Become an Alzheimer’s Survivor: Dr. Richard Isaacson’s Breakthrough Approach

23:42We check cholesterol. Cholesterol is a risk factor for heart disease. It doesn't necessarily cause heart disease. There's other blood biomarkers. We tested function that are also very big risk factors like lipoprotein, little a, which is genetic. So you can actually map a person's trajectory by knowing their biomarkers. We do the same thing for metabolic health. We can measure glucose or insulin or A1C and see the trajectory of it going up before they get diabetes. So there's a proxy for this in medicine. But with dementia, we don't really do that. And what's really remarkable about your work is that you're not just doing neurocognitive assessments.

24:16You're not just measuring normal things like omega-3 fats or vitamin D or blood sugar or cholesterol or blood pressure, which are all important and have to be managed if you're going to reduce risk. But you're finding that these particular blood biomarkers, you're doing new tests that are from protein signatures expressed in people early, decades and decades before they even forget their keys for the first time. I'd love you to sort of break down some of the things that we're looking at now that are blood biomarkers. And at Function Health, we basically have a blood biomarker panel that helps identify that risk, including APOE4 testing and APOE testing, which is a gene for risk for Alzheimer's.

24:56Looking at PTAO217, which is another marker, AD4240, which is amyloid biomarkers. But you're going way deeper than that. Yeah. So, you know, when it comes to blood testing for Alzheimer's, and by the way, five years ago, whenever we last spoke on the podcast, like never in a million years, whether it was two years, five years ago, 10 years ago, 20. years. Never in a million years did I would have ever pictured myself having a lab in Boca Raton, Florida, developing. Well, there's a lot of Alzheimer's disease. That's what they call it. And it should be called something else. Joke Bruce Ames, who's a very famous scientist said on epidemiology, which is population studies.

25:33He says, if you did a study of a population in Miami, everybody be born hispanic and die jewish i can i can say that that's true from the evidence i've seen we had to create a lab we had to go deep on the blood tests like i i'm not a basic science guy like i never like centrifuging blood and and developing at-home testing using different devices and you know develop starting with a panel of say a thousand and now coming we're we're down hey hey, we're down to 150 tests and we're getting it down. And my goal and our goal at IND and elsewhere, we are trying to develop what will one day be termed the cholesterol test for the brain.

26:16And if we're talking baseball analogies, we're still in the first inning, in my opinion, of a nine-inning baseball game where the tests we use now, I think, are good in certain ways and I think can be helpful. For example, if a person has symptoms and the doctor and the person with symptoms is wondering, are those symptoms from Alzheimer's disease? Then yeah, there's this P-Tau-217 test is a very good test. It's not a perfect test, but it's a good test. But we're just taking things with a very different lens and we're looking at people ages 21 and up to understand what the signature of proteins should be.

26:58What is the normal values of these proteins? Because when you start doing a regular cholesterol test to prevent a heart attack or stroke, and you start doing those tests in people's, say, 60 or 70 and above, that's oftentimes, a lot of times, too late. The cholesterol test for the brain, I envision a day where people are going to come to the office, and I hope that our work will help inform this, but people in their 20s and 30s and 40s and 50s and 60s and 70s and beyond, before they have symptoms, will get this panel of tests and we're just starting to like, I think the, the, we were in the black and white television phase.

27:33I think we're, we're now in the color television phase where I can kind of see what the five to seven, maybe 10 markers will be. And we can track these tests and we can do it in a way that we can, um, you know, lower cost, improve, increase access, and then give people digital tools to like help interpret it and give that person care. So what we, what we believe is that we need to look earlier and we need to look more deeply and we need to look at other markers. And And then the other problem is that some of these markers that may be positive, uh-oh, got a positive Alzheimer's blood test. What if the person had a virus that morning?

28:05What if the person got a blood draw in the afternoon rather than the morning? You know, these are things, and what is a normal value for someone in their 20s or 30s versus someone in their 40s or 50s versus someone in their 60s or 60s? Like what are the reference ranges? The reference ranges. And, you know, most of the research that's been done are people with dementia, people age 55 or 60 and above, and we need to start earlier. So the focus of our research is to figure out what is this cholesterol test for the brain going to be. And these tests, we're going to want to talk a little bit about them in detail.

28:38The way I think about them is they're kind of early warning signs. They're not necessarily the cause, but they're the things we can look at that are resulting from causes that drive those biomarkers to be abnormal. Yes. To me, the word is biomarker. It's a biomarker. It's a marker of a biological condition or disease. Amyloid to me does not cause Alzheimer's disease. I've just never felt that way. Why are there people without amyloid that have a clinical meaning like, you know, talk to the patient, looks like they have Alzheimer's. They don't have amyloid. Oh, I wonder, well, I guess amyloid didn't cause Alzheimer's in that person.

29:15But by definition, you have to have amyloid to have Alzheimer's. Like our instruction manuals are like totally wrong. I mean, Rudy Tansy, who's a friend of OrthoAIR, is an amazing guy who's an Alzheimer's researcher. We just said amazing guy like in unison. So I hope he hears that. And he's a deadhead. So like - He's a cool dude. And he discovered Nobel Prize quality science on the very unique early Alzheimer's genes through lucid dreaming, if that tells you anything about the guy. He said that there are patients who have brains full of amyloid, but die old, cognitively intact, meaning normal.

29:50And he said, what's unique about these people, and I'll look at your perspective, is that they have certain genetic variations in their immune system that don't mount an inflammatory response. So as far as I understand the literature, Alzheimer's, the end result, is the end result of an inflammatory process in the brain. And there are many things that can cause inflammation, from infections to toxins, to diet, to prediabetes or diabetes, to a mold, to Lyme disease. I mean, Chris Christopherson had, quote, dementia and Alzheimer's, but Trani had Lyme disease, and he got treated with antibiotics, and his dementia went away.

30:27So I think we have to think more about what the underlying pathology is, which is inflammation, and then why is there inflammation, and then hunt down the sources and the causes of inflammation and remove those. And I might believe lower these blood biomarkers that are around. Even a few years ago, they weren't really available. These things like P-tau-217 or amyloid biomarkers like AB4240, other P-taus like 181, 231, neurofilament, light chain, which is more for brain damage, or something called glial fibrillary acidic protein or GFAP, beta-synuclein, which you're actually developing the test for.

31:06So there's all these novel biomarkers that are going to be available clinically and probably in the not too distant future where you can go get a blood test and you can say gee you know where are my levels you know it's like is my blood sugar high is my cholesterol high is my blood pressure high and those are risk factors and then these that tell you that you need to do something and the question is how do you figure out what to do in each individual if you're treating everybody as an NM1 or as a precision medicine or personalized medicine what's the actual clinical workup what are you looking for and then how do you identify the targets and what are you doing for those targets that you find?

31:41The way that I do it in my, in our research program and clinical practice, what I would call it the A, B, C, D, and E of Alzheimer's and neurodegenerative disease prevention. Okay. A, B, C, D, and E. And then when someone can't access a doctor or can't get into a research trial, we have, you know, five sites in the U S and in the United States and Canada. And if you can't access one of those sites, and if you can't see a preventive neurologist, then we do it through software. And I'll explain how that is. And We got funded by the National Institutes of Health. We conducted a very large, almost 1 ,000-person NIH-funded randomized controlled trial that showed that free software online, you go into the website, retainyourbrain.com.

32:20It's all free. Retainyourbrain.com. Retainyourbrain.com. If there is anyone out there with a brain that wants to like— Wait, I have a brain, I think. I think you do. You definitely have a brain. You have a very robust brain. It's functioning, checkmark, neurologist approved. I'm going to give the Cliff Notes version and the ABCs and these. But if there's anyone out there, like we just spent six years developing. And this was before AI was cool. We just developed. We put my brain, you know, a virtual neurologist in your pocket and retainyourbrain.com. It's available by web, tablet, cell phone, whatever.

32:52It's all free. And you can get access to this type of education and, you know, does a risk assessment. You can do cognitive games, feel like games, whatever. And then the software will tell you what to do. It's mostly based on your history. You're not necessarily doing blood work or baby steps. Yeah. In time, in time. But, but right now it's, it's, it's all, it's all inaccessible and there's, you know, no cost. And, and, you know, doing the blood tests would just add another layer of that. That's amazing. But right now, clinically, that's what we do. And from a research perspective, we do use the blood test for sure.

33:21So, so the retain your brain, which is what we all want to do is retain our brain.com is a platform that you develop that basically has downloaded your thinking into a system that allows you to assess people, identify their individual issues, then make specific personalized recommendations that they can implement, even without a whole bunch of diagnostics. And it's free. So everybody should go check that out and do it. And if you have a family history of any of these neurodegenerative diseases or you're worried about getting it, get on it. And it's free. Now, what I'm talking about is when someone comes into your office or you're part of this 250 % research study, how deep do you go?

33:57What are you looking at? What are you testing? Oh, we go really deep. Yeah. Tell us what you're, because I think this is important because people don't know what to look for. And I think there may be many physicians listening to this podcast. Hopefully there's some philanthropists who have family members with these diseases who are gonna listen to this and go, wait a minute. This is a place where I can make a huge impact that is being neglected by the outdated medical research establishment and the antiquated thinking about a reductionist model disease and the fear of doing too many things at once in a patient.

34:32I think that's the joke is like you have to treat everything, right? If you have low vitamin D or low omega-3s or you have prediabetes or you have heavy metals or you have mold or whatever you're finding or you have high cholesterol, you've got to treat all those things. You can't just treat one thing, but that's what we do in traditional medicine. the a b c d and e of alzheimer's and neurodegenerative disease risk factor risk reduction prevention management is a paradigm that we published on it nature mental health on january 2024 was the last time we kind of updated the paradigm and it's all again doctors out there listening any health care providers you can read the paper but the a is simple it's anthropometrics so what does a stand for anthropometrics is body composition body fat muscle mass.

35:18I also kind of throw bone density in there. Bone density, grip strength, also an important proxy. And why is that important? As you go through this, I'm going to kind of have you go through and explain why it's important. Yeah, sure. And by the way, I'm going to talk about things and people are going to be like, wait, what is this guy? He's a neurologist. Why isn't he talking about neurology? Why is he talking about belly fat? Yeah. So I believe, and you wrote a paper on this, I think back in 2007 about how our brain disease is really like body disease. And I'm paraphrasing. I don't remember what the title was.

35:43Is it a disease of the brain or a body disorder that affects the brain? So I believe Alzheimer's and, and, and I mean, this is going to sound like heresy, but I believe neurodegenerative disease many times or most times, those are big statements, are medical conditions that have secondary negative effects on the brain. So just like when a person has diabetes, the sign of end organ damage is kidney failure or tingling and numbness in the toes or something called macular degeneration where people lose vision, you know, because of diabetes. I believe medical conditions, the neck and below things, affect the brain.

36:21That's a heresy because most neurologists stop looking at anything below the neck. Yeah. And I'm like, I'm an old time family doctor. Like I'm an intro, you know, I, I, I feel like I practice a one third internal medicine, one third, uh, preventive cardiology and one third, you know, preventive neurology, which is a field that, you know, you just barely exist. So, so what I'm going to talk about now is going to be very medical. So, and I'm glad I'm with you because you can, you can translate it. So, so a anthropometrics, uh, again, but it's a fancy, uh, long term. And I couldn't use B cause body composition is the next letter, but everyone needs to know their numbers.

36:55belly fat, especially as the belly size gets larger, the memory center in the brain gets smaller. Women that have increased waist circumference, okay, visceral fat, meaning fat around their body organs, women are at a 39 % higher risk of dementia. Wow. That have fat around their visceral organs and belly fat. And you know what happens to women during the perimenopause transition? It gets really, really, really hard to lose belly fat. And there are things that we can do to change that. So we track all these things And we use belly fat, muscle mass, you know, people lose 1 % of muscle mass per year.

37:30I mean, like, like people like muscle mass is not easy to build and, and doctors don't focus on like, why are people talking about weight? Like stop talking about weight, body composition, talk about body composition. Everyone needs these scales. Okay. They're a couple hundred dollars, but you know, everyone needs to know their body fat. We want to lose fat. We want to gain muscle. We want to put on muscle. We want to lose body fat. A lot of people take these, you know, weight loss drugs. Okay. They have some really interesting features. that maybe too high a dose. We'll talk about - Like the GLP-1 drugs.

37:57Yeah, the GLP-1 drugs. But we shouldn't be tracking weight. I don't want to hear about someone's weight. I want to hear about body fat, body composition, and muscle and bone density, which is really critical. So the A, all of these things in anthropometrics are brain markers. So we track those. The B - So measuring your belly fat is a brain marker is what you're saying. 100%. Yeah, muscle mass and belly fat, absolutely critical risk factors to prevent cognitive decline, dementia, Lewy body dementia, Parkinson's. These are all metabolic factors that actually do influence these diseases. They're all connected.

38:33They're all connected. So what's B? B is blood-based biomarkers. And what do I mean by blood-based biomarkers? I don't just mean the brain markers. I mean cholesterol markers. I mean inflammatory markers, markers of inflammation, nutritional markers, metabolic markers, and then a bunch of hormones. Metabolic markers meaning like, looking at blood sugar and so so fasting blood sugar fasting insulin um you know there's a lot of us may have heard of something called a hemoglobin a1c or glycosylated hemoglobin or hba1c and you know people say oh above 5.7 is pre-diabetes and 6.5 or whatever is diabetes m metabolism memory if you want to have memory decline don't mind your metabolic risk factors Like metabolism and memory is so critical.

39:22And because they even call Alzheimer's type three diabetes, right? Alzheimer's diabetes of the brain. Yep. And there's a lot, a lot of overlap with, with the, with the, with the pathophysiology, which is a big word for, you know, potentially why these disease happen and, and metabolic health. Um, you know, if you want to fast forward cognitive decline, we don't want to do that. You know, high cholesterol, high blood sugar, high blood pressure. These are all things that can, you know, fast forward, uh, cognitive decline. And also cholesterol is really complicated. I'm not sure how much time we have to dive into this, but like there's good cholesterol, there's bad cholesterol, like HDL.

39:55That's the good stuff, right? Well, maybe not. It's a little confusing. There's a lot of confusing stuff with cholesterol. all and and it is and it's unfortunately richard most doctors even cardiologists don't fully assess cardiovascular i literally just got an email from a friend of mine who's a doctor at mass general's an internist who's very well educated on the top of his field harvard at harvard yeah his wife did function health and found she had a lipoprotein a of 500 which is and no one's ever checked she said no one's ever he's like her doctor wouldn't check it i wouldn't check it And now we did a full cardiac workup.

40:31We can actually manage our risk and look differently at our health. And at Function Health, we do these very deep biomarkers for cardiovascular risk that are far just beyond our regular cholesterol panel, including ApoB, which never gets checked, lipoprotein A, particle size. We look at function of HDL. You said HDL's not all the same. Some good, the good isn't just all good and the bad isn't all just bad. It's kind of a false framework. And so we're able to look at the nuances of what's happening. And we look at insulin, which again, is never tested. So a lot of things you're talking about are things that now people can access for a very low cost.

41:01And the accessibility is critical. And, you know, in 2007 was the first time that I ever had these markers checked in me. And that's like almost 20 years ago. And I got my first calcium score 20 years ago. Thank you, Dr. Agattson. He was one of my old mentors. Like, I mean, I got thrown into this because I had mentors and people that thought differently, thought in a contrarian way. You know, Dr. Agattson, for example, the calcium score, I think he invented that in like, i don't know 89 90 and it became part of the guidelines the physician you know consensus guidelines in 2018 it took 30 years to make you know the guidelines that like you know okay if you have high cholesterol maybe we should look at the heart to see if there's you know plaque and you know because by the way you can have like just the way you can have amyloid but no alzheimer's you can have extremely abnormal cholesterol and clean arteries and i have patients like that i'm I'm like, wow, your LPA is high.

41:52Your ApoB is high. Your particle number is high. Your particle size is small. Clean as a whistle. Yeah, clean as a whistle. And that's the thing. And this is precision medicine and personalized care. So anyway, we look at all these markers, and we look at ApoB. We look at LP little a. We look at LDL. We look at particle size. I mean, if you have to choose one, like I choose ApoB as a good proxy. We always check LP little a. We look at markers of absorption. is someone, you know, if someone has high cholesterol, instead of just throwing them on a drug that, you know, um, you know, in the grand scheme of things may work for 70 or 80 % of the population.

42:26What if you're in that 20 or 30 % where you're not the right person? And I think you and I, uh, whatever we may be, I have a different version of, of my cholesterol is not high. It's just borderline, but I'm an over absorber of the cholesterol that I eat in my food, in my stomach. I don't overproduce cholesterol. also. I don't need a drug that would stop, a statin drug. That's not the right drug for me. Generic drug calls it azetimibe. It's a plant sterile inhibitor. That's the right drug for me because I've had that checked since 2007. And right now I'm able to control it without a drug. But if I need a drug one day, that's the one I would choose.

42:58It's basically also called azetimibe. It's interesting because I have genetics and I've done my cardiovascular genetics and I have a very strong family history of heart disease and I'm a hyper absorber. And when I actually started taking this drug, it was like I dropped like a stone. Because you had the right drug for you. And it's not that cholesterol is eating from eggs. It's the cholesterol that's produced by your liver and bile. It's excreted in your bile. It gets reabsorbed that you kind of have to manage. For people that are listening, you may say, oh my, what is it? Like, how do I get these tests?

43:32Like, it will be available. All this stuff, and some of this is available now. All this, what we talked about just now, always all the L3 function health for$499. And there's add-ons for cardiovascular. You also are going deeper on blood bond markers. I want to stay on the B because, because you are looking at additional things that we offer as add-ons like a function, but P-tau and amyloid and ApoE and neuroflaminate light chain, other things, but you're going even deeper into these, the stuff we're doing, like, you know, we're, we're developing blood tests like that. That's our goal. And some of these tests are like not anywhere on the market yet.

44:03And there'll be, at least two years before. I believe that we have a potential test that if someone is worried about taking a statin, for example, and they want to know, are they the person that probably shouldn't take a statin because it may or may not hurt X, Y, or Z, we're working on a blood test to figure that out. By the way, I can't believe I'm saying this. This is not me. I'm not like that guy. I'm a clinical guy, but I had to do this because no one else is going to do it. And for some patients with dementia, taking a statin might be a bad thing. Yeah. And you need to track everything and you got to figure out which drug is the right drug for the right person.

44:38And, you know, we're, we're working on this through ind.org, which is our nonprofit. That's the Institute for Neurodegenerative Diseases, right? Yes, yeah, but ind.org, and people can learn about all this stuff, and we have so much education, you know, all for free online. And we're trying to develop these tests, and we're trying to, like, you know, figure this stuff out. And, you know, when it comes to brain markers, I think, again, the markers that are out now are good, and I'm glad they're here. But there is so much nuance and so much confusion. And, you know, my worry is, is that someone may get a test and then it's positive, but it's not really positive because of a variety of reasons.

45:14So like the take home here is what we're doing is we're doing like, for example, ratios where we divide this by divide this. We take this marker, that marker and that marker, and we put it in a formula. And and that is the type of stuff that's not, you know, I wouldn't say it's available yet. It's coming soon. but to me when a person does not have symptoms of cognitive decline and wants to understand their risk i believe that the current tests available are good but we need more we need more higher fidelity i believe that we're if our work keeps moving at the rate it's going within a year or less maybe a year and a half we're just going to be able to ramp up that fidelity to make these blood tests more accurate, more accessible, more meaningful.

45:56And it can help guide us to say when that person changes their exercise routine or changes their diet or starts on a GLP-1 drug because their doctor said they were overweight and they had a little diabetes and they want to, well, then we're going to track these markers and we can then show, is there a ground truth? Is there, you know, and using that person as their end of one control, can treating risk factors for cognitive decline actually impact in a positive way brain biomarkers of disease. And we're getting really close. So between ind.org, allslabs.org is one of the arms that we're investing a lot of money to try to figure this out and develop these blood tests.

46:36And then honestly, once you have access to the testing and you have access. Will you be able to include your lab tests in that if you put that in as data? Yeah. I mean, in time, we're, you know, for people without symptoms, for the panel that we want to deploy. I feel that we're not there just yet, but that's the future. But you could, I mean, you could have them check their blood pressure. You could have them do a body composition. And they do that. Have them check their cholesterol or their insulin. And they type that all in. Or the heavy metals or the vitamin D or whatever. You can add all that data in to retrain your brain now.

47:08Can you do that? Well, so yes. So for example, one of the key things about retain your brain is there's tens of millions of people out there that have a gene called APOE4. So having one, 25 % of the population, 25 % of the people listening today has one or more copies of a gene called ApoE for the four variants. You get one from mom, one from dad, a two, three, or four. You and I have both been tested for this. We know lots of people that have been tested. About 1 % of the population has two copies of E4. And honestly, one of the key drivers of why we created this free automated software is because when someone has an ApoE4 variant, they're scared, right?

47:44And they can type in what their gene, they got tested through 23andMe. It's scary when you find that. It's like, oh, shoot, I don't want to know. I don't want to test it. And doctors say, well, don't test it because there's nothing you can do about it. So don't make sure you don't test it. And that's wrong. That's entirely wrong because if you have an APOE4 variant, I'm going to tell you to do all these different things. And if you don't have an APOE4, I'm going to tell you to do different things. And if you have two copies of the APOE4 variant, which is, again, 1 % of the population, doesn't mean you're going to get Alzheimer's, but you may be at higher risk.

48:10So I'm going to tell you to do these things that our research for the last, you know, 15 years have studied to show may be effective. And then this software, you type in that you have the ApoE4 variant, and it's going to tell you, you know, what you can do to reduce your risk. So it's more personalized. It's more personalized, yeah, to help manage risk factors for Alzheimer's disease. So long story short, there's a bunch of blood tests that are available now that you're already measuring that are easily accessible through your doctor, or, well, they might not order, but then Function Health for$490, dollars and things like your blood sugar insulin you know cholesterol particle size lpa apob all the nutrients omega-3s all that we we can get that now but there's another layer that you're doing that you're developing your lab that are new biomarkers that are specific for uh neurodegenerative diseases that we can measure and then are lowered or changed or improved by doing various interventions that are specific to that person yep so it's not like there's one thing you do to fix saw all that.

49:05It's a whole bunch of things you do. Exactly. And while we are just starting to scratch the surface and we're in the first inning of a nine inning baseball game, the fidelity and the accuracy, I'm telling you in 2026 and 2027, these are going to be amazing years because my belief, my hypothesis right now is that you, Mark, are going to need these five tests to track over time. Me, I'm different. I'm going to need these four tests and a woman, especially during the perimenopause transition, two out of three brains affected by Alzheimer's, these are women's brains, and we got to do something about that.

49:37A woman may need six different blood tests that we follow and we track, and then they make a change, or they take hormone replacement therapy, or they do something, and then those six markers improve, and then we know we're on the right track. So I think we are within maybe 18 months away or less from having this roadmap clear. the holiday season is upon us and between parties family and everything else your body deserves a break sunlightens infrared saunas are the perfect way to give it exactly that their advanced infrared technology heats you gently helping you detox relax sore muscles and even support a healthy immune system imagine taking just 30 minutes to yourself sweating out stress boosting energy and coming out feeling renewed and here's the kicker starting now means you can ride into the new year feeling healthier and more energized than ever.

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51:45and we could go a lot more into the blood oh yeah i think i think there's ones that we're even not looking oh so many metals like tick infections like mold exposure and i i've only talked about kind of some of the traditional ones but like these inflammatory markers that we're looking at and the immune you mentioned dr tansy earlier i mean a third of our markers are focused on the immune system and inflammation like and we're i'm a neurologist right we're supposed to be talking about brain proteins. No, we look at inflammatory markers. We look at cascades. We look at interleukins. We look at CCLs.

52:14We look at TNF-alpha. We look at so many things. And then if someone, oh, interleukins. Those are all blood tests for inflammation. Exactly. Yeah. In our multimodal panel, you know, we have this guy who he has psoriasis and it's mild psoriasis. Okay. It's mild psoriasis. He can deal with it. He doesn't want to take a drug or change his diet or do whatever because it doesn't bother him. It's fine yeah well this guy also has an apo4 variant okay and this guy's 49 years old you're like oh there's inflammation on this person like so wait a minute and i look at the panel and i say but but call him bob bob um hey bud you got an apo4 you got a interleukin 17a which is a inflammatory marker that's elevated in people with psoriasis and bud your amyloids uh higher than it should be for a 49 year old no towel okay check mark okay nothing nothing too worrisome but the train's gonna go off the tracks if you don't do something and then you change your diet this guy also had high cholesterol he wasn't treating started zettia azetamide because he was an over absorber of cholesterol not not a statin he was afraid of statins okay he didn't need a statin anyway uh and omega-3 fatty acids his omega-3 fatty acids were in the toilet and he's like oh i don't really like fish.

53:26I'm like, then take the cap. And sardines. Sardines are albacore and tuna's high in mercury, but like in a wild salmon, at least once a week, but wild salmon has all sorts of stuff in it too. So you take certain supplements that are high quality and everything improved. The interleukins came down. His inflammation came down. His psoriasis gets better. The amyloid comes down. Everything about his everything improves through some mild changes that were personalized for him, right? And that's the key. We could talk about blood biomarkers. I mean, what you're saying just to be honest with you is heresy.

54:00I was literally talking to one of the key funders of Alzheimer's research in the world, and he looked at me straight in the eye and said, there's no way and proof that you can lower these biomarkers of Alzheimer's. It's not been done. It's never been done. You can't grow brain. You can't lower these biomarkers. We're gonna try to find a drug that's gonna fix it. And I'm just thinking to myself, no, actually, I've seen these things change. You've seen these things change. And that's what's so exciting because you can now start to intervene with multiple different approaches and actually start to change those biomarkers that are risk factors for or indicators of damage that's happening at a subclinical pre-symptomatic level, but it's still happening.

54:42It's like the Bogalusa heart study where they looked at fatty streaks in the arteries of teenagers who were eating crappy He died in Louisiana. They were prelude to heart disease that they were going to get in their 30s and 40s. But we could see it in their teens. In May of 2024, there was a CNN documentary that came out and Dr. Sanjay Gupta came down, you know, Sanjay. And he actually joined my research study and it's been really great to get to know him better through that. You know, I've known him for a long time. And this guy named Simon was profiled in this documentary. And documentaries are interesting because, you know, they send a film crew and they get to know people and they see people for years and they get to know them.

55:14and and if that guy that doesn't believe that the stuff that i'm doing and our team is doing is possible he thinks it's it's it's heresy he thinks it's not real well simon was followed for years and we have his brain on the same mri the same magnet the same software we have it in 2022 we have an image in 2024 and we have an image in 2025 and simon is an 8-bouille-4-4 he's got two little kids okay he's in his early 50s now mid 50s got that's 8-bouille-4 is the high risk he's got me so his name and he's been totally public and he's obviously been in the documentary if someone out there is listening to this and doesn't think this is possible like i should call simon right we're going to link to the documentary in the show notes yeah we're going to link to all your studies all your research all your website it's all there it's all there like this there's now you've seen the scientific slides because i sent them to you but the brain volumes grew and then a year later his brain grew again his amyloid and tau at the first at the documentary stage, his amyloid improved and his amyloid actually normalized.

56:14His tau was still a little bit there. It's gone. Everything, amyloid and tau are gone. His symptoms are improved, even though he still is doing great and he had some subjective symptoms. His brain grew twice. This is all real. So just for everybody listening, this doesn't happen, right? Brains don't grow. They just atrophy as you age. That's orthodoxy. And what you're challenging is a paradigm that's so stuck, but you're seeing objective evidence and you're not the only one. I mean, there's others like Del Bredesen and others who's been on the podcast who've shown that you can increase the size of the hippocampus, the memory center of the brain.

56:50You can increase the brain itself and reduce the atrophy. And that leads to changes in cognitive function and improvement in outcomes. We have a saying that we say it a lot, promise not to overpromise. And we're cautious and we want to like undersell just to be extra safe because we need to like really prove that this works. But my gosh, I mean, when you see it once, you're like, wow. When you see it twice, you're like, wow. And now I've seen it so many times. I'm still like, wow. Right. Because I'm in awe. It's a miracle. It's a miracle. Because compared to what we were trained in in medical school, it just doesn't happen.

57:27But I'm still, I try to be conservative about it because if I get too excited about it, people won't believe it. But the story after story after story is there. Take us through some of the kinds of ways and the things that you're finding and the treatments that you're doing that are part of the cocktail of things that are available. Sure. So let me finish on the A, B, C, D, and E first real quick. The C is cognitive testing. And again, a lot of people don't want to do cognitive testing. A lot of people in our research don't want to do it. if someone, you know, wants to, you know, you know, we try to make cognitive activities, we call them cognitive activities at retainyourbrain.com.

58:00You join, you get to know yourself, you can, you know, track or, you know, assess or whatever word you want to use with these cognitive, we call them, you know, activities because they seem less, you know, worrisome, but we do track cognitive function in our ABCD &E model. D is DNA. We do look at some genetics, especially the APOE4 variant, which is super, super, super important to personalized care, not to deduct or deduce, sorry, if you're going to get Alzheimer's, but it does help personalize care. And the E in the ABCD and E is emotional and social support and health and, you know, stress management, staying socially engaged, having a meaningful life, mindfulness-based stress reduction is something that we, you know, advocate for, you know, learning new things.

58:45the e is something we really really really take seriously and we have to focus on the biological the cognitive and the psychosocial in order to get people off the road to neurodegenerative disease. And you're talking about these social connections and relationships and having meaning and purpose and connection and belonging. And it even speaks to how things like hearing loss or visual loss will actually cause people to withdraw from these social connections, which actually accelerates dementia. Yeah, 45 % of cases of dementia may be preventable if that person does everything right. And 45 % to me is a very conservative number.

59:21I think that number is going to be, you know, from a, you know, evidence-based way and the next big study to come out, it's going to be 50 % or 60 % or whatever magic number it's going to be. But the majority of cases, in my opinion, of dementia may be preventable if that person does everything right and we get ahead of things before symptoms. And in that 45 percent, the Lancet 2024 paper, 8 percent of cases of dementia are attributable to the modifiable risk factor of hearing loss. 8 percent. And now whether you have hearing aids, if you can't hear this age 50 and above or whatever word, whatever age you want to use, get a hearing screen.

59:57You don't have to, I mean, you should go to an audiologist and see a doctor, obviously, if you can, but, but you could do this on your headphones. Now you could do it on a computer. You can get a hearing screen and people that have hearing challenges. You know, my mom, I fought with my mom about this, like for, for, for years, like wear a hearing aid. You'll be more engaged. It may help prevent dementia. um you know that's that's that's not a pill um that's not a dietary change it's just have a hearing vision loss um there's so many things that we can do to screen and intervene so so again going back to like what what are the things that you're actually specifically using and how do you kind of customize the treatments and what are the what is a cock what are the cocktail of therapies and what are the what's the what besides the things we've already talked about you know that are so easy to measure, what are the kind of things that we should be testing for and looking for?

1:00:47And what are the kind of interventions that seem to be promising? So, you know, in our 2019 paper where we showed really back then, like for the first time that through multimodal, meaning multiple therapies at once, that we personalized or the title of the paper was individualized clinical management of people at risk for Alzheimer's disease, something like that. when you individualize treatments on average back in our 2019 paper people got 21 different interventions so if there's someone out there listening that wants a magic pill or wants to do one thing or two things um i'm sorry to say but it's it's it's not like one or two things can do this because alzheimer's and neurodegenerative disease they're complicated right any chronic disease of aging right diabetes can you take a magic pill to prevent or cure diabetes no can you eat a magic blueberry.

1:01:37I love blueberries. I think blueberries are great, right? Well, you can't eat a magic blueberry and prevent or cure diabetes or Alzheimer's or whatever. The people that did the best were people that followed greater than 60 % of the recommendations. So if we gave 21 on average, if you followed greater than 60%, people did better. People with mild cognitive impairment, the earliest symptomatic phase of Alzheimer's actually had improvements in cognition, like, again, heresy. It hadn't been shown like that. So this is symptomatic early dimension. Symptomatic. Well, so both. We had two groups. We had the early treatment group and the prevention group.

1:02:07And I think that the take home for people listening is that there are so many things you can do. I'm going to go through those in a second. On average, we gave 21 different things. Ooh, that sounds like a lot. The people that had early cognitive symptoms needed to follow greater than 60 % in order to have an impact on their cognitive function. Benjamin Franklin, right? Announce the preventions where the pounded cure. 100 % agree with that. But the people before they had symptoms, whether they followed greater than 60 % or less than 60 % of the recommendations, they still had cognitive optimization.

1:02:39Their cognition improved at 18 months in our 2019 study. So the earlier you are, the less you have to do to move the needle. The later you are, the more you have to do to move the needle. So that was our 2019 paper. And I think that was really critical. What are those 21 things on average? Well, those are average. In our whole universe of things, we've probably recommended right around 50 different things across all of the, you know, thousand plus people that we've seen. But the two kind of categories that I put it on are in are, I would say, non-pharmacologic and then pharmacologic. And in the non-pharmacological bucket, you know, for example, extra.

1:03:19There's non-drug. Yeah, non-drug. So non-drug, and you know, in the pharmacological bucket, I mean, I guess you could, I don't know where to put the vitamins and supplements because those are like really important and critical, but like wherever you want to put those, exercise on a regular basis is by far the number one thing a person can do to reduce their risk of cognitive decline. um you know if you put mice on a treadmill um their amyloid can go down and most people don't realize like people say oh there's these new anti-amyloid drugs i want an anti-amyloid drug that'll fix me right well they're expensive they have side effects there's a whole thing and i do believe in them in the right person at the right dose for the right duration of time but if someone out there today wants to reduce the amyloid in their blood and in their brain tomorrow they should start on an exercise program that's approved by their physician and, and, and targets the thing that they need to target.

1:04:10And there's major papers published within JAMA, like just walking prevents Alzheimer's. Yeah. I mean, anything is better than nothing. And, and, you know, someone who's sedentary, I'd rather they walk. I think walking is physical activity and physical activity is better than nothing. But to me, physical exercise, especially when we get past a certain age, we need to be mindful and we need to be intentional about how we do this. so if a person is going to say well i'm going to go walk three times a week and i'm going to prevent alzheimer's well not if you have excess belly fat and not if you have if you're under muscled so someone that wants to use exercise as a primary lever to pull needs to figure out well what are they trying to do so for example if someone needs to lose belly fat you know um walking slowly is probably not going to be enough you need to get into a higher you know what we call zone two or steady state cardio, where the heart rate goes to 60 to 65 % of, of, you know, the person's maximum.

1:05:04The best way to kind of approximate that if someone wants to get into fat burning mode is where they can still have a conversation with someone, but the person that they're talking to can hear that they're a little bit short of breath. They can hear that they're exercising, but they can still carry on a conversation. To me, that's in the zone two. And you need to get, I would say at least 40, 45, 60 minutes of, of that. And walking alone may not be able to do it, but fast walking sometimes with a weighted vest or up and down hills like that, that could be a way to get. In Austin, there are a lot of hills.

1:05:34So in Austin, it may be very easy to get into zone two, to get into the fat burning mode, but that's a way to do it. And for people that are fit and their doctors say, okay, doing fasted walking, fast walking with a weighted vest early in the mornings before they've had any, maybe black coffee, but if you don't have any carbohydrates in the system. You may be able to burn fat even more efficiently, but again, some people, you know, shouldn't start like that. But the belly fat, you know, you're not going to fix it by doing crunches or ab exercises. It's basically sugar and starch that are driving it.

1:06:06And if you cut out sugar and starch, which is driving metabolic disease, which is a big part of Alzheimer's, you're going to fix it quickly. Incredibly. And I think, you know, if you're trying to just lose body fat, but not realizing that if a person has a lot of muscle, they're more metabolically active and they can break down, break down, whatever you need to build muscle mass. People should be doing strength training at least twice a week, you know, depending on their individual situation. If someone is trying to lose body fat, they should be doing zone two, you know, fast walking with a weighted vest, you know, three times a week for 45 to 60 minutes.

