of this is kind of like if I had to use a television analogy, maybe we're at the

01:15:40.220 black and white television, but at least we can see a picture. We're not at color and we're not at

01:15:44.440 high def. But I think that my understanding is evolving. And I think it has to do with brain

01:15:49.400 bioenergetic pathways and an individual woman's risk versus a man.

01:15:53.740 Now, that's interesting because you also brought up Alzheimer's disease has been referred to as type

01:15:58.360 three diabetes or brain diabetes, which of course is also an energetics pathway. So that would suggest

01:16:04.680 that there seem to be at least two, maybe three or more completely distinct, which is not to say

01:16:11.940 there's no overlap between these, but paths towards the disease. Because the other one we didn't even

01:16:15.900 talk about was a vascular path. Two or three, I think there's like 12 or 16.

01:16:19.840 Yeah. I mean, I talk because I'm sort of a simpleton on this topic. I generally refer to it as three or

01:16:24.220 four different paths to the same place where you have the same final common pathway. Everybody's

01:16:29.000 accumulating amyloid, beta and tau, but you can get there through microvascular disease, which then

01:16:35.800 becomes basically a disease of hypoxia. You can get there through diabetes, which then becomes an

01:16:41.940 energetic problem. You can get there as you described through a separate sort of mitochondrial

01:16:46.700 dysfunction. I mean, you can think of a dozen things that could lead to mitochondrial dysfunction

01:16:51.160 among them. The one you described, which to me strikes me as the Occam's razor explanation for why

01:16:56.960 women would disproportionately have this difference from men.

01:17:00.320 There's this great paper about this by Schelke and Atiyah. I've read it. It's great.

01:17:05.900 You know, there was an interesting paper, Richard, about three years ago. It was a very small paper.

01:17:12.340 I don't even remember how many women were in it, but I remember it was surprisingly small.

01:17:16.860 And it was, if I recall, also heterogeneous in ApoE type. And it asked the question, if you took

01:17:23.540 these women who were either perimenopausal or early menopausal and you treated them with HRT,

01:17:29.160 did you improve cognitive performance? If I believe the result of that study was you did only in the

01:17:34.920 women that had an E4 gene, but not in the women that did not, to which my interpretation was maybe you

01:17:40.840 were just underpowered to detect a difference in the non-E4s, but because the E4s come with another

01:17:45.860 risk, you didn't need that many women to see the benefit. So is it your practice today in the

01:17:51.220 clinic to use hormone replacement therapy in perimenopausal women?

01:17:54.560 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

01:17:58.280 very specific scope of practice. I've never prescribed statins. I've never, I don't treat cholesterol

01:18:03.240 per se, although actually thanks to you and others, I've learned a lot about plant sterols versus

01:18:08.100 Zetia. And, you know, I'll make tacit suggestions and I'll use omega-3s and that kind of thing with

01:18:13.200 cholesterol. Same thing with hormones. I would never prescribe.

01:18:15.720 Do you have physicians that you, that are willing to work alongside you in these areas?

01:18:20.980 I mean, I have preventative cardiologists that we see eye to eye. I have primary care doctors that

01:18:25.620 I can see eye to eye with. I have one reproductive endocrinologist in Texas who we see eye to eye and

01:18:31.680 we speak the same language. I don't really have an endocrinologist or a hormone doctor that I can

01:18:36.520 refer patients to where we can have cogent conversations because I think the area is just

01:18:42.200 so hazy. The level of evidence is so hazy. And I'll just tell you my, you said APOE4 may have

01:18:47.340 something to do with, I also think metabolic status has something to do with this. Roberta Brinton

01:18:51.280 has looked at, you know, women with vascular risk, so high cholesterol, diabetes, you know,

01:18:56.260 high blood sugar, whatever, that maybe those patients are the one that respond preferentially to

01:19:00.760 hormone replacement therapy. But there's a lot of precision medicine in here that is very hazy.

01:19:06.540 That being said, my kind of off the shelf answer would be women early on in the perimenopause

01:19:12.640 transition for the first two, five, maybe seven years, hormone replacement may be a good idea.

01:19:18.100 I just, it probably is a good idea, but I just don't know if you need to take a pill, which pill,

01:19:23.400 what ratio of what to what, and is a cream probably better. I may gear towards the latter,

01:19:29.320 but I actually just don't know. There's a study without pregnant alone, which I think is going

01:19:32.840 to be very interesting. So I just, I have strong feelings about this. So we're going to go have

01:19:38.580 dinner after this. We're going to talk for probably two hours just about this topic. This is a huge

01:19:45.020 passion of mine and I know what's happening right now. Someone's listening to this and they're going,

01:19:49.100 wait, just tell us the answer. And no, I don't want to get into, I don't want to jump on my soapbox

01:19:53.420 about this because I want to come back to talking about this. So you alluded to one of the most

01:19:58.360 interesting things in your clinic. Now, I don't know, are we, is the manuscript submitted so that

01:20:02.420 I'm talking about the matrix of MTHFR by ApoE biomarker versus cognitive thing that is that

01:20:08.980 submitted yet published? We literally have, so just give you a brief snapshot. So we started the

01:20:13.760 Alzheimer's prevention clinic in 2013, took about a year and a half, just under two years to get the

01:20:18.640 IRB approvals and get all of their ducks in a row with getting the cognitive assessments and the IRB

01:20:22.940 approved and whatever. So since March of 2015, the last three and a half years and change, we've been

01:20:29.480 recruiting patients into a registry where we basically follow patients across primary prevention,

01:20:34.640 secondary prevention, and tertiary prevention of Alzheimer's disease dimension. I can define those

01:20:38.900 in a minute. So when we have this data, we are deep, deep, deep in the data analysis phase. And we

01:20:46.500 literally have, no joke, over a thousand pages of results, data tables, graphs, and I've only scratched

01:20:54.780 the surface. So let's explain the intervention. Taking a step back, you're saying, look, we're

01:20:59.020 going to stratify patients by four things. One, genetics. And the genes you looked at were ApoE and

01:21:05.100 MTHFR. Can you say a little bit about MTHFR for the listener? MTHFR is confusing. When I started the

01:21:10.920 program, I thought MTHFR was a whole bunch of whatever. And now I don't believe that anymore.

01:21:15.360 MTHFR is methyl tetrahydrofolate reductase gene, something like that. MTHFR, if you have multiple

01:21:21.960 mutations. Do you know how many patients have come to me and said on their test, when they look at

01:21:26.120 MTHFR, they're like, why does it say motherfucker? And I'm like, no, actually it's methyl tetra.

01:21:33.100 Exactly. So it's quite an interesting gene. You can Google and find all sorts of stuff out there,

01:21:37.800 but MTHFR does have a role in Alzheimer's risk. But to me, it is, you know, you can take different

01:21:44.640 roads to Alzheimer's. It's one of those roads. It's a metabolic road through homocysteine. I mean,

01:21:49.100 is that what your hypothesis is? Exactly. Yeah. And basically methylation,

01:21:53.220 detoxification, you know, whatever word you want to use. I don't love using these words because I

01:21:57.020 just, it's very hazy. But if you have multiple mutations, two mutations in one of your main

01:22:02.680 MTHFR genes, the 677 gene, you know, and this is the back of the napkin. I'm not sure if this is

01:22:08.720 technically correct, but just for listeners, the person may have problems or be inefficient at

01:22:14.200 metabolizing B vitamins. And because of that, they're in the downstream cascade of biochemistry,

01:22:20.380 homocysteine goes up and it's a marker for something not working efficiently and well and

01:22:23.880 detoxifying, whatever you want to say. When it comes to MTHFR, homocysteine in people with Alzheimer's

01:22:31.260 risk, and this is precision medicine, where if someone has an elevated homocysteine,

01:22:35.140 but they're treated with B vitamins, they can slow overall brain atrophy and improve memory.

01:22:40.720 However, that will only work if you have optimized omega-3 fatty acids. So this precision component

01:22:45.520 of understanding the person's individual biology is necessary because if you don't have high

01:22:50.200 homocysteine, you probably don't need this stuff. You probably don't need B-complex vitamins.

01:22:55.220 So in this case, MTHFR is helpful in terms of looking at the gene because if someone is taking

01:23:01.060 the regular B vitamins, if you look on a B12, it says cyanocobalamin. If you look

01:23:05.120 at folic acid, it says folic acid. We're giving the person extra folic acid and cyanocobalamin.

01:23:11.120 We're giving them the B vitamins, but their homocysteine is not coming down. They may need

01:23:15.040 a more metabolically active form. And there's different racemic mixtures and there's different

01:23:19.440 biochemical blah, blah, blah that we can talk about in different forms and different companies

01:23:23.420 that make it. Actually, the company that I use for my practice, you told me about because literally

01:23:28.200 reliably, it's in that little bottle and the yellow bottle.

01:23:31.560 It always works. It absolutely always works. And you can do the prescription version and that

01:23:37.040 actually probably always works too. It's just a little more expensive, but it definitely always

01:23:40.220 works. So I'm going around the block to get across the street because it's complicated. But

01:23:44.820 when a person is not responding to traditional B vitamins, I will then step it up and give them

01:23:50.620 methylcobalamin B12 and methylfolic, whatever folic acid, methyl tetrahydrofolate, whatever version of

01:23:59.900 folic acid. And the combination that is usually enough to get the homocysteine down. So this is a

01:24:06.660 nice example of precision medicine and pharmacogenomics in our Alzheimer's prevention

01:24:11.500 practice. And I think the table or the image that you're referring to is when we basically take all of

01:24:16.980 our patients and we map different people with different genes, do they respond to different

01:24:20.720 things? That's right. It's every, the X-axis would be, or the top of the table would be each of the

01:24:26.740 APO-E combinations. So here's all six of them. And then each of the MTHFR combinations, there's two

01:24:32.800 genes, four combos per gene. So eight of those. And then it's basically in response to the lifestyle

01:24:40.240 intervention program, where did we see an improvement along which biomarkers and or which

01:24:45.260 element of cognitive testing? But I guess just to be clear, we're not going to be able to show that

01:24:48.720 table here. That's not yet published. Right. Oh, no, no. I mean, that's on page 700 to 900. Yeah.

01:24:54.120 So, you know, the first paper that we got accepted. I show that to patients all the time, but I mean,

01:24:58.240 that poster's great. Yeah. That's a poster we presented last year, but you have to put the cart

01:25:02.740 before the horse or whatever that saying is. But first you have to get the methods paper published.

01:25:06.780 And this is pretty amazing that we got this published in the Alzheimer's and Dementia Journal,

01:25:10.360 Journal of the Alzheimer's Association. And this is currently available, just recently published.

01:25:14.620 Yeah. We'll link to anything and everything that you let us.

01:25:17.720 My primary care doctor, who you got to meet in Miami, this guy, Dr. Wolf, you guys are like two

01:25:21.720 peas in a pod. He basically said, oh, this is your manifesto. I'm like, that's not my manifesto. It's

01:25:26.060 just, you know, whatever. But he called it the manifesto. It's 11,000 words of everything you need

01:25:30.240 to know about how to manage a patient for Alzheimer's prevention. And we've created a free...

01:25:34.440 And that will be accepted in one journal article?

01:25:36.500 It's 3,000 words, 3,500 words in the main thing. And then we have all the rest in the appendices.

01:25:41.420 Yep. And I can't believe it, but it was all accepted and it took seven months.

01:25:45.160 But basically, we've actually, since this is hard to read an 11,000 word article,

01:25:48.680 we've actually created a free online CME course for physicians basically using this...

01:25:54.540 Will that be ready by November?

01:25:55.640 Yeah. So ALZU.org.

01:25:57.600 So we'll make sure we absolutely link to that. Is there value in there for patients as well?

01:26:02.120 So ALZU.org is a free site that is for the public. So for the public, if you want to learn everything

01:26:08.280 about what is and what is not in our control about Alzheimer's disease, ALZU.org is a completely

01:26:13.320 free site to learn about everything. Then there's the healthcare provider page. If you go to the

01:26:18.400 little healthcare provider tab and you type in your information, you can then enroll in the

01:26:22.340 healthcare provider course and actually receive CME credit for it.

01:26:25.080 So there's actually a valuable CME course out there. Like, are they not the most useless,

01:26:29.280 idiotic things on the face of the earth?

01:26:31.080 Okay. Not the one.

01:26:31.980 I mean, once in a while, you find a gem like this.

01:26:34.080 Hey, yeah.

01:26:34.420 Every time I do a CME course on nutrition, I like have to deliberately answer the questions

01:26:38.460 incorrectly to pass the test.

01:26:40.680 Right. Yeah. It's a CME is one of those things. We've tried to really use CME to our effect because

01:26:46.440 no one knows about this stuff. Doctors just don't know.

01:26:49.500 Well, that's great.

01:26:50.660 You know, we're trying to get the word out. We got the methods paper out. That's done

01:26:53.660 explaining the intervention.

01:26:55.300 Let's explain it sort of at a high level. The intervention is a lifestyle intervention that

01:26:59.020 is multimodal. Patients are stratified, as I said, by genetics. So you have an MTHFR,

01:27:04.560 APOE. You also have an anthropometric.

01:27:07.100 We try to keep it simple. So the ABCs of Alzheimer's prevention management. It sounds

01:27:11.240 kitschy, but I really think ABCs actually fit. So A is anthropometric. We look at body

01:27:15.880 fat. We look at lean mass. We look at visceral fat. Where is the fat? You know, I learned

01:27:20.340 a lot of this stuff. We really take a deep dive. It's not just about weight and BMI.

01:27:23.980 Like, that's just like the worst. No, it's about body fat. Where's the fat metabolically

01:27:27.200 active? Yada, yada. Then the B is for biomarkers, blood-based biomarkers, specifically

01:27:32.860 cholesterol markers, especially the deeper dive.

01:27:35.860 I just want to take my hat off to you, Richard. You do more detailed lipid profiling than most

01:27:41.760 cardiologists do. I remember the first time I sat down with you, I was fully expecting

01:27:46.040 you to just whip out like the LDL, HDL, triglycerides, or this. And you went deep. I mean,

01:27:51.980 you had ApoB, you had LDL-P, you had particle subtype. You really got into it. And I was like,

01:27:58.380 why is the neurologist knowing all of this stuff when every cardiologist seems to like still be in

01:28:04.860 the dark ages on this?

01:28:05.880 That drives me crazy. You know, it's interesting. We have four cardiologists now in the practice,

01:28:09.160 actually one who listens to the podcast. I give him a shout out. She probably shouldn't say his

01:28:13.340 name.

01:28:13.500 Yeah, let's not say his name.

01:28:14.500 What's up? Really great guy. Actually, he's been a great, he's a patient, but he's been a mentor and a

01:28:18.540 teacher to me too. And, you know, we have cardiologists in the practice and one was like

01:28:22.440 totally anti, like, what are you ordering? And he's still anti all that stuff, but he really wants

01:28:27.020 to know his numbers and he really wants me to interpret it. But, but for his patients, you know,

01:28:30.420 it's like, I don't use this stuff.

01:28:31.400 What are some of the other biomarkers you focus on?

01:28:33.600 So the four main categories are cholesterol, but deep dive cholesterol, inflammation. However,

01:28:37.920 there's just four inflammation labs and they're just not great, but it's just in our panel.

01:28:41.480 So what are you looking at besides CRP and fibrinogen? Do you look at IL-1 or IL-6, TNF?

01:28:47.200 Yeah, I wish. Yeah, baby steps. It's a myeloperoxidase and LP-PLA2, which I don't

01:28:53.560 exactly know what to do with, but yeah, fibrinogen, interesting and high sensitivity CRP. Now that I

01:28:58.900 see all the results in our outcomes, HSCRP is probably the most informative, but you know,

01:29:03.920 something like myeloperoxidase is a risk factor for vascular cognitive impairment later. That's a

01:29:09.240 new study. So I don't exactly know what to do with the inflammatory markers, but we're checking them.

01:29:13.360 And what stands in the way of adding some interleukins to that?

01:29:15.920 Some of the money, Benjamins. I would love to get better nutritional biomarkers,

01:29:21.560 which we'll talk about. We do it in the serum. We'd absolutely need to do it in the red blood

01:29:25.220 cell, but we need to send it to a different place and a different FedEx account.

01:29:28.400 This is the thing. Can I just, I'm just going to get back on my soapbox. God damn it. I'm allowed

01:29:31.920 to do this. I guess this is the one perk of having your show. If you're listening to this and you're

01:29:36.820 in some way touched by Alzheimer's disease, either because you have a family member who's got it,

01:29:40.740 or you're concerned about anything like that. And you're considering like funding research

01:29:44.180 in Alzheimer's disease. I can't emphasize enough the importance of funding the type of research

01:29:48.280 that Richard does, whether that means funding Richard directly or somebody else, because

01:29:51.360 Alzheimer's prevention is so underfunded. It is an embarrassment to this disease state. And so,

01:29:59.760 and I've had patients who have said to me, you know, a loved one just passed away and I'd like to

01:30:04.840 throw a hundred thousand dollars at something for Alzheimer's research. And I think to myself,

01:30:08.640 luckily those patients like to give that money to you because you can do more with a hundred

01:30:12.140 thousand dollars in your clinic. A hundred thousand dollars doesn't buy you five animals

01:30:16.220 to do a study on a drug that has a 99.6% chance of not working. Let me repeat that. The success rate

01:30:24.540 of pharmacology for Alzheimer's disease is 0.4%. In other words, 99.6% of drugs brought forth to treat

01:30:35.380 Alzheimer's disease are abject failures. Now, if you are interested in the philanthropic side of

01:30:40.620 Alzheimer's disease and you want to put more money in that pot, you must ask yourself the question,

01:30:45.380 which is what is the definition of crazy? Is it throwing more money into the same pile? That's

01:30:51.060 taking the same approach to a disease that's not working? Or is it possibly looking to this novel

01:30:56.480 idea of Alzheimer's prevention? Okay. Rant over off the soapbox. Let's go back. And it's funny. Like

01:31:01.800 if I would have had $75,000 more three years ago, I would have had the right biomarkers. So I could

01:31:11.600 definitively say about which omega-3, which this, which that I could have for $75,000, you know,

01:31:18.460 we've gone through $8 million in five years. Okay. That's not too bad actually. I mean,

01:31:23.820 for a major research program, 5 million of it, philanthropy, 3 million NIH and other grants,

01:31:28.040 $75,000 extra, I could have definitive evidence about which omega-3s to take. Is it ALA, DHA, EPA? I

01:31:35.300 think it's DHA and EPA, but I wasn't doing the right biomarkers because I couldn't afford the right

01:31:39.520 test. So for the littlest tiny investments, you know, we have a data set with 3,000 pieces of data

01:31:45.640 on every patient. We have such a deep phenotypic characterization. I have thousands of pages of

01:31:51.160 data. I don't know how I'm going to write this up. I need to hire two full-time people for $50,000

01:31:55.840 per person. We can churn out papers, you know, two papers every few months. So the take-home point

01:32:01.500 is in an imprecise world, in an imperfect world where I don't have unlimited funds, we have to be

01:32:06.320 cautious. So we've done the best we can, but oh man, I wish if we could have TNF alpha interleukins

01:32:11.540 and CD50s and I wish we could. Yeah. And I think the way to think about this, again, if you're

01:32:16.640 listening to this and you're trying to understand how should funding be allocated, you have to think

01:32:21.960 about this as how would you hedge, right? So I'm not suggesting for a moment that no effort should

01:32:26.460 be made at doing research around Alzheimer's treatment. I mean, the disease is devastating

01:32:31.080 and you don't have to meet but one person who suffers from this disease to think we should be

01:32:35.440 throwing heaven and earth at figuring out how to treat these patients. The question is how would you

01:32:40.800 balance that portfolio? Because right now that portfolio is about 99 to 1. $99.9 are going into

01:32:47.060 treatment, 0. $1 going into prevention. I'm asking simply, what if it were 90-10? What if it were $90

01:32:53.560 that go into treatment and $10 into prevention? In reality, I think if it were 10-90, we'd move the

01:33:01.040 needle even more if we were willing to acknowledge that, hey, a lot of people can't be helped right now,

01:33:05.940 which is an awful message to consider. So anyway, I do think that prevention suffers from a number of

01:33:12.300 things. It's way squishier. There's always going to be a bias against the idea that you can get

01:33:17.200 people to change behaviors, lifestyle behaviors. In other words, it's one thing to get a patient to

01:33:21.840 take their pill. It's quite another thing to get a patient to change the way they sleep, the way they

01:33:26.180 meditate, if they do at all, the way they exercise, the way they eat. These things are harder to do.

01:33:32.660 That's the downside. The upside is if you can do those things, I think the evidence is pointing to

01:33:38.200 you can have a much bigger impact. Oh, yeah. And if when you do this precision medicine approach,

01:33:42.480 where you look at their cholesterol, inflammation, metabolism, we'll talk about in a second,

01:33:46.520 nutrition, biomarkers, genetics, and you take all these factors and you look at their body fat and

01:33:51.240 you look at their cognitive function, which we'll talk about, the A, B's and C's, you can then give

01:33:55.900 them a personalized precision medicine plan and they end up getting that right plan and then

01:34:02.380 the outcome is better and then they're going to have positive reinforcement to where they're

01:34:06.940 going to keep doing it. I have people that say, I haven't been able to lose weight my whole life.

01:34:11.380 Are you doing the wrong thing? You were on an elliptical for 20 minutes, three times a week.

01:34:15.900 That's not going to get you to lose weight. That may get you to maintain yourself a little bit,

01:34:19.300 but not really. You need to do high intensity interval training. You need to lose body fat.

01:34:22.820 Here's your fat. Here's your this. Here's your that. When you attack it with knowledge about

01:34:26.900 the non one size fits all approach and the N of one do everything and everything based on your

01:34:33.060 individual biology and genetics, that's when a person can have the most success. When they have

01:34:37.600 success, it's positive reinforcement. Yeah. And I think seeing those biomarkers improve,

01:34:42.380 I saw three patients today in clinic and in all cases, we're reviewing labs and it's really,

01:34:47.820 I love it. Yeah. They really like to be able to, especially the ones that dial into this stuff that

01:34:51.900 think, oh, wow, look at how this change led to that, but not this. And what do I need to do more here?

01:34:57.000 And I mean, I guess in the end, one of the challenges is you and I both have a luxury that

01:35:01.580 not, not a lot of doctors do, which is we have small practices that allow us that luxury of time.

01:35:07.940 And so hopefully some of these other tools you're developing will allow physicians to be able to

01:35:13.080 scale themselves a little bit by saying, look, I, you know, Dr. Smith might not have as much time as

01:35:18.940 Dr. Isaacson to sit down and spend an hour with each patient going over this stuff, but I can at least

01:35:24.540 point a patient to a tool that can help streamline this process. Yeah. When I'm sleeping without any

01:35:30.180 PR, without any, or anything, just because the way the internet works, when I go to sleep and wake up,

01:35:35.100 my ex-girlfriend with the phone, the phone thing, who I was trying to show off and impress,

01:35:38.980 she said, well, you work so much. And every time you give a lecture, okay, fine, but make money while

01:35:44.620 you're sleeping. Well, it's the same thing. I want to help people and educate people I'm sleeping.

01:35:48.120 You're right. I see seven patients in a day, sometimes five, because it takes a lot of time.

01:35:52.260 But when I'm sleeping over a thousand patients are on that free education website with two hours of

01:35:57.500 interactive educational content about Alzheimer's prevention, that's how we impact lives. So I'm

01:36:02.580 hoping that we can increase that from a thousand to 8,600 patients while you're sleeping. I would

01:36:07.940 get the reference. The astute listener will get the reference to that. So does my pocketbook.

01:36:12.440 Absolutely. So, and it's, everything's free and we don't charge for any of this stuff, but that was an

01:36:15.860 inside joke. So I guess as we go back to the A, Bs and Cs, so the other bio blood biomarkers that we could

01:36:20.820 probably wax poetic and talk about for another several hours is metabolism, because I believe

01:36:25.480 Alzheimer's disease is a metabolic disease in the vast majority of cases. And we look at,

01:36:29.880 again, if we could talk about this for an hour. Is that becoming a mainstream view yet? I mean,

01:36:32.640 that was such an out there view six, seven years ago. Is it less out there now? It's hard to ignore

01:36:38.760 the fact that patients with type two diabetes have a disproportionate risk.

01:36:42.780 What the amyloidocentric people and the tauists, the amyloid and tau people.

01:36:46.420 The tauists. I mean, that's a sweet title. That is cool. Right. I would like to be a

01:36:51.100 tauist. Yeah. I call it amyloidocentric, but other people say the Baptist. Baptist means

01:36:55.060 bapinuzumab, which is an anti-amyloid drug. Anyway, the Baptist, tauists, whatever. I'm a

01:36:59.900 mitochondrialist or whatever it is. What I would say is those people that don't get it, most people

01:37:05.320 don't understand that the leaders in the Alzheimer's field that are like leading major

01:37:09.540 initiatives, like two of the most major initiatives in Alzheimer's disease, one is led,

01:37:14.160 actually both are led by non-clinical physicians that have never seen an Alzheimer's patient.

01:37:19.680 Soapbox rant number two coming up now. This would be a good time to hit forward by two minutes if you

01:37:26.240 don't want to hear the rant. You know, few things chap my ass more than the leaders in the field

01:37:34.140 treating clinical diseases who don't treat patients. And I often get asked, like,

01:37:39.640 do you one day see yourself not actually practicing medicine, but instead just focusing on the types of

01:37:45.880 research and collaborative things that you want to do? And the answer is always no. The day you stop

01:37:49.680 seeing patients is the day you stop getting humbled by and reminded of what the hell you do this for.

01:37:56.080 And what you just said is staggering. Yeah, I would not have guessed. Yeah. When I found out this one

01:38:01.660 person had no clinical training and basically did some radiology trash, I don't want to talk about

01:38:06.040 specifics, but in the other person, like a related kind of field, but not psychiatry, not geriatrics,

01:38:11.840 like not the traditional anything drives you crazy. And then, and then you have this conversation

01:38:17.620 with them or you say, Oh, Hey, nice to meet you. And they say, I heard about you. Give me the scowl.

01:38:22.180 They give me that scowl. At least they're saying now, cause you're such a low life neurologist who's

01:38:27.640 like on the ground, actually touching these patients. Yeah. Like I heard about you. You're that guy,

01:38:32.920 prevention. At least they're saying multiple shots on goal. Maybe we need to look at other

01:38:39.900 targets aside from amyloid and tau. That's at least what they're saying. All right. We'll take

01:38:43.640 that's progress. I'll take it. And the tomatoes are getting thrown at me less and less, which is

01:38:47.080 good. So let's go back to metabolism. And for a guy who doesn't cook, this is a highly inefficient

01:38:51.160 use of tomatoes. Like if someone threw a bunch of tomatoes at me, I could make some nice sauce.

01:38:55.440 I've turned on my oven once and that was in 2001. Before you started storing your textbooks in there?

01:39:00.800 My textbooks are, that was in 2001. I started putting my textbooks in there cause I had no

01:39:04.380 room in Boston. I actually, I've put my textbooks and other things in my oven for a long time. I

01:39:09.060 live in a tiny apartment. I have two dogs, two cats, guy on the couch is a problem. Guy's got

01:39:14.760 venting. I talked to my therapist. Are you trying to figure out why your fiance hasn't moved to New

01:39:18.940 York yet? I wonder why. Yeah. I have no insight into why she's still in Florida. And the guy's got long

01:39:24.060 hair. Oh no, she's in California. Oh, she's in California. She's in California. Yeah. One of those

01:39:27.280 things. We have a bi-coastal dog, cat, whatever guy on the couch. Definitely got to go by the time

01:39:31.860 she comes back. Is he listening to this? No, he's not a podcast listener. So there's no risk that he's

01:39:37.320 going to be offended by the fact that you said he's got to go. No, no, I don't have to cut that part

01:39:41.400 out. No, no. He's got long hair. The hair's everywhere. It's just like so messy. Anyway, back to

01:39:47.540 metabolism, metabolism. What are you measuring metabolism? Do you do oral glucose tolerance test?

01:39:52.000 Well, Dr. Peter Atiyah has schooled me on this more than one time, and I would love to. However,

01:39:58.840 we can only do as much as we can do. Yeah. And the time and the trickiness, but sure, I'm not

01:40:03.860 doing everything as precise as I need to. And you're the one that's taught me about how you can have

01:40:08.560 fluctuations and sugar up and down, but then the average hemoglobin A1C is normal, but you're missing

01:40:13.960 those other things. So we do it better than maybe the average Joe, but we look at hemoglobin A1C,

01:40:20.180 we look at home IR, we look at fasting insulin, we look at fasting blood glucose, which I really

01:40:25.100 like, even though it's imprecise, it just does give me a good snapshot. We look at adiponectin,

01:40:29.580 which is confusing sometimes. So, you know, these are some of the main, we used to look at more

01:40:33.520 things and then it was expensive. So we do the best we can, but then we triangulate. So the key here

01:40:39.680 in the A, B, C. Are there any other classes of biomarkers? Oh, sorry. Nutrition, nutrition. Yes.

01:40:43.700 And what do you look at there specifically? This is our problem because we look at saturated fat,

01:40:47.960 monounsaturated fat, DHA, EPA, ALA, you know, all this sorts of stuff. Based on what? Food

01:40:53.760 frequency questionnaires? No, no. In the blood. Oh, you're measuring RBC levels of all of these.

01:40:58.340 No, that's the problem. We're measuring serum levels. It's a problem. Oh yeah. That's a problem.

01:41:03.600 I know. We'll add that to our discussion. That's hence my $75,000, whatever that got sucked away

01:41:09.820 back in 2013. We, and that was 2015. We had money for this and then things happen sometimes.

01:41:15.680 So what's the C? The C is as important as the A and the B. And I never would have said this five

01:41:22.060 years ago or even thought that I would be talking about something this ridiculous, but C is cognitive

01:41:27.540 function. That doesn't sound ridiculous. Well, well, using cognitive function to personalize or

01:41:32.800 individualize a person's care from a biological perspective, that sounded ridiculous to me five

01:41:38.660 years ago. But we look at processing speed, attention, memory, executive function, all of these

01:41:44.480 different cognitive domains. When I see lipids, I now see executive function. When I see vitamin D

01:41:49.980 and homocysteine, I say, Hmm, could that be processing speed? When I see metabolism problems

01:41:54.420 and high visceral body fat, that's screaming memory, metabolism and memory. And what we do.

01:42:01.500 So this is news to me. Like I didn't. Oh, me too.

01:42:03.980 Yeah. So are you seeing this as, is this just basically a blind squirrel has found some nuts?

01:42:10.380 Like you're just digging through your data and these patterns are emerging?

01:42:13.720 No, not data. No, this is clinical. This is clinical observations.

01:42:16.280 That's what I mean though, because you're still generating clinical data.

01:42:18.820 Yeah. This is pre data analysis. And you know, some of the data analysis doesn't even hold up

01:42:23.020 with maybe my clinical observations because people are different. And when you lump Bob and Jim and

01:42:27.640 whoever else together all in a bunch.

01:42:29.100 So these are just very loose sort of observations that are becoming now testable hypotheses.

01:42:34.780 Right. And the testable hypotheses are tricky here because what we do is more traditional

01:42:38.400 statistics. We do your means and averages and you know, all the fancy least squares means and

01:42:43.940 whatever Bayesian yada yada. But we probably need to be doing N of one studies and N of one is a way

01:42:49.980 to, which brings us back to AI. Yeah. I mean, until you have the AI engine.

01:42:53.860 Totally. And I was a computer door in a past lifetime and I would do artificial intelligence

01:42:58.700 with my life. If I had a billion dollars tomorrow, I would fund my research and get the right people

01:43:03.380 on the bus to do all the things I want to do. And I would focus professionally on programming and

01:43:07.840 artificial intelligence because that's how we can really beat this stuff. That's in the same

01:43:11.740 getting in my rant or my, that was my soapbox time. But long story short is N of one people where

01:43:17.540 you can make these associations and you average it all together in the cohort and it gets too hazy,

01:43:21.800 but metabolism and memory, metabolism and learning and memory specifically.

01:43:26.600 And what we do here, and this is the key triangulating on the A's, the B's and the C's.

01:43:31.620 So never say, Oh, your blood sugar fasting is 97. You need to do X, Y, or Z differently.

01:43:38.420 No, no, no, no. 97 that's above 95. And that's my cutoff of normal for brain health,

01:43:43.760 memory and cognitive function, which is less than the 100 cutoff, which in med school,

01:43:47.740 it was 125 and then 116 in residency. And now it's 100. And hopefully in five years,

01:43:52.380 it'll be 95. I don't know what you think fasting blood sugar is appropriate in terms of a reference

01:43:56.920 range. But for brain health, I think it's 95 based on some work from Germany. So what we do is we take

01:44:01.700 the A's, the B's and the C's, we triangulate the information. Only then do you make a clinical

01:44:07.900 decision. And you can't just treat based on one, you have to interpolate everything. And when you do that,

01:44:14.420 that's when you can come up with the clinical precision medicine plan.

01:44:16.940 So what cutoffs are you using on your lipids these days? Let's just go with LDL particle.

01:44:21.340 Oh gosh, this is confusing because there's, I don't want to talk about bimodal curves and maybe

01:44:26.260 people with too high HDLs can be bad. And I mean, there's a lot of complexity here and it's an

01:44:31.420 individual and this is a phenotype thing. Like I just C-TEP, C-ETP, cholesterol, ester transfer,

01:44:36.880 whatever. I don't know what that gene is called, but I can see that the person has the gene

01:44:41.000 because I can feel it in my gut and I can look at the labs and I can just, I can see.

01:44:45.120 Based on their HDL cholesterol, you mean, or the combination of their HDL particle and their

01:44:48.980 HDL cholesterol and size. It's really hard for me to give generalities because there are certain

01:44:53.500 people where the rules don't apply or the rules apply backwards. So LDL cutoff, sure. Absolutely

01:44:59.580 below a hundred. I'd love below 70. What about in the particle? Sub a thousand, but 600, 500 better than

01:45:06.040 eight or 900 maybe, but I don't really know for sure. And are you concerned that statin use,

01:45:12.120 even though at the population level, statin use is always associated with a lower risk of dementia

01:45:16.680 that in certain individuals, it can exacerbate it. I hate to say this, but yes. And five years ago,

01:45:21.620 I would have said, heck no. Statin should be in the drinking water. I'm very pro-statin period.

01:45:27.600 Just like you said, population-based. I'm very pro-statin because of this clinical observation

01:45:34.020 where you see patient after patient after patient and you see genotype and then phenotype and

01:45:38.260 whatever. I do believe that different statins work differently in different people. I think

01:45:43.160 there's a gender difference. I think when in doubt, low dose is better. I think people with APOE4 genes,

01:45:48.340 especially two APOE4 genes, holy cow, you have to be careful. I think you were the one that taught

01:45:53.040 me about Livolo. And then I learned more about, you know, Crestor and high potency and low potency

01:45:56.820 and lipophilic and blah, blah, blah, you know, and how atorvastatin showed to be beneficial in men

01:46:01.420 with slowing hippocampal atrophy, but not in women. And, you know, and I've just seen men

01:46:06.180 change from one cholesterol drug to another because, hey, their numbers look great, but now

01:46:11.280 their memory got worse. High potency statin, APOE4, maybe we need to come down a little bit. So

01:46:16.500 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.

01:46:24.420 Yeah. I mean, I think this is one of those things in medicine that I think is very hard for people to

01:46:28.920 understand, which is how can something like a statin potentially be good and potentially be bad.

01:46:34.280 And the reality of it is it can be very positive from a vascular standpoint, can be positive from

01:46:40.300 an inflammatory standpoint. It could be negative from a cholesterol biosynthesis standpoint in a

01:46:44.800 susceptible individual. And so, I mean, like you, I consider myself pro everything under the right

01:46:50.700 conditions. I'm pro hammers when I have a nail and a piece of wood, but I'm pro Phillips screwdriver

01:46:57.900 when I have a Phillips screw and a piece of drywall. Perfect. Yeah, that's a great point. So

01:47:02.580 then there's plant sterols and Zeti and this and that and omega threes. And I'd like omega threes

01:47:07.560 to get down. And you mentioned earlier on the omega three front. I mean, I think in the last

01:47:11.360 year and a half, actually during the time when we were writing that manuscript, I think it became

01:47:15.220 a little bit more clear that it might even be the DHA. And it works better in E4s, but it just takes

01:47:19.860 years to work to have the most robust. It takes two and a half years, I think, to recycle the amount of

01:47:25.020 DHA in a person's brain. So when you study it for six months, then you're only getting 20%.

01:47:28.640 Which again, I'm sorry to do a rant number three soapbox again. When someone says such and such an

01:47:35.540 agent was studied and it had no effect, should you immediately dismiss the intervention? Only if you

01:47:42.460 can be confident that it was studied correctly and that the time course of the disease and the

01:47:48.920 intervention were appropriately matched. And it's that latter point that almost always seems to be

01:47:53.840 the missing link. And that's a great example of that. Frankly, half the primary prevention studies

01:47:59.280 in disease, I think, miss the mark because they don't understand the time course of the disease

01:48:03.420 that's being studied. And the other part about this is, you know, if you do this one size fits all

01:48:07.400 and you give say omega threes to everybody, but people with high omega threes maybe don't need it,

01:48:12.240 but then they lump the results together. Well, guess what? The study is going to be negative.

01:48:15.900 Maybe you should have just given the omega threes to the people that actually needed it.

01:48:19.440 And that would have been your enrollment criteria. Then your outcome would have been

01:48:22.880 different. So precision medicine and this whole one size fits all thing is just, you know,

01:48:27.160 very dichotomous. So, so yeah, we take these ABCs and we generate evidence-based and safe from

01:48:33.180 patient education, you know, two hours more online, interactive education online for free

01:48:38.400 patient counseling with me and Holly. And then we, um, really type out a whole plan. And this is four

01:48:45.760 pages, five pages, sometimes in which patients, not to get too tactical, but I know that a lot of people

01:48:50.200 listening to this are probably chomping at the bit to know some of the things. I mean,

01:48:53.360 we've alluded to a number of these things now. Another one that's really come on my radar in the

01:48:57.440 last two years is a specific type of curcumin called theracumin. Can you talk a little bit about

01:49:02.580 what that is, how it works and why? Sure. And I have nothing to disclose. I did a Medscape piece

01:49:07.640 on theracumin and man, I got tomatoes thrown at me in the comment section. This one ER doctor in

01:49:12.800 Kansas, hopefully he's not listening to this. I actually called him. Hopefully he is listening. Yeah.

01:49:16.280 Well, I actually called him to discuss and the secretary in the ER said, all right, we don't give

01:49:20.440 your whatever out, but you know, I have nothing to disclose and I don't sell supplements. You don't

01:49:25.580 have a supplement company on the side? No, I wish I have hundreds of thousands of student loans. My

01:49:29.840 fiance has a 450,000 student loans. I have a recommendation. If you could start monetizing your

01:49:35.900 bling phones, there might be a way to start putting a dent in those. This is a very unique

01:49:41.520 audience is interested in these though. So I'd have to spend money to find that person.

01:49:46.040 If you know any oligarchs, that's what usually, uh, if you can find a Chinese billionaire,

01:49:51.000 I have a Chinese phone and then this white alligator skin one. So we want to part with

01:49:56.300 this. So you wrote this thing in Medscape about theracumin. Yeah. And, and I got, and he's trying

01:50:00.560 to sell things. So just for, just for disclosure, I wish, but I've made a conscious decision not to,

01:50:06.600 I live in a one bedroom apartment with two dogs, two cats, and a guy on the couch. It's my bathroom

01:50:11.140 is the size of a closet. I live in New York city. I have tons of loans. I am negative when it comes to

01:50:16.580 my net worth since moving to New York five years ago. I don't need a sob story. I have a roof over

01:50:20.940 my head. I'm very fortunate, whatever, but I am not trying to make money. I'm not trying to sell

01:50:24.680 stuff. So although I probably should not, I'm not selling my phone though. So when it comes to

01:50:29.660 theracumin, it is a specific type that comes from Japan and this Japanese company from my

01:50:35.200 understanding basically made this nanoparticle, small particle version. Now there are versions

01:50:40.120 of curcumin that may be optimized for absorption and blah, blah, blah. But in the Alzheimer's study

01:50:45.740 by John Ringman and colleagues, when they did a randomized study on curcumin for mild to moderate

01:50:50.080 Alzheimer's, the study was negative, but when they did the blood samples, the curcumin was being

01:50:55.660 swallowed and not being absorbed in the blood. So I wonder why curcumin didn't work. So this basically

01:51:01.500 led to this Japanese company putting together this theracumin version, nanoparticles, whatever

01:51:06.360 it is. And a study by Gary Small and colleagues basically showed that after 18 months of using

01:51:11.220 it, when you look at PET scans, there was less amyloid in the group that got the real optimized.

01:51:16.420 So does that mean we should be using theracumin even in our non-high risk AD patients that we would

01:51:21.060 otherwise be giving curcumin to?

01:51:23.420 Well, precision medicine, no one size fits all. So sorry to get back on that soapbox, but

01:51:28.500 no, not everyone I don't think needs curcumin. I think it depends on what their ABCs are.

01:51:33.020 You know, if they have some inflammatory stuff, well, I'm not checking the right inflammatory

01:51:36.760 stuff. So I can't use that as a biomarker. If they have some memory stuff, well, maybe

01:51:41.160 if they're at higher risk and they have an APOE4 gene, maybe.

01:51:44.280 What was the dose of theracumin in that small study?

01:51:46.620 Small meaning the author, not the size.

01:51:48.580 Yeah. It's two pills a day.

01:51:50.680 So it's like 500?

01:51:51.900 600 maybe. It's two pills a day. Read the label, read the study. I'm forgetting, but it's one

01:51:56.400 pill a day for a week. And there are several companies that sell theracumin now or just

01:51:59.720 one?

01:52:00.060 Several companies. Yeah. So again, I'm not vouching for any brand, but as you said earlier,

01:52:04.020 Peter, you know, you, you taught me which methyl yada yada to use and it works every time. And

01:52:08.920 it's like, finally, we have a good version. I do vouch for certain.

01:52:12.200 For the listener, the brand that we've switched to across the board is Gero's. They have a combined

01:52:17.340 lozenge that's methylfolate and methyl B12.

01:52:19.300 Yeah. It's the yellow bottle, but.

01:52:21.040 Yeah. A little yellow bottle with a pink lozenge.

01:52:22.900 So, you know, we choose specific supplements because we know that they work and they're

01:52:27.180 verified and, you know, we've used them and we can see it jumping in the blood. So we know

01:52:30.280 it works. Theracumin is, or theracumin, I don't even know how to pronounce it. I don't think

01:52:35.200 everyone needs to be on it, but I do think if you're going to be on it and you have amyloid

01:52:40.800 in your brain, you better be on the right stuff. So that's important. Should someone take more?

01:52:44.600 I have no idea. I've never told someone to take more, but I have this family that two,

01:52:48.940 multiple to actually two families, three that have the APOE4 gene and the TNF alpha gene. Well,

01:52:53.980 how does curcumin work? They're on a TNF alpha pathway. What we've been doing is then we can add

01:52:58.520 additional labs that cost money, but you got to do what you got to do sometimes. And we look at CD50

01:53:03.700 and other inflammatory markers and TNF. And while TNF isn't really changing, for example, in multiple

01:53:08.480 patients that we put on this theracumin, the CD50 is increasing. So I don't exactly know what

01:53:13.900 that means, but I do know that their memory is not getting worse and maybe hopefully over time

01:53:18.080 we'll get better. So has anybody commented on this rise in CD50? I've never really talked about it

01:53:23.860 before. I mean, you've sent me this, these data, but is there anything in the literature about CD50?

01:53:28.320 I'm not aware. I, you know, my brain can only hold so many things. I'm a one third preventative

01:53:33.400 cardiologist when I shouldn't be. And, you know, I have a great guy, Randy Cohen, bless his heart.

01:53:37.540 He's just been, I email him and he emails you back at 48 hours. I have this phone a friend list of

01:53:42.680 people that are way smarter than me, but, but, you know, I, I'm one third preventative

01:53:45.760 cardiologist, make believe one, I'm one third neurologist and one third primary care doctor.

01:53:49.460 And I just can't internalize all this stuff. So I email you and I have this like group of like 12

01:53:54.800 to 15 mentions that just help me for free. And it's amazing. So don't know what to say.

01:53:59.940 What do you think of as kind of like the five most important things you tell a person? So let's say

01:54:06.360 you're at a cocktail party and someone finds out what you do for a living. By the way, when I'm at a

01:54:11.680 cocktail party, if I'm ever asked what I do, there are only two responses.

01:54:16.020 I sell carpet or sofa beds. That's what my dad did. That's a great answer.

01:54:19.500 I'm either a shepherd or a race car driver.

01:54:21.720 You look like a race car driver.

01:54:23.500 I thought you were going to say I look like a shepherd.

01:54:24.960 No. Well, you have that a sheep thing in the corner over there.

01:54:28.700 Yeah. Yeah.

01:54:29.780 The sheep herding stick.

01:54:31.060 Yeah.

01:54:31.640 Race car driver is a great.

01:54:33.760 It's just a great way to not have to talk about formula one.

01:54:36.320 Yeah.

01:54:36.540 I wish. But let's say you're at the cocktail party. Someone corners you in a moment of weakness.

01:54:42.700 You explain exactly what you do, or they've listened to this podcast and they see your

01:54:46.760 picture and then they come up to you and they go, Hey, you're Richard Isaacson. And they say,

01:54:49.920 look, I'm 30 years old, right? I'm as healthy as a horse. There is nothing wrong with me. I

01:54:54.620 couldn't even begin to relate to cognitive impairment. But you know, my grandmother was diagnosed with

01:54:59.560 Alzheimer's disease when she was 70 years old. And by 80, she was dead. And let's just assume that

01:55:04.660 the patient doesn't know their APOE status or any of these other things, you're not going to see this

01:55:09.320 patient again. You know, you're at a cocktail party in Los Angeles and you're flying back the next day.

01:55:14.500 What are five things that you would put in the no regret move list that you could say to that

01:55:20.960 person, even at a general level?

01:55:22.560 I hate to be general, like too general, but one is knowledge is power. Learn about brain health now

01:55:30.260 because brain health incremental changes that you make now at 30, 40, 50, whatever the earlier,

01:55:34.940 the better, but throughout the lifespan, learn about brain health. So I will refer them to this

01:55:39.360 website. Again, it's free ALZU.org. There's been 1.1 million people that have been on the site.

01:55:44.560 I'll never be able to treat a hundred thousand people in my clinic. So go to the site, learn

01:55:49.840 every single thing possible. I can't tell you everything. Are there diagnostic tests that people

01:55:54.340 can do to get a sense of their own cognitive abilities? There are, we don't give results at this

01:55:59.120 time. We have like one test that gives results, but it's for research purposes. So it's for

01:56:02.840 tracking. It's for tracking. So a patient can say, I'll take the test on ALZU once a year.

01:56:07.380 There's email reminders to tell you to take it. And do they get results if their performance

01:56:10.980 deteriorates or do you get a result? No, this is for research purposes only. So everything's

01:56:15.180 decoded. So right now we don't give results, but give us a little more time. And we unfortunately

01:56:20.700 don't have the funding to analyze this 1 million strong cohort, because when you get a million

01:56:25.440 points of data, it's very expensive to analyze and we don't have the right statistical team.

01:56:30.440 So step one is at least go and familiarize yourself with all of this information.

01:56:34.000 Yeah. And I'm not trying to be like, oh, whatever. I'm not trying to like, everyone wants that. Like,

01:56:38.120 what do I do now? Do I, what pills should I take? How much should I exercise? What's the magic dose?

01:56:42.380 To me, it's like, if you're going to really get serious about brain health, it's just not that

01:56:46.280 simple. Our intake at the clinic, it's an hour and a half cognitive testing, hour and a half with me

01:56:50.820 filling out a 45 minute survey, taking courses online before you can even get an appointment with

01:56:55.620 me. You have to do all this pre stuff. Alzheimer's prevention is not simple. Take the time. You're

01:57:00.480 going to be watching YouTube or flipping through Facebook or doing whatever the heck you're doing

01:57:04.240 to waste time on your cell phone late at night. Take the course online. You're going to learn

01:57:08.600 things, internalize them, make incremental changes. Number one is education. Nelson Mandela said education

01:57:13.500 is the most powerful tool to change the world, whatever, whatever the quote was that I mangled. But

01:57:17.880 education is number one. Number two is know your numbers. Okay. What do I do? They want me actionable

01:57:24.200 tips, actionable that no, take a step back, know your numbers. What is your blood pressure? What is

01:57:28.260 your pulse? What is your body fat? What is your weight? What is your cholesterol? What is your blood

01:57:32.700 sugar? Know everything about yourself. Your body is a temple. That's a saying. Know everything about,

01:57:38.380 you know, you and I use the aura ring. I believe I use the whoop biosensor, nothing to disclose,

01:57:43.040 whatever. I know everything. I do have something to disclose, which I disclose publicly. I have invested

01:57:47.540 in aura and I advise them. So please make sure everybody knows. Yeah, of course. So I want to

01:57:52.100 know everything about my physiology, about my sleep, how many hours, when I go to sleep, when I,

01:57:56.780 whatever, how much my exercise is, what my strain is, what my output is, what my average heart rate is,

01:58:02.060 my, my resting pulse. I want to know I'm a data junkie. Right. Now the person's ready to spill their

01:58:06.840 drink on you. They're like, I got it. I'm going to memorize the site. I'm going to learn everything

01:58:10.340 about me. But I want to know, is there anything that I should be doing more or less of with respect to

01:58:16.280 exercise, food, sleep, meditation, yoga supplements? Are there any no regret moves?

01:58:23.020 So exercise is the number one thing any person can do. The only thing a person can do right now,

01:58:28.040 if they have amyloid in their brain to reduce it or slow the accumulation is exercise on a regular

01:58:32.380 basis. Yeah. When we were writing up what our white paper that eventually became the basis for the

01:58:37.740 paper we collaborated on, I remember when Dan first presented to me just internally, like

01:58:44.200 all of his findings, I guess I should take a step back and explain why we did this. Cause I think it

01:58:49.060 provides an example of how we started working together. But I remember he said that he was

01:58:53.160 like, Peter, you're not going to like this answer, but like, there's literally only one thing in the

01:58:57.820 literature that suggests that you have any hope of mitigating Alzheimer's disease. And I was like,

01:59:03.060 let me see if I can guess. And I came up with like 10 guesses and they were all wrong. And he goes,

01:59:06.800 no, it's exercise. And I was like, okay. I mean, I get that exercise is important,

01:59:11.680 but are you telling me that in the literature exercise is the only thing that meets level one

01:59:16.180 evidence for the treatment of Alzheimer's disease? And, and look, I mean, that's an important thing

01:59:21.020 to know. I would say risk reduction. Yeah. Risk reduction. So again, we could wax philosophically

01:59:25.240 on why, by the way, the reason we ended up doing this is we read a review article by Dale Bredesen,

01:59:32.040 who many of the listeners will probably recognize. I don't know Dale. I've never met him. I don't even

01:59:36.920 think we've exchanged emails, but we read a paper that was a pretty exhaustive paper based on his

01:59:42.300 recommendations for Alzheimer's prevention. And we just wanted to start from first principles and

01:59:48.260 there were 200 or so references in the paper and poor, I don't know, Dan or Bob or one or two

01:59:54.900 analysts got the task of please go and get every one of those references and make sure the references

01:59:59.740 line up with what's being said. And I don't think this is deliberate. I think this is just the nature of

02:00:05.320 what happens when people are writing papers, but like we couldn't verify a third of these

02:00:08.480 references. For example, there was one reference that said, take resveratrol. And we went to that

02:00:13.760 paper and that paper, while it was about resveratrol, it had nothing to do with resveratrol

02:00:18.100 and Alzheimer's prevention. So, so that's when we decided we just wanted to do this from first

02:00:21.060 principles. We wanted to go and take a first principles approach. And we had an unusual

02:00:25.460 methodology, as you recall, which was start from an intervention, look at an intermediary and

02:00:30.580 understand a mechanistic pathway. And then how does it lead to the convergence of a final common

02:00:34.500 pathway? And so in many ways, Dale's work was helpful to get us started, but we felt that we

02:00:39.520 wanted to do better. Could we do better if we were able to abandon everything that had been done?

02:00:45.020 So exercise, let's go back to the woman at the cocktail party. She wants to exercise. Is there

02:00:49.960 a type of exercise? Do we have any belief that you talked about high intensity training? Do we believe

02:00:54.580 that that's better than sitting on the elliptical for 30 minutes or going for a run or lifting weights?

02:00:58.840 Here I go again, not one size fits all, but know your numbers. What is your body fat? What is your

02:01:03.620 muscle mass? Men, body fat is less important. Potentially muscle mass is probably more

02:01:07.700 protective on brain health. Women, body fat is. Why do we think that is? A smart people smarter

02:01:11.600 than me have told me this mechanistically. What is it? Glucose disposal. Is it other circulating

02:01:16.340 factors? IGF seems to be somewhat protective. That's not path over my pay grade or whatever that's

02:01:21.780 saying is. Yeah, I don't, I'm not a hundred percent sure, but I can tell you that mixing it up is

02:01:26.500 important. The vast majority of evidence out there is aerobic exercise, minimum of 150 to 180 minutes a

02:01:33.440 week, for example, and that's mixing it up. Most people would say based on the preponderance of

02:01:38.320 evidence, two thirds cardio, one third strength training, but someone's going to have to personalize

02:01:43.220 it based on themselves. You know, for me, I spun this morning, I do spin class. I was never a spin

02:01:48.280 person like, and this is not, I don't want to get, I go to flywheel. I love flywheel and peloton. Why do

02:01:53.380 I like those two? Because I know my numbers. I can see my, it's actually competitive because I can,

02:01:57.400 I can race against people in the class, but it tells me what my torque is, what my average output is.

02:02:02.120 And that way I can know, I can see, well, what is my pulse? What is my strain?

02:02:06.180 So just to be clear, when you talk about, I think anybody can dog it, but if you're doing a peloton

02:02:10.140 class, right, you're working up a sweat. I mean, it's, it's a very different experience than I'm

02:02:15.460 going to go on the elliptical and watch the news while I'm raising my pulse from 80 to 90. That

02:02:22.060 doesn't seem to count as exercise. Oh no. And it's like, and I talked about the patients all the time.

02:02:26.480 They say, Oh, I go to the elliptical three times a week. I do 45 minutes. I'm like, really? Well,

02:02:30.380 yeah, that's great. I don't mind it. I talk to my friends. I text them. I do that. I watch TV

02:02:35.400 in my spin class. I can't talk. I can grunt. That's about it. I can grunt. And then I am a

02:02:41.900 absolute mess. And I, and the amount of, you know, my average pulse rate during a class is over one

02:02:47.800 50, you know, one 55 ish, sometimes higher, sometimes lower. And my max is going to be say one

02:02:53.120 80, you know, give or take, I know these numbers. So high intensity interval training is important,

02:02:57.360 but you got to be careful because if you do too much, you're going to burn muscle. So I have to

02:03:01.400 hurt yourself. Yep. Exactly. And you know, I started off very low weight and I was getting back into

02:03:05.800 exercise several years ago. And I, um, you know, now I'm at higher weights, but I do weights at least

02:03:10.600 once a week. I hate weight training, but I should probably do it twice a week. I probably, I only do

02:03:14.100 it on average once, maybe once and a half. You definitely need to be doing it two or three times.

02:03:17.440 Hey, it's a big, it's a big problem. I completely understand you and my primary care doctor who was

02:03:22.360 like a clone of you and son in a different way. If you want no other proof point, just look at

02:03:27.440 Oliver Sacks. Do you know like what a beast that guy was? There was like a power lifting champion in

02:03:33.260 medical school and residency. When he passed away, there were some really, really remarkable

02:03:38.600 tributes to this man who not only is, I didn't have the luxury of knowing him. Did you?

02:03:43.260 He lectured at a seminar. I talked to him for about 10 seconds.

02:03:45.700 Oh, wow. Yeah. I had, I'd never had the luxury of knowing this remarkable human being, but I was

02:03:51.000 amazed after his passing to learn so much about him that I didn't know. Cause you know, you always

02:03:56.040 saw him and he looked like a fit, strong guy in photos as an older guy, but then to see pictures

02:04:00.100 of this guy in his twenties and thirties, I was like, my God, neurologist power lifter.

02:04:05.180 You're the neurologist DJ. He can be the neurologist power. Indeed. So muscle strength.

02:04:10.860 So she's loosening her grip on the glass. Now you've actually given her that,

02:04:14.360 that leads to my next question. Should she be drinking alcohol or more to the point? Should

02:04:19.000 she think about moderating her alcohol? So alcohol wouldn't go in my top five because

02:04:23.720 there's a lot of other stuff. Meaning moderation of alcohol would not be on your top five?

02:04:27.140 Not in like my five, like most important things. You know, Niefsee and Collins in 2011 or so came

02:04:33.060 out with a paper that basically said one to two drinks a day in men and one drink a day in women

02:04:37.080 is probably protective. Then you have all these new UK studies that show actually, if you do zero,

02:04:42.020 that's better. So there's the data is a little bit all over the place. I kind of hedge my bets and

02:04:46.660 I say women four drinks a week, men seven to 10 and other people that are really smart that I work

02:04:52.800 with says less. I'm sorry. Is the distinction you make in women to be lower because the risk is higher

02:04:58.080 or do you think it's related more to body mass or muscle mass? The latter body mass, muscle mass,

02:05:02.560 and the data and the data with the data shows. I'm not sure. I find those data kind of suspect.

02:05:07.260 I think there's so much healthy user bias in those data that I, but again, I think one also has to

02:05:13.080 balance, you know, I sort of think of alcohol. Like I think of Tylenol. There is no dose of Tylenol

02:05:18.760 that isn't taxing your liver, right? So if you are asking the question as a hepatocyte, the smallest

02:05:25.260 cell within a liver, how much Tylenol is too much? It's like any amount becomes too much. Any amount

02:05:33.480 becomes taxing. So the question is, if you take a hepatocentric view of Tylenol, you should never,

02:05:39.060 ever, ever consume it. But the reality of it is we're not just walking livers. We're walking people.

02:05:44.100 And sometimes we have fevers and sometimes we have pain and things for which Tylenol is a remarkable

02:05:49.200 drug. So we have to balance that. And so similarly, I would say alcohol is a known hepatotoxin. There is

02:05:54.700 no dose of ethanol that isn't on some level chronically toxic to the liver. The question is,

02:05:59.940 we're not walking livers. Therefore, are there benefits of alcohol that may, in the early stages

02:06:05.540 of administration, offset some of the downside? And I think the answer for some people probably

02:06:10.800 is yes. I mean, I have patients who, if they don't sit there and sip their cognac at night,

02:06:16.580 it's very difficult for them to unwind. And while I could sit there and lecture them about how they

02:06:20.140 need to pick a different unwinding practice, in the end, if you can monitor a bunch of things,

02:06:25.460 you know, you sort of take the view that says, look, it's, there's no measurable harm that's

02:06:29.880 being done by this. Your liver function tests are incredibly low. Your coagulation factors are low.

02:06:35.260 It's not producing other adverse harm. Maybe there's benefit, but it'll be interesting to see

02:06:39.180 how that story shakes out in Alzheimer's disease, because you could certainly come up with plausible

02:06:43.700 hypothesis on either side of that. Yeah. I have much stronger evidence than other things. So since

02:06:47.600 the evidence is murky, I always hedge my bets, like you say sometimes, and less is more,

02:06:52.940 but I'm not sure a little bit. So where's the, where are the things where you feel stronger?

02:06:56.360 So, so nutrition has to come after exercise, but again, education, know your numbers because

02:07:03.200 nutrition is a close second, probably. I mean, honestly, vascular risk factor modification is

02:07:08.940 probably after exercise. So I should probably put nutrition next, but vascular risk factor modification,

02:07:13.960 cholesterol, diabetes, blood pressure control, the sprint mind study, just if you haven't heard about

02:07:19.780 the study, it's like a major, major, major important study in the field that needs to be

02:07:23.620 on like every, yeah, it's really modified the way I think about blood pressure management.

02:07:27.440 Yeah. I mean, and this was a five-year study. It was the sprint study, which is trying to figure

02:07:31.120 out do people, you know, because lowering blood pressure less than 140 has always been a little bit

02:07:35.860 unclear, like does it improve outcomes? So the study in cardiovascular disease was, and I may be

02:07:40.300 paraphrasing, but does, is 140 is better or is 120 better? It's systolic. And, you know, there's always

02:07:45.380 been this like dogma where, oh, you got to be careful. You can't lower blood pressure too much

02:07:48.660 in someone who's older because then they're going to, over 70, oh, they're going to pass out and

02:07:51.660 they're going to have bad outcomes and fall. So in the sprint mind study, they ended the study early

02:07:55.700 because the outcomes were so much better in the 120s that actually it didn't, there were no side

02:08:01.760 effects either. So they stopped the study early. Well, the sprint mind study then looked at outcomes

02:08:06.200 several years later. Sprint mind study, this is just like a several years in follow-up, like not like 10 or

02:08:11.280 20, just even after a few years. And this intervention was not that long, actually showed

02:08:17.100 a reduction in, in the people that had blood pressure more tightly controlled to a systolic

02:08:23.160 of 120 actually had a reduction in development of MCI, mild cognitive impairment by 19%. Like that is

02:08:32.960 huge. Over how many years? Two years? I think it was like after three and a half ish, four years of

02:08:37.880 treatment of lower. And then they stopped the study at five years or whatever. And then three

02:08:41.680 years later or something like that, I'm mangling it. But long story short, I mean, 19% risk reduction

02:08:47.020 of MCI. And then you add in the exercise and the blueberries and the low carbs and the, this and

02:08:51.680 the precision medicine. I mean, we're talking tangible, like real, real stuff.

02:08:55.900 All right. So let's go to nutrition. Why blueberries?

02:08:58.980 Anthrocyanins. I'm mangling how to pronounce that too. Robert Krikorian, pioneer, I believe in the field of

02:09:04.540 nutrition research and Alzheimer's disease. So the antioxidants you think provide benefit?

02:09:08.700 He would be the person to ask about this, but I know he has a paper that he's been trying to figure

02:09:12.460 out. Is it the blueberry? Is it the anthrocyanin? Is it the whole fruit? Can you just take out the

02:09:16.920 compound? I don't know that I'm a hundred percent sure. I think it may just be the compound. I'm going

02:09:22.400 to... I actually got an email about this in my news. You know, we get those newsletters every day

02:09:25.860 about Alzheimer's disease. And I think they mentioned this in today's newsletter, which was,

02:09:31.280 yeah, just the idea was, could this be one of the more potent antioxidants that could be studied in

02:09:35.900 clinical trials? Because, you know, Dr. Krikorian is looking at, you know, not just blueberry intake,

02:09:40.140 but he's a wild blueberries is a non-wild. And we say, okay, well, what about blueberry powder? Can

02:09:44.540 we just take the blueberry powder? Well, then can we go even deeper? Can we just take the active

02:09:48.120 ingredient? So nutrition research, people say, well, first of all, nutrition research is hard to study,

02:09:54.560 but there's a science to nutrition research. And, you know, just randomizing a hundred people to one

02:09:59.260 diet versus another. People aren't mice. You can't just like make sure that they eat that diet.

02:10:04.180 People go to McDonald's and like do other things that they shouldn't do. So nutrition research is

02:10:08.660 inherently difficult. Wait, McDonald's is bad? McDonald's is... I'm just taking notes here for

02:10:12.220 the girl at the cocktail bar. Right. No, McDonald's is not... My cousin Stacy caught me at McDonald's

02:10:17.760 once and got pictures. It was a problem. But, you know, everything in moderation, everything in

02:10:22.040 moderation. I have had two McFlurries, Oreo McFlurries in the last year. Like once in a while,

02:10:27.540 I'm not judging by the way. I'm just craving one myself. Oh, Oreo McFlurries, man. Like forget it.

02:10:33.520 Anyway, long story. You don't, you don't even have sugar in your house. I had put xylitol in my

02:10:37.400 coffee. Killing me, man. So nutrition would be, you know, lower carbs, good carbs versus bad carbs,

02:10:42.640 green leafy vegetables. So, so, so important. Any role of fasting, any early data on intermittent

02:10:47.280 fasting or caloric restriction? Well, I don't have data in my practice just yet, but we recommend

02:10:51.740 our diploma diet is looking at 12 hours versus 16 hours and the differential effects.

02:10:56.220 Unfortunately, I have looked at that data, not written up, non-published. There's a lot of

02:11:01.740 noise. I think 16 is better five times a week, better than 12. I don't know the 12 works. The

02:11:08.460 error bars in our data are so wide. I think your sample size is too small and there's too much

02:11:12.740 variability at this point. You sent me some of those data a couple of weeks ago. Yeah, I think I did.

02:11:16.380 Yeah. I, that's why we need to take all these different clinics and all these different programs

02:11:19.880 and get a uniform data set. So, so that's a pretty good list. I think you've given her five things.

02:11:23.800 Yeah. And you know, stress reduction is important and you know, whether it's meditation or blah,

02:11:27.540 blah, blah, do whatever you need to do to de-stress deep breaths. Sleep is super important. I'm

02:11:32.060 getting adequate sleep. You don't lose fat and you don't get healthy if you're not sleeping well. And

02:11:36.200 it's the same thing. You age terribly when you're not sleeping well. So there's, there's a lot of

02:11:41.060 components, sleep, stress. So I guess the reciprocal to this question, we're now no longer at the cocktail

02:11:45.520 party, but we're sitting back here at the table. Everything that you described to this woman

02:11:51.200 is quote unquote lifestyle based. Meaning the top five things that you suggested that she would do

02:11:58.660 once she understood her baseline all have to do with modifying how she eats, drinks, exercises,

02:12:03.640 sleeps, and manages stress. What that makes me wonder is when we see the incidence and prevalence

02:12:12.680 of Alzheimer's disease today higher than it was 40 years ago. Well, the, I'm terrible with this. I

02:12:19.120 shouldn't admit this on a recorded podcast, but the rate of Alzheimer's cases actually coming down.

02:12:24.380 The incidence is coming down. Instance coming down, but prevalence is going up because of our aging

02:12:27.520 population. Okay. But the incidence today is still much higher than it was 40 years ago, even though

02:12:31.500 it's less than what it was 10 years ago. And as you said, of course, the prevalence, which is, I think

02:12:35.580 of the prevalence as the integral, right? It's the area under the curve of what you're accumulating is so

02:12:39.060 much higher. Both of these facts taken together suggest there was something triggering

02:12:43.340 environmentally Alzheimer's disease more today than 40 years ago, which is usually a constellation of

02:12:48.260 these lifestyle factors. So do you believe that the difference in prevalence today from the year

02:12:56.400 we were born is what percent a result of the changes in these environmental factors you just

02:13:02.460 mentioned versus what percent an increase in awareness and diagnostic acumen? I've written on this

02:13:07.400 and my answer is, I don't know, but it's some combination of both. It's both. It's both. Yeah. I mean,

02:13:11.960 you know, Alzheimer's is a huge stigma and shame right now. People are coming out of the shadows and

02:13:16.940 talking about it more. And there's like young people that are talking about, you know, Seth

02:13:21.360 Rogan has this charity, Hilarity for Charity, and they're raising money for Alzheimer's education in

02:13:26.540 young people. I mean, they're talking about Alzheimer's in high school students and college

02:13:29.700 students and medical students. I mean, like the conversation is not only like getting better,

02:13:34.220 but you have like people that are speaking up on its behalf and kind of adding a new flavor to it.

02:13:39.080 So there's much less stigma, much more attention to it. Doctors are talking about it. It's not just

02:13:43.900 senility. Oh, that's normal with age. We now have biomarkers. So sure, sure. We have all that,

02:13:48.840 but we, it's, this is definitely lifestyle component to, you know, sitting all day. There's

02:13:54.180 like sitting as a new smoking. I think, you know, that I've heard whatever about that. That's like

02:13:58.640 really bad for the brain. It's not just bad for the, the bigger the belly as the belly gets larger,

02:14:02.600 the memory center in the brain, the hippocampus gets smaller. So, you know, metabolic conditions and

02:14:08.960 lack of activity and sedentary lifestyles. Like it doesn't just affect the belly and the body. It

02:14:14.360 affects the brain because they're all connected. So that reminds me of another question that I have,

02:14:19.820 which is how much does mental activity ward this off? You know, we hear so often the anecdote of

02:14:27.780 Bernie was working his little tail away, beavering away. And then when he retired to play golf,

02:14:33.280 it all went to hell in a handbasket. And then the other one you often hear anecdotally is

02:14:37.960 once so-and-so's spouse passed away, oh my God, the remaining spouse just regressed completely and

02:14:45.600 seemed to have this accelerated case of Alzheimer's invention. So the, the idea here being once that

02:14:50.260 person retired and they weren't cognitively engaged and they were not to say golf is cognitively

02:14:55.380 bankrupt, but presumably it's less cognitively engaging than whatever that person was doing

02:14:59.040 before. Or once the sense of purpose, the social support vanishes again, anecdotally, this seems

02:15:05.440 overwhelmingly the case. Is there any data to support that? So yes, but it's complicated.

02:15:13.780 The cognitive reserve. Can't one thing just be freaking simple. No, Alzheimer's prevention. No,

02:15:18.980 no, man. This is, this is, you sound like me, man. Yeah. Everything's complicated. Everything's

02:15:22.980 complicated. I wish I could give you a concise bullet point state, you know, like I'm a bumper sticker.

02:15:27.060 Yeah. Live TV. You got to give them like a quick snapshot, not on this topic. So

02:15:31.520 early life risk factors for Alzheimer's are different than midlife and late life and early

02:15:37.380 life risk can be mitigated most so by long-term educational attainment. That's the best evidence

02:15:44.880 we have. We also have to be clear, has that been normalized for socioeconomic status? It strikes me

02:15:50.540 as almost impossible to normalize that for socioeconomic status above my pay grade. Don't know the

02:15:55.880 literature as well as I mean. The point here being like people who go on to get secondary

02:16:00.360 and tertiary education are going to have lower risk. Is it because of the things that enable

02:16:06.460 them to do that, perhaps having more resources lead to them doing other healthy lifestyle things

02:16:12.720 that go beyond the education? I hope the studies have controlled for that, but I know it's impossible

02:16:17.580 to control for everything. But that being said, I think early life educational attainment,

02:16:20.980 for example, musical experience, midlife and midlife musical experience, as well as early

02:16:25.700 life, absolutely can give build up greater cognitive reserves that when you get Alzheimer's,

02:16:29.840 you're more resilient. You have this resiliency. The other aspect is, and I don't know enough

02:16:33.920 about music, but when you were the cello playing to bass guitar playing guy, what part of the brain

02:16:40.360 is getting exercise when you do that? It's very multimodal. It's the parietal lobe is the music side,

02:16:45.180 maybe on the right side. The reading music notes is kind of like language. So it'd be the left

02:16:49.980 side of the brain and that's visual. It's basically an association courtesy is basically

02:16:54.680 the whole brain is talking to each other. So I think music is a great way to recruit different

02:16:59.760 parts of the brain to work together. And the stronger those pathways get, the better the person

02:17:03.440 does. And again, teleologically, that makes so much sense. I guess it begs the question. I would argue

02:17:09.380 we will never know the answer to this question because if we're going to have to rely on very loose

02:17:14.380 epidemiology, which can never be fully controlled and suffers from all of the usual problems that

02:17:19.620 epidemiology suffers from, the question ought to be, is there any harm in believing that the

02:17:25.960 epidemiology is right? Attaining a higher level of education, staying more mentally engaged,

02:17:30.600 sustaining more loving social supporting relationships, having a greater sense of

02:17:34.260 purpose, learning to play a musical instrument. I mean, is there a chance that doing those things

02:17:37.540 increases your risk?

02:17:38.540 Well, I don't think that there's been any evidence to suggest that it increases risk,

02:17:41.860 but then there's this whole, you know, the naysayers will say, well, what is the cost?

02:17:45.940 What are the trade-offs? What's the opportunity cost? What's also the, how much does it cost?

02:17:49.760 Like music lessons, you're going to pay money to do music lessons or buy a guitar, but shouldn't

02:17:54.220 you be like buying healthy food? So there's a lot of confusion. And there's, when we get reviewers

02:17:58.860 of our papers, this comes up all the time. So I'm not sure. All I can say is when you build a better

02:18:04.380 backup pathway in the brain and you, there's a saying, if you don't use it, you lose it. Well,

02:18:10.280 someone that has Alzheimer's and is very cognitively engaged and has a good backup pathway,

02:18:14.020 they're not going to decline as quickly. That being said, once the disease takes hold and maybe

02:18:19.040 they stop working or they stop, they lose their sense of purpose, you can have a much more sharper

02:18:23.300 decline. So people with high cognitive reserve, high cognitive backup systems are resistant to

02:18:28.080 the effects of the amyloid, but there's a time that comes when they decline and those people decline

02:18:33.580 much more sharply than others because they had like this emergency backup system. But sometimes when

02:18:39.080 the parachute fails, the person goes down and in Alzheimer's disease, that's a subtle,

02:18:43.960 that's a nuance I wouldn't have predicted. It makes sense. The mechanism that you postulate makes

02:18:48.920 sense. And you gave the other example of the woman whose husband passed away and then she just went

02:18:54.680 downhill because when you have a collaborative relationship and you know, when one person's

02:18:58.600 brain isn't working well, but you have another person to cover for you and do the dishes and feed you.

02:19:02.640 And then that person has gone aside from depression, serotonin and you have all that. Oh, I see this

02:19:08.460 all the time. Like I knew she had it, but then the husband and you know, caregivers of Alzheimer's

02:19:13.700 patients have terribly higher medical illnesses. And when, when the husband dies and he was the

02:19:20.560 primary caregiver and the wife has Alzheimer's, that person will decline absolutely exponentially.

02:19:25.840 I saw this in a high school teacher of mine. I mean, I see this all the time.

02:19:29.320 You know, Richard, your passion for this is palpable. And I mean, I feel like we could talk a lot more

02:19:33.940 about other things, including, I think some of the stories of your patients are some of the most

02:19:38.440 remarkable stories, both the successes and the failures. Truthfully, the failures are what keep

02:19:44.380 you doing what you're doing. And you are probably the hardest working neurologist. What's the, the

02:19:49.440 expression, the hardest working man show business, you are the hardest working neurologist and show

02:19:54.160 business. I know you personally, so I can say this from a, you know, from a close perspective.

02:19:59.320 Your drive to help patients is a beautiful thing. And I know that the patients that you get to work

02:20:04.280 with directly are blessed. And more importantly, I think your work will have a tremendous impact on

02:20:09.840 people that you will not have the luxury or privilege of laying hands on because there's only one

02:20:14.400 Richard, but there are lots of neurologists like you who I think want to be able to do more. And I

02:20:19.480 think it's really special that you have built the team around you that you have that I didn't actually

02:20:24.280 know the story about the Dean of the medical center at Cornell, taking this big chance on you.

02:20:27.920 I mean, I knew it was obscure to have an Alzheimer's prevention clinic. Of course,

02:20:31.500 you now have the largest Alzheimer's prevention clinic in the United States.

02:20:35.300 It's a really heartwarming story to know that a big name medical center would take a risk on a young

02:20:41.840 up and coming neurologist and sort of give him the keys to that kingdom. And I hope that if one person

02:20:48.500 listening to this is sort of thinking, you know what, that's the way I want to deploy my philanthropic

02:20:53.740 dollars in Alzheimer's disease, maybe I'll hedge on the side of prevention. Hopefully this discussion

02:20:58.720 will have been worth it for you. Yeah. And I appreciate that. You know, I never asked for a

02:21:01.940 single dollar until the bottom dropped out about a year ago. And, you know, you, Peter helped and

02:21:05.460 I've never asked for money. I've never asked for a single dollar. It's the worst feeling in the world.

02:21:08.920 Oh man. But it's like so little can go so far. You know, I sent you on the way over here,

02:21:17.060 an abstract, like the hot off the press. Literally we finished it at 4 32 PM and I forwarded to you and

02:21:22.140 I got here at five and I forwarded this to you. And like, you read the final statement and you know,

02:21:26.480 this hasn't been published yet. So I can't exactly read it out loud or whatever. And you read that

02:21:30.340 statement and you're like, Whoa, if this is the abstract and if I'm about to read this paper and

02:21:34.120 this paper holds water, this statement, wow, we're so close and you know, we're every day we're

02:21:42.440 moving closer. But that being said, we have thousands of pages of already collected data

02:21:46.720 that we can't really jump into. So I appreciate your call to action. And I can tell you that our,

02:21:51.540 our philanthropic funds that have come in, we use immediately. And yeah, the ROI on those dollars

02:21:56.540 is remarkable. You know, there are a lot of people who say, look, I mean, maybe I can only part with

02:22:01.060 $25,000, $50,000, which in New York philanthropic cervicals is nothing, right? You don't get your

02:22:05.900 name on a bench for that much. What a difference it can make in your clinic.

02:22:10.200 Oh, several thousand dollars is helpful, but yeah, 50, 25, a hundred. I mean, I could just do so much

02:22:15.600 tomorrow, but I'm not asking for money because that's just not how I was raised.

02:22:18.880 Yeah. Yeah. No, screw it. I'm asking for money for you. Well, with that said, Indian or

02:22:24.980 Persian or Turkish tonight for dinner. Ooh. Um, there's a neurology resident happy hour that I

02:22:32.120 may need to stop by for a second. So maybe somewhere near there. Okay. Okay. Figure it

02:22:35.940 out. That's like a few blocks away, but yeah, I'm a, I prefer food with no taste. So, and I don't do

02:22:42.080 onions, garlic, shallots, scallions. Oh, for heaven's sake. I don't do alliums. I'm going to go

02:22:45.960 have dinner by myself. I also don't do cilantro, but no, no, no. But I like, I like plain Jane. We'll,

02:22:51.060 we'll find something to talk about glucose and metabolism. Very well. All right. Thanks so much,

02:22:55.500 Richard. Thanks, Peter. Appreciate it. You can find all of this information and more at

02:23:01.020 peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to

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02:23:18.240 is to sign up for my subjectively non-lame once a week email, where I'll update you on what I've

02:23:22.820 been up to, the most interesting papers I've read, and all things related to longevity, science,

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The Peter Attia Drive - October 01, 2018

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

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