The Daily Habits That Protect Your Brain At Any Age: The New Science Of Dementia Prevention with Dr David Perlmutter #674

32:48I think these medications are excellent. I think that the ability of using levodopa to help an individual with their rigidity in Parkinson's and some of the anticholinergics as it relates to addressing the tremor are valuable, allow people to continue on with their lives. But the disease continues to progress underneath that symptom-based approach readily. And maybe this sounds a little bit divergent, but in 2024, a fascinating study, and I talk about it in the book, was published in the New England Journal of Medicine. 135 Parkinson's patients were randomized to receive a GLP-1 ozempic-like drug or placebo for one year.

33:35And the results were dramatic. The group receiving the placebo continued to decline as we would see in Parkinson's, but the group receiving the GLP-1 drug stabilized, in fact, slightly improved on what is called the Unified Parkinson's Disease Rating Scale, a standardized way of assessing how a Parkinson's patient is able to function in their daily life. So this is the very first time, well, I'm gonna actually say it's the second time. It's, I'll tell you the first time in a moment, that the actual underlying metabolic issue in Parkinson's was addressed, and look what they found. Now, I'll tell you about the first, was actually our study in the 1980s using intravenous glutathione published in the journal Movement Disorders.

34:25Intravenous glutathione was given also to improve mitochondrial metabolism, and our patients demonstrated pretty dramatic improvement on the very same scale used in the more recent GLP-1 study. Let's be clear. I'm not saying that, you know, Ozempic is the treatment for Parkinson's. That's not the take-home message from what I just described. Because this GLP-1 was specifically chosen because of its ability to make its way into the brain. And in fact, now it's not available on the market here in America because it's been associated with some changes in the pancreas. But that said, what do GLP-1 drugs do?

35:06Well, they don't just lower appetite. They don't just control our blood sugar, the blood sugar control being why they were originally developed. And now we're seeing a variety of other outcomes in people taking the GLP-1 drugs. But one study that I did describe in Brain Defenders just mentions how in type 2 diabetics, mitochondrial function is improved in people using these GLP-1 drugs. that is huge because mitochondrial dysfunction is at the heart of what is going on in the alzheimer's and parkinson's brains and in all neurodegenerative conditions i gave a talk at what's called the institute for functional medicine ifm i know you're familiar with that group 20 years ago where i said alzheimer's is an acquired mitochondropathy means you know by and large it's not inherited we could talk about what that means in a moment but a a problem with our cells' energy-making machinery, our mitochondria.

36:03And again, we mentioned earlier, when the mitochondria become dysfunctional, that shifts our microglial cells from becoming supportive to becoming destructive. So we need to then take a step back and ask ourselves, again, thinking about what I just said about the GLP-1 drugs targeting mitochondria. Again, I'm not saying this is our answer. I did say in the book, and for those who read the book, the language I use was pretty strong. I'm open to it. I am absolutely open to it. I mean, you know, a lot of what my work is all about and yours too, really are the lifestyle issues that people are getting wrong and people can improve because that's very empowering.

36:45That's the take-home message. People do these things and have better health. But, you know, as are you, I am open to anything that fulfills the notion of risk-benefit ratio. And if the benefit of GLP-1 drugs in an Alzheimer's patient seem to be very favorable in the face of not such a significant risk, I'm all in. You bet I am. That's going to be part of the toolbox. I think it's our duty as physicians to keep an open mind and put in our toolbox whatever satisfies risk-benefit ratio. So that said, we will see what happens with GLP-1s and the brain. We know that recently the study on oral ozempic semaglutide was published in Alzheimer's patient's interventional trial and did not meet its endpoints in terms of improving or slowing their rate of decline.

37:43That said, perhaps it was because it was oral and semaglutide coupled that didn't make its way to the brain. But we will see. Researchers are hard at it, not just certainly looking at GLP-1s, but at a variety of ways of targeting not only mitochondria, which will help our microglial cells, but the microglial cells themselves. Yeah. So many things you've touched on there, David. Just to summarize, to make sure everyone's sort of in the same place as we are in our heads. Number one, metabolic health is crucial. You mentioned that maybe these GLP-1 agonist trials are demonstrating that actually when we address metabolic health, and of course you can address metabolic health with lifestyle as well as with drugs, actually the impact on brain health is profound.