1:06:41So exercise is not just like, you know, going for a walk is better than sitting on the couch, but being intentional about your physical activity and physical exercise routine is what it takes to really have an impact on brain health. So exercise is one of the interventions. Diet, let's talk about nutrition. There's the mind diet, which is Mediterranean. And the way I think about it is if food is medicine, what's the drug? What's the dose? What's the duration? And I think, yes, the mind diet, which is a sort of a modified Mediterranean diet, lots of omega-3 fats and anti-inflammatory foods, great.

1:07:14But there's different levels that you can push on the gas pedal to get more effect. I had a patient once who had MCI, mild cognitive impairment. She had a whole bunch of problems, the 21 things, and we fixed all them. Her thyroid was off. She has heavy metals. She was pre-diabetic. She had methylation issues and high homocysteine. She had low omega-3 fats. I mean, just the list went on and on. And we fixed everything, and her cognitive function dramatically improved. And then after like three or four years, she started noticing a little bit of the dwindling. And I said, geez, why don't we try a ketogenic diet?

1:07:46because I've been reading about ketogenic diets and changing the metabolism of the brain by cutting out all sugar and starch and carbohydrates, pretty much, and eating 75 % fat. And we did it, and the lights came back on. And I was like, holy cow. So again, how do you approach diet with all this? Yeah, well, so nutrition and dietary patterns versus single or multiple nutrients. Like this is a long topic, and you and I both have written books about this, and we could talk about this probably for an hour. But to me, different diets, you know, we're not in the realm yet where precision nutrition is like easy off the shelf, straightforward.

1:08:25But different people, I believe, need to follow different dietary patterns. And I, too, back in, I think, 2007 was the first time that I put someone on a ketogenic diet and saw something that I just did not think was possible. But then I've had other people where I put on ketogenic diets and like things kind of went the wrong way. And to me, you know, we're going to get there very soon where one day we'll have, you know, whether it's a blood test or a genetic test or something where we could put into a computer and the computer will spit out exactly what the person could eat. Until we get to that time, I think you think about the big bucket.

1:08:59So the Mediterranean style diet, fatty fish, brain healthy fats, omega-3 fatty acids, especially people with one or more copies of the APOE4 gene. And like we have to have enough omega-3 brain healthy fats. Otherwise, people will have cognitive decline. And the synapses - Because a lot of your brain is made up of DHA, which is 60 % as far as I remember, which is - And DHA and EPA are the two most brain healthy fats. And DHA is especially important for people with one or more copies of the ApoE4 variant. So brain healthy fats, that's PUFA's polyunsaturated fat. Then you have monounsaturated fats, monounsaturated fats.

1:09:35It's like, if you want to drink olive oil, like an ounce or two a day, and your doctor says, okay, that's like anti-tau protein. Like, that is good for people. But it's got to be good olive oil. It's got to be quality. It's got to be bitter and burn the back of your tongue. Otherwise, it doesn't have the polyphenols. Exactly. And 60%, one study I read of the alcohol, of the, of the, of the, olive oil out there is corrupt. Exactly. So, you know, getting quality olive oil, like literally taking a shot of it, one or two shots a day, or pouring it on everything. You know, I have olive oil stashed in different parts of the house and just pour it on, pour it on whatever I can get it in because I need it.

1:10:09And if it burns the mouth, yep, that's exactly the proxy as a taste to it. So avocados, olive oil, fatty fish, brain healthy fats are like so critical. Green leafy vegetables. So, you know, berries, you know, half a cup of strawberries or blueberries two to three times a week. Nurses' Health Study published over a decade ago showed you could delay cognitive decline just by eating berries on a regular basis by two years, just from one intervention. That's why I gave you a berry shake this morning. You did. It was good with goat milk whey, which was a first for me. So I appreciate it, which is really nutritious and actually tasted really good.

1:10:44So, you know, green leafy vegetables, high antioxidants. People should be eating mostly plant-based. I would call it plant-rich. Yeah, plant-rich. Yeah, plant-rich, plant-rich. And, you know, totally different because plant-based is vegan yeah oh no that might be problematic for people mostly plant rich okay yeah that's a better and i wouldn't maybe yeah i don't know the exact terminology but you know and then like meat is all not created equal like like red meat grass-fed beef is totally different than other beef that isn't you know whatever so i think people need to eat you know where they feel comfortable with whether ethically or otherwise they need to get protein levels whether it's through whey protein through goat or whey protein through regular milk from cows.

1:11:23I think each person needs their own individual kind of thing. And some people may be more sensitive to one thing versus the other. And there's lots of different. And I saw you putting like cocoa polyphenols in your mouth this morning. I travel with dark cocoa powder, which is completely ridiculous, but I never leave home without my dark cocoa powder. And yeah, I have coffee in the morning with dark cocoa powder because to me, actually caffeinated coffee, I think is brain healthy and has been shown to have better brain outcomes. Dark cocoa powder, again, it has to be like pure and not have the heavy metals in it and things like that.

1:11:51But dark cocoa powder can help with insulin regulation, blood pressure control, and has shown to be beneficial for brain health too. So Richard Isaacs starts this morning with a mocha. I do. A mocha for your memory in the morning. And it's funny because mocha is actually one of the names for a test where you use a Montenal cognitive assessment test, which is actually something you can actually do at home. It's something you download on the internet and it's a pretty good way of tracking your brain health. Exactly. Yeah. We don't want people to do it too much at home because then they practice and the doctor see the doctor and they memorize the test.

1:12:22But I don't disagree. Yeah, for sure. There are definitely ways to track. So fatty foods, omega-3 fats, monosatrial fats, berries, leafy greens. You know, nuts and seeds. Antiochus, nuts and seeds. You know, balancing the omega-6 with omega-3s. There's so much nuance with nutrition, but I think that's it. Also the ELF diet. What's that? Oh my. Eating moss in the Arctic Circle. I just, Dr. Mark Hyman on a dietary pattern that he's never heard of. Wow, this is a great day. I'm never going to forget this day. The Ulf diet. Eat less food. Oh, eat less food. Yeah, yeah. Like Michael Pollan, they eat food, not too much, mostly plants, right?

1:13:01Yeah, so just less. Like, people just eat so much in excess. Like, it's crazy. And, you know, there was a study out of Mayo that showed that people that ate, like, I think the cutoff was like 2 ,100 calories a day, less than 2 ,100 or more, have, you know, delayed cognitive decline. And again, this is like imprecise. So the Okinawa principle, right? Harihachibu, which is eat a percent full. Percent full, exactly. Harihachibu, that's exactly it. So the take home here is, though, if you're trying to gain muscle, well, you better eat sufficient protein and calories because you need both carbs and protein to build muscle and you don't want to like just, you know, starve yourself.

1:13:37And there's good carbs and bad carbs and know the difference. That's really key. Berries and leafy greens are carbs, right? Exactly. Yeah. And, you know, some whole grains in moderation, I think, are okay, but not if a person's not active, you know. So anyway, yeah, nutrition's, you know, tricky. You know, vitamins, we talked about, you know, omega-3 fatty acids, but vitamin D, especially people with one or more copies of the APOE4 variant, we check vitamin D. And just like you mentioned earlier, we don't just tell everyone to take vitamin D. but I think the statistic in Miami, as an example, 60 % of the people in Miami, even with sun exposure, are deficient in vitamin D.

1:14:13So we check vitamin D. We have to be naked between 10 and 2 in the, and then morning, 2 in the afternoon for 20 minutes. And if you're not, you're not going to get out vitamin D. If you're a lifeguard, you will, but otherwise forget it. Exactly. People wear sunscreen now, people are indoors. And yeah, I usually tell people you need 15 minutes of, 12 to 15 minutes between the hours of 11 and 1 to try to split the difference. I don't want to, you know, it's hard to know for sure. But, you know, we check vitamin D and supplement if needed. We also talk a lot about B-complex vitamins and B-complex vitamins, again, are not something that's one size fits everyone.

1:14:47The Vitacog study, which was published over a decade ago, showed that when people had a marker in their blood called homocysteine, if homocysteine is high, the people that took B-complex vitamins, B12 folic acid and a tiny little bit of B6, those people not only did they have slightly improved memory function on cognitive testing, but those people actually also had slower shrinkage of the memory, sorry, of the total shrinkage of the total brain size. So to me - Yeah, I think it was a paper published a number years ago in JAMA or a New England Journal I read where if your homocysteine was over 14, you're 50 % more likely to get Alzheimer's or dementia.

1:15:19And that's, again, something we test at function health and also methylmalonic acid, which is a marker B12 function. And I remember a patient who came to me who was a very successful businesswoman, was on multiple boards. She was in her early 80s. And she's like, I got diagnosed with MCI, mild cognitive impairment, early dementia. And she was pretty upset. And I'm like, well, I don't know. Let's see what we find. And she had extremely high homocysteine and high methylmalonic acid, which is a marker of B12, which are probably better than measuring folate and B12 in the blood. Probably had a double MTHFR mutation.

1:15:51She did. She had the genetics that made her having trouble with her metabolic pathways. Yeah. And she was older and probably not absorbing B12, which is common. as you get older, you get less stomach acid and so on and so forth. There are people that get acid blockers. They don't get, I mean, that's what that made me crazy. I mean, there's the third most leading prescribed drugs after statins and psychiatric drugs is the acid blocking drugs, which are now over the counter. And they, they're, they're dangerous to take long-term, fine short-term, but long-term. And so I, I said, I found this and I gave her a B12 shots and I gave her high dose of methylfolate and some B6, some of these methylating nutrients and completely cured her MCI.

1:16:29Now, it's not that everybody with MCI or pre-dementia has that problem. It's just that she had that problem. And then a number of years later, probably five years later, I got a call from her and I thought, oh, she's probably going downhill. And I'm a little worried about her. And I saw her in my schedule and I'm like, what's going on? She says, well, I'm going for a trek in Bhutan. She's 85. And I want to know what I should be doing to prepare and take and blah, blah, blah. And I'm like, okay, great. Amazing. Yeah. What else supplements? What other supplements? Vitamin D, fish oil, the B vitamins.

1:16:58Yeah, I mean, turmeric, I think, you know, curcumin, the active ingredient in curry. I think in certain people, especially with elevated amyloid levels in the blood, you know, we usually, we sometimes use this. And I think in terms of like the big picture, those are like the one size fits many ones. But I mean, the list just, I mean, the list is really long. So, I mean, there's definitely other things people can do. But the take home here is, you know, we check it in the blood. We do the history and then we personalize the plant for them. So I think nutrition and exercise are like critical, critical levers.

1:17:33And, you know, in our research study that we presented data that I can talk about because we presented this at the 2025 Alzheimer's Association International Conference in July 2025. And we showed that when you looked at, and I'll talk about different interventions in a moment, but if you look at multimodal lifestyle intervention that included exercise, nutrition, vitamins, supplements. Sleep. Sleep. Stress management. Stress management. Keeping the brain engaged, learning something new. Yep. Seeing a doctor on a regular basis to make sure their blood pressure, cholesterol, blood sugar is all modified in an optimal range specifically for them.

1:18:12When you put all those together, but no drugs, if you look at the groupings of the categories of the people we followed. So intensive lifestyle intervention. Intensive lifestyle intervention. of all the interventions that we tried moved the needle the most. More than any of these billion-dollar amyloid drug studies, right? In our study that we've, and this hasn't been fully published, but I can talk about it because we present an abstract form, there are people that, for example, took GLP-1 drugs. And GLP-1 drugs are tricky because, you know, I believe that too high a dose, if you're not eating right and doing the right thing, you can, you know, lose muscle and have all the things lower dose.

1:18:47You know, I'm more of like the microdose crew when it comes to GLP-1s. glp1s positive effect on biomarkers you know in my opinion based on the our results you know impressive results when used in the right person at the right dose for the right duration of time well they improve metabolic health which and there's many roads to roam to do that right if you radically improve your diet i mean i mean before glp1s were on the market i was reversing diabetes getting people lose 200 pounds 100 pounds 150 pounds you you can do it it's just it's just and i think my guess is that they would do a head-to-head comparison of glp1s and the same diet that you would eat if you were on GLP-1s, there would be no difference in any of the biology.

1:19:24That's my point. So while multimodal treatments, you know, I would say work the best, the other categories that worked exceptionally well, that meaning exceptionally well to me means statistically significant improvements in a variety of pathologic proteins that are associated with neurodegenerative disease. So you're testing, not guessing. We test everything. Let me try these 20 things and let's cross our fingers and maybe do a, like a sort of semi-subjective, objective tests, which is a bunch of questions. We try something. You're actually looking at blood tests that show changes. Try one thing, we repeat it.

1:19:56We don't try 10 things. Well, for multimodal interventions, we try a group. And then if we're going to try a drug, we're going to recheck the 150 biomarker proteins. We check the proteins on different machines, in duplicates. Every blood test we do, we run twice. This is not normal. This is not cost-effective. We do it anyway, because we care about quality, not about anything else. But, and we just try to do things as rigorous as humanly possible. And what we show is that when we do these tests, we call these N of 1 studies, we'll try a GLP-1 and we'll check. We'll try hormone replacement therapy, like hormone replacement therapy, bioidentical hormones for women during the perimenopause transition in the right woman at the right dose.

1:20:37The women in our little hormone replacement therapy group. Believe it or not, the age ranges from 42 to 67. We have multiple women that have actually started on hormone replacement therapy with approval and agreement by the GYN and the primary care doctor and our team. We've had, I'll just say what I feel like I should say, amazing success with using hormone replacement therapy. And when that rapid drop of estrogen comes in a genetically susceptible woman you know we did this whole women's brain imaging study at Cornell and spent you know millions and millions of dollars on this women that had you know hormone replacement therapy on board had better brain volumes and less amyloid but it had never really been proven in a study that you could use H hormone replacement therapy and then there's that women's health study that used like synthetic hormones and horse urine derived whatever like when you use a bioidentical patch and you use progesterone and we talk to the GYN and we talk to the doctors, hormone replacement therapy during the perimenopause transition has helped improve brain biomarkers associated with Alzheimer's and neurodegenerative disease risk.

1:21:47It's been striking. So this is more than just what has been done before, which is population based studies, which can't really directly look at cause and effect. You're actually looking at blood biomarkers that changed and improve the blood biomarkers that are associated with neurodegenerative disease. That's a big deal. And the other thing I want to just say is that the consensus most of that I've heard is that it's important to start right away after your menopausal transition. But what I hear you saying is that you can actually start it later. What? End early. I want to start. Both. I would say yes, start early.

1:22:18Does that mean every woman should be on porn replacement therapy? Like what are the implications here? Yeah, this is, these are, these are really, you know, and by the way, why hasn't this been better studied. Why are we the only group to my knowledge? Because we have misogynistic research infrastructure. It's just so, it's demoralizing. It's just so wrong that women are taught that like, oh, you're having night sweats. Oh, oh, you don't feel good. Oh, you're having brain fog. Oh, okay. Sorry. You know, we'll see you back in six months. Perimenopause is a neurological disease. Like you're just going to have a woman suffer.

1:22:55These are, these are symptoms that are treated. Oh, go change the temperature in your room and maybe you'll sweat less or maybe change your sheets, get better sheets. Like, like, no, this is a medical condition. Like really, or like, you know, the cooling thing, like, okay, are a weighted, like, fine. Okay. Treat the problem. And what we've shown is that, you know, through ridiculous amounts of time, effort, money spent and research, which needs to be quadrupled or probably increased even much more than that, we've shown that when we use hormone replacement therapy in the right woman at the right dose, the right duration in collaboration with a multidisciplinary team, when we start seeing the estrogen drop, even if the symptoms are very mild, you get the estrogen back up, the tau starts coming down.

1:23:43Even though the tau wasn't elevated to a degree where we're like, uh-oh, sky is falling, but the tau is higher than it should be in that woman who's 47 years old. And this whole concept of like, you know, it's normal. Well, no, optimal is where we want a brain protein. Normal, a little borderline, a little high. Like, no. In order to have the most benefit, we need to make these incremental changes. And hormone replacement therapy during the perimenopause transition, to me, is one of the most impactful tools that we can use to reduce the risk of cognitive decline, dementia, and Alzheimer's disease in women.

1:24:20And I think, you know, it's tricky. I think there's risks and benefits with every one of these decisions. But, you know, I've just seen too many women suffer, and it's just not fair. So if they're symptomatic, or if you do evaluations, you have a higher risk based on your Alzheimer's risk score, which you've developed, then maybe it's a good idea. But even if you're not symptomatic. Well, I think if you're symptomatic, it's like, how could you not? I think it's like, you know, it's unethical not to try to figure out how to. In our cohort, we track estrogen, estradiol levels and other hormone levels.

1:24:51You know, I mean, women 21 and above. We also, this is crazy, but like, you know, this hasn't been done before to my knowledge. We do multiple blood draws through the menstrual cycle to try to figure out like as estrogen and progesterone change during the cycle, guess what? P-TAL-217 changes and these other markers change too. How has this never been done before? So we have women, we have like, thank you. Thank you. I'm not going to say their code numbers in our research study. They get six blood draws on day one, on day three, on day seven. Like we get six blood draws during the menstrual cycle.

1:25:23We're just trying to figure out like, what should the P tau be at what, depending on what day the blood was drawn, we need to correct for what the tau level should be based on where the estrogen and progesterone is. Like these are things that just haven't been figured out yet. And these are the types of questions we're asking. And these are the types of things that need to be figured out. And when you take this approach, precision, personalized, individualized approach, we've seen women in their early 40s, like 42 is the earliest we've started, where we've seen the estrogen going down and we've seen the amyloid going up.

1:26:00Well, maybe they're a little symptomatic, but it's not really bothering them. But we're going to start on low-dose hormone replacement therapy. If everyone is in agreement, And guess what? She feels better. Her cholesterol comes down. That's interesting. Her amyloid is improving, even though it wasn't abnormal. And this is really the key. Like we have to personalize these therapies and we have to, you know, we also just monitor for a change. We've been monitoring these women for so long. We see the change and then you intervene. And so, so to me, it's if symptomatic, like, please talk to your doctor.

1:26:36And if your doctor says, tough it out, like go to another doctor if you're pre-symptomatic um follow it closely i think women pre-menopause perimenopause should should probably get checked every six to 12 months for these brain biomarkers and hormones um so essentially what you're saying is if you're symptomatic don't suffer and if you're not symptomatic and you have a lot of risk factors and some of these blood biomarkers that were emerging or abnormal then it's better to get out early even if you're not symptomatic. I believe that specifically in people that are at the high, women that are in the highest risk category, which are APOE4 positive, especially women with two copies of the APOE4 variant.

1:27:15Some of the most striking improvements, actually one, one woman is actually lives in Austin. One woman is in California. I mean, I know these cases like, you know, the back of my, my, my, my mind, like I, like you just start and you see everything improve. This is honestly, Richard, why we co-founded Function, and I don't mean to kind of oversell it here, but these tests are not things that your doctor likes to order or often will order. And for very low cost, we've dramatically reduced the cost. You can get all these biomarkers, including APOE4 and some of these brain biomarkers. And then you can kind of start to decide what to do and take control of your own health.

1:27:50I want to ask you about guys because two thirds are women, but then one third is guys. Do guys benefit from hormone replacement therapy in terms of testosterone? Great question. I think the literature has been I would say the literature has been not conclusive is how I would answer this question. It doesn't mean it helps or hurts. It's just the evidence has not been sufficient for, I would say, the vast majority of the times that I've looked into the data. I would say more recently, I would say it's more likely than not, but not a certainty that using hormone replacement in men, specifically testosterone in the right man at the right dose for the right duration.

1:28:31That's all different, different discussion and like which types and how many times a week and what version and is it the cream or is it inject? Like there's a lot of confusion here, a lot of confusion. And then what else is going on? Like what other hormones? Cause sometimes when people use testosterone, they're also doing like five other things. What I would say is if hormone replacement is used judiciously in men and the person is putting in the work exercising and trying to build muscle mass in addition to taking you know lower and i mean some of these testosterone levels i see are just like really really high and like a lot of these a lot of the doctors i've spoken to who specialize in this like are not bothered by this in any way shape or form and i'm just like no you want a physiological level because then your estrogen levels will go up because you convert testosterone to estrogen, then you start having sex, you know, libido issues and other issues that are, it's like, it's a, it has to be done right.

1:29:24Exactly. So, so, so with all of these caveats, I would say at this moment today, I don't have a definitive answer, but I would say it is more likely than not that when testosterone replacement therapy is used cautiously and judiciously, there is a beneficial brain effect. I'm talking very carefully and generically because is it truly Alzheimer's protective, vascular protective, cognitive health protective for a reason other than like maybe age-related cognitive decline? I don't fully understand the pathological protectivity of testosterone, but there's something that is protective cognitively.

1:30:05I'm just not sure if it's strictly Alzheimer's pathology. Well, it's kind of the motivation hormone, right? And when people drop off in motivation, they withdraw from life. They stop doing the things they want. They might not want to exercise as much. It's kind of like a dirty cascade. Okay. So we've got, we've got nutrition. We've got exercise. We've got certain supplements can be helpful. We've got hormone therapy. You know, you didn't really say a lot about sleep, but I think that's another pillar and correcting sleep disturbances and also sleep apnea, but also even being careful of sleep drugs, the benzos or Valium or that category of Xanax, Ativan, those drugs are commonly used and they do have impairment functions in the brain.

1:30:44So you have to be careful with sleep. Yeah, sleep. I mean, we could spend probably a whole podcast just on sleep. Give me a couple of minutes on sleep. Yeah. So, you know, everyone out there has to make a plan for sleep. You know, you could be burning the candle at both ends, pushing, pushing, pushing, sleeping five, six hours a night. If you're exercising, doing everything right from the exercise and nutrition perspective and not getting adequate sleep, you will not have adequate brain health. It's not going to happen. So everyone out there needs to prioritize and make a plan for sleep. I have people where the only thing they changed after I've read them the riot act was their sleep patterns.

1:31:17The only thing they've changed and the impact on their brain biomarkers. Objective blood test. Every, I mean, objective cardiovascular tests. I wear all these trackers. We track everything in all of our patients. I mean, the only, this is like crazy, but the only thing that changed in an otherwise optimized person, if you get sleep right, the amyloid can come down, the cognition can improve. Sleep is so critical. You know, it's not just about, you know, getting what's the magic. In our study, we did a study on this. We tried to figure out like what's the optimal sleep and like 7-11, that's how I remember it, like 7-11, seven hours and 11 minutes.

1:31:53The people that slept more than that did better cognitively. The people that did less. but seven hours and 48 minutes last night. Great. I'll take it. That's, that's good. And, you know, obviously, you know, it depends on the sleep quality and deep sleep is restorative sleep. That's when the trash gets taken out. The amyloid gets, you know, taken out in the garbage. Um, you know, REM sleep is when short-term memories are consolidated or really formed into long-term memories. So there's sleep quality and there's sweet sleep, um, quantity. And the number one way to get more sleep quality is to sleep longer, to have more REM and more deep sleep.

1:32:24Like that's a cheat code. Um, you know, to me, you know, actually retain your brain.com is the, the, actually I'm, I'm in a routine right now. What retain your brain does is gives a person, um, suggestions. And, uh, as I'm holding my coffee, I don't know what time it is 11 or 12, 12 in the afternoon. Um, I am not allowed to drink coffee after 11 PM based on my, um, time's up, time's up, you know, because, um, you know, caffeine lasts for five, six hours, the half-life. So if I'm drinking coffee at two or three or four o 'clock in the afternoon, I still have caffeine in my system as I'm going to bed.

1:32:58So, so, so to me, um, you know, taking a, making a plan for sleep, you know, sleeping in a dark room, like if there's a little bit of like light coming in from the window, just plugs and eye shades. Yeah, exactly. Um, weighted blankets. Some people really like those like, um, you know, for cooling temperature, like cold rooms and heavy blankets, cold rooms and heavy blankets. Yes. You heard it here first. I mean, these are like really easy things that people can do. The other thing is... In fact, I'm reinstalling my air conditioning while you're here because it's an older house and it needs updating and it wasn't cooling down.

1:33:28When I put it at 65, it was only getting to 70. I'm like, that's not good enough. Yeah, I agree. My other routine that I got, the brain healthy habit that the software recommends, because I typed in the thing, like, what are my issues? And it said sleep is my issue. So it's been telling me to help me make my sleep better. And put electronics to bed was the brain healthy habit that was recommended it to me well what does that mean every night at 9 30 p.m my alarm goes off as a reminder that says power down your electronics so at 9 30 i try to wrap up and by 10 i try to put you know like our biology wasn't meant to have two cell phones like like this you know at all times with the light and whatever else and there's my there's my there's my grateful dead bear got the got the bobby and the wolf brothers show a couple years ago for those who don't know what he's talking about it's Grateful Dead and Bob Weir and his band called the World Brothers.

1:34:20I was waiting online to get into the show. Someone miracled me with that. Too many inside jokes. Yeah, sorry. Old deadhead jokes. But like, why are we on our cell phones right before bed? Like that causes rumination. If you want to fast forward brain aging, worry. Worry about everything. Like that will make rumination or worry is the number one thing that basically fast forwards cognitive decline. Two more things I want to cover before we close out. We've got sleep, got nutrition, exercise, we've got supplements, we've got hormones. And you mentioned there are like 50 different choices. So there's a lot of things.

1:34:56And people can look at your research, we can link all your papers, all the media on you, people can learn more. There are two other pieces. One is, what about pharmacologic interventions? Because drugs have a role. And kind of what are the star players here? and and um and also like what about brain exercises like brain games learning language so those are two things we need to talk about but i think they're key pieces of keeping and retaining your brain i'm equal opportunity i got i got no skin in this game i take no you know funding from pharmaceutical companies any any anything like that um i'm equal opportunity if it's a drug a vitamin a supplement and it's relatively safe and i would be willing to take it myself or give it to a family member, it is on my list of potential intervention.

1:35:46So I'm not pro-work on anything. I'm pro-evidence and I'm pro-safety. That's all I am. In our research study that we presented in July 2025 at the International Alzheimer's Conference, paper is getting ready to be published, not going to be published yet. These papers take years and years and years to publish. The general categories of drugs that worked the best, well, we talked about hormone replacement therapy and we talked about glp1s and those drugs uh drug categories worked um honestly um amazingly well like it's just it's just i was i was floored by it there are uh three other drug categories that people have heard of many people are probably taking and then there's one drug category that is more specific for alzheimer's so the next four categories that i can talk about briefly are cholesterol treatments, and those are two statins as a category, and I'll explain the nuance there.

1:36:43And then ezetimibe or Zetia, which is a plant sterol inhibitor. And we've broken out groups into statin use versus Zetia use. That's the brand name, but it's all generic now. And then the other categories were, I think this was in the paper, SSRIs, selective serotonin reuptake inhibitors. And then the final category was anti-amyloid drugs. So these are drugs that we've studied and these are things that we've studied in our cohort. You're also talking about GLP-1s too are part of this. Oh yeah, yeah. GLP-1s and hormone replacement therapy are definite check marks. And I would say in our study, multimodal interventions work the best.

1:37:19GLP-1s and hormone replacement therapy, I would say, work the next best. And then there's these four other categories which we studied and across a variety of biomarkers, but maybe not as like, not home run grand slam um there were statistically significant improvements across select blood biomarkers so basically what you're saying is the basics work better than these fancy drugs that we've been billion dollars researching and have shown very incremental benefit yeah and they're not like zero but they're yeah and they may be additive to an overall package of it true true and in the right person at the right dose um ezetimibe the plant sterile inhibitor i i never in a million years would I have like ever said that I would be saying something like this.

1:37:59But you know, we're developing these blood tests. And you know, we talked a lot about Alzheimer's today, but alpha-synuclein, alpha-synuclein is a pathologic protein that builds up in the brain of a person with Parkinson's disease and Lewy body dementia. Like we are working on these blood tests. Like this is crazy. Never in a jillion years, like what I've ever, regardless of my family, my brother, my brother's son, my brother's brother-in-law, like we see these drops in alpha-synuclein protein using some of these things and these are Parkinson's related things. So I don't fully know what this means yet, but what I would say is the cholesterol drugs in the right person at the right dose in the right duration, um, you know, your mileage may vary, um, work and it's improving what I believe to be brain health risk and brain health outcomes.

1:38:43Statin. Let's talk about statins. The people that start on statins in our cohort are not your typical, um, you know, crestor rosuvastatin 20 milligrams like the amount of people i see on high dose statins it like just blows my mind 85 percent of the cholesterol lowering effect of rosuvastatin or crestor comes at five milligrams of the dose so you get 80 of the benefit at the lowest dose yep and no one knows this and like and i think that's correct i mean that's what i've read and that's what i've been taught but like if the majority of the effect come at low dose like Like, why do we keep, like, to get an extra 5 % or 10 % benefit when you, like, keep pushing and pushing and pushing these doses that are just, like, really high.

1:39:26To me— And those cause mitochondrial injury, and that is important in keeping your brain healthy, is having healthy mitochondria. Yeah, and, you know, the side effects go up and across, you know, a variety of ways. In our cohort, lower-dose statins in the right person that are biologically attuned to respond to statins, meaning when we do the blood test, it says, you should take a statin because it's, you're an over producer of statin genetically or biologically. So lower dose statins, um, do show brain positive effects in our research. But you guys are throwing at everybody. You're doing tests to say, oh, you're somebody who produces more cholesterol.

1:40:00So you and I don't, so statins wouldn't be good. And even I have the gene that makes me have myopathy or muscle damage. If I take a statin, I have that gene, I tested it. So statins are not good for me. And they also cause mitochondrial damage. And if you do the test this helps you personalize or precision approaches, you're going to get a better effect with less side effects. And there's a friend of mine, David Fagenbaum, who created a company called Every Cure, which is about using drugs that have mechanism of action for diseases for which they were not developed, right? So what you're talking about is azetamide or zetia.

1:40:36It works for Alzheimer's, but it was a cholesterol drug. But it has an effect that maybe we don't even understand why, but it's working on some pathway that's independent of just the cholesterol lowering, because it's not just about lowering cholesterol, because you could actually lower cholesterol just as much with another drug, but not see the same benefit. Exactly. And, and, you know, these are, again, these are - Am I catching on? You are, you're catching on. You've been to this rodeo before. So, so anyway, I would say cholesterol drugs when used in the right person at the right dose for the right duration of time are protective against dementia and Alzheimer's pathology, and maybe even Lewy body and Parkinson's, but I want to be really conservative, not fully published yet.

1:41:09Like we're just, we're just learning. SSRI, selective serotonin reuptake inhibitors. And again, so in our cohort, does that category of drugs? Actually, we have zero people in our cohort on Prozac. The only people in our cohort that are on SSRIs, I think this is because escitalopram or Lexapro, it's all generic now, escitalopram has been shown of all the SSRIs in a study that came out in neurology like a few years ago to have the best, you know, lowering or attenuation effects on amyloid. So in our little group, you know, we have a group of preventive neurologists, preventive cardiologists, preventive medicine specialists, internal medicine doctors, that treat the patients in their own individual clinics and whatever.

1:41:52And then they're in our research study and we track the biomarkers. We all have gotten the memo that escitalopram, I'm going to sound like a broken record at a pretty low dose. You know, we have a guy now on five milligrams. I almost never go, I mean, I don't, I don't usually go high. And by the way, We're not treating, you know, I'm not a psychiatrist. We're, you know, mild depression versus major depression. Those things, I'm not going to get into the nuance. But the majority of people in our cohort that are on SSRIs are on escitalopram or Lexapro 5 milligrams, I would say, on average. And in our cohort, it's a small group, but we also saw some, but not, I would say, slam dunk robust effects from low-dose escitalopram, low-dose Lexapro.

1:42:34So this is really important. I just want to set a step back because we kind of have to wrap up. But I think that, you know, for those of you listening who have a family history or who are suffering from memory loss or are concerned about getting it, you know, what you're saying, Richard, Dr. Isaacson, is that for the first time in history, we're actually able to do preventive neurology around neurodegenerative diseases and that you can actually slow or even reverse the changes that happen that are measurable by new and innovative blood biomarkers that you're developing and that are ones that are already developed and are available.

1:43:12And you're seeing change in brain structure, growing brains, and the function of brains, improvement in cognition. And you're not using the old paradigm of a single drug for a single disease, using over 50 different things that you pick from depending on how you want to personalize the treatment. That if you see one person with Alzheimer's, we've seen one person with Alzheimer's, and that this field is changing radically in such a way that we'll actually be able to help us avert this catastrophe of 47 million people who are in the pre-symptomatic stage of Alzheimer's that are measurable by these blood mire burgers, that it's going to cost us$18 trillion over the next 30 years.

1:43:51This is revolutionary. And if anybody's listening who cares about this issue, who wants to help, And again, I have no affiliation with you other than being your friend and having a bond over the grateful dead and following your work for years. This is where the money needs to go. This is where the philanthropic dollars need to go. This is where NIH funding needs to go. If you're listening, Jay Bhattacharya, this is the future because it's what I have seen over 30 years in the practice of functional medicine from a very amateur scientific perspective. I'm not a researcher, although I've done some research studies.

1:44:26is what I wrote about in my book, The Ultramind Solution, 15 years ago, or more than 15 years ago now. And I think we're at this transitional moment in history where for the first time, we're getting a handle on this horrific condition. Yeah, you get a heart attack. Okay. You have chest pain. You get a bypass. You get a new heart transplant. You're still you. When you get Alzheimer's, you lose you. You lose your family members. It's a catastrophic disease. And everybody's terrified of getting it and nobody should be afraid of doing the diagnostic test to figure it out. And now at Ezra, which is a company we bought with Function, we actually can do brain imaging and we can do quantitative brain imaging, which is a more advanced service we offer, but we can actually start to track these things over time.

1:45:10And so you can begin to do these things. You can go to retainyourbrain.com and start to kind of get ahead of the game. So Richard, I just want to say thank you for what you've done. Thank you for the insights, for the aha moments you had in the hallway with that guy with the bishop dementia we never know how we get doing what we're doing but i hope that your work continues i hope that you get it funded not to 10 or 20 million dollars but we need a billion dollars we've spent so many billions of dollars and wasted them this is an area that needs real serious funding because what you're seeing is real it's not quackery it's not heresy well it kind of is heresy but it's actually a valid scientifically and and we need to get behind it.

1:45:51So thank you for everything you've done. Thank you for what you're doing. You're leading the pack for the rest of us. And I just appreciate everything you are and everything you're doing. So thanks for being on the podcast. Thanks so much, Snyder Hyman. If you love this podcast, please share it with someone else you think would also enjoy it. You can find me on all social media channels at Dr. Mark Hyman. Please reach out. I'd love to hear your comments and questions. Don't forget to rate, review, and subscribe to The Dr. Hyman Show wherever you get your podcasts. And don't forget to check out my YouTube channel at Dr.

1:46:17Mark Hyman and for video versions of this podcast and more. Thank you so much again for tuning in. We'll see you next time on The Dr. Hyman Show. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic, and Function Health, where I am Chief Medical Officer. This podcast represents my opinions and my guests' opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only and is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided with the understanding that it does not constitute medical or other professional advice or services.

1:46:51If you're looking for help in your journey, please seek out a qualified medical practitioner. And if you're looking for a functional medicine practitioner, visit my clinic, the Ultra Wellness Center at ultrawellnesscenter.com and request to become a patient. It's important to have someone in your corner who is a trained, licensed healthcare practitioner and can help you make changes, especially when it comes to your health. This podcast is free as part of my mission to bring practical ways of improving health to the public. so I'd like to express gratitude to sponsors that made today's podcast possible.

1:47:21Thanks so much again for listening.