38:34You mentioned that often if we want to optimize our brain health, there are multiple things we have to do. Not just one thing, not just two things, but we have to address it from multiple different areas. You also mentioned about Dale's work. And I've, like you, been a friend of Dale's for many years. And I went, I think it was in 2016, I went out to America to Palm Springs. And I worked with Dale for about 10 days on this deep immersion with patients. And I met some of his patients who have had their cognitive decline reverse. And we worked on patients together for a few days. It was very, very inspiring to look at that research.

39:16This is 10 years ago now. So this is not as new as people think, this idea that actually there is something that you can do about Alzheimer's, particularly early stage Alzheimer's. You also mentioned, David, that there are cases of reversal or at least reversal of symptoms. Of course, it's much easier to do that at the earlier stages. In the later stages, it can get harder. But I have seen it, David, like you have with patients in early cognitive decline. And yes, we want to get involved way before that stage. But even at that point, there are things that you can do that make a meaningful difference in that person's life and their family's lives.

39:59We're going to talk about these things. We have touched on diet and how important it is to take out ultra processed foods as much as we can from our diets. So I guess the question I have for you, David, is how have your dietary recommendations evolved over the years? And are there some sort of core principles that you can share with people to say, listen, if you want to keep your brain well for as long as you possibly can, this is what you should do when it comes to diet. I've done my very best recently to simplify the notion of dietary recommendations because there are so many diets. There's probably a diet for every letter in the alphabet, whether it's paleo or primal or mind diet or med diet or green med diet.

40:48And I think it's very challenging for patients to think they need to adopt a certain diet and follow it to the letter in order to achieve an outcome. So this time around, and this is book number 16, I looked not at the diet, but at the outcome. And I said that really, I don't care what name you want to attach to your diet. Let's look at what that diet should do. And to be very simple about it, because I think that's what people really need. Because when you try to adopt a certain diet and you have to have an app or a follow-up book, it's very challenging. So I said, I want you to be on a diet that keeps your blood sugar under incredibly tight control, that offers up your body a lot of dietary fiber.

41:35In other words, it's mostly plant forward, a diet that is colorful. So we're going to get lots of different polyphenols. And that emphasizes not only adequate amounts of protein, but good fats as well. Leave it at that. And I describe what adequate amounts of protein are in terms of grams per kilogram, ideal body weight. And I also describe in depth, as you saw, what are the good fats. That's it. So I wanted to open the door to people to embrace their ethnicity in terms of their food choices or not, whatever they choose. Thinking about that, the idea of a Mediterranean diet, when you travel around the Mediterranean, you really see that they're not doing the Mediterranean diet anymore.

42:21I just got back from there. And it's, you know, this, we originally called it the standard American diet, the SAD diet, which became the Western diet. Face it, it's the global diet now. You know, just dramatically emphasizing ultra processed foods, you know, your theme for our time together today. So this is a global issue. And, you know, it explains why there's 53 million Alzheimer's patients in the world right now. And that number will triple by, you know, by 2050. So you call it out as an epidemic, and it is. And it's something over which we have control. The fact that it's increasing so rapidly argues against it being genetic, because our genetics have not changed.

43:05Our metabolism has changed. And I would add to that, our epigenetics have clearly changed as well. As a matter of fact, we could talk about the work, interestingly, of a Dr. Sarah Marzi. She's actually in the United Kingdom. I had her on my podcast recently, who's talking about how epigenetic changes are really underlying, you know, a lot of what's going on in the brain. We'll put a pin in that and deal with that later. But, you know, getting back to what you've been talking about. So I'm trying my best to simplify these dietary recommendations such that people can look at their diets in terms of how I am metricizing my body?

43:47In other words, what's the outcome of the food I'm eating on my blood sugar? Yeah. That is a leap that takes you away from chapter and verse following a specific recommendation that a doctor has developed to actually looking at outcome. What is it doing to my blood sugar? To me, and you might agree, I think that's one of the most important issues that goes awry when people are eating inappropriately. So, you know, really emphasize for people the idea of knowing what your blood sugar is. Even if you can't get a continuous glucose monitor, go to the pharmacy and buy a finger stick. It's available to anybody.

44:27And I know it's not pleasant sticking your finger, but do it once a month and see where you are. But it's really that important. Again, the fiber for the microbiome, the polyphenols, We could talk about that in terms of why that's important for the brain. The right kind of fat gets back to your original question, what has changed? I think one of the biggest changes that I emphasize now that really was not emphasized earlier, very, very early in my career, frankly, respectfully, before you were born, and that is the position on fat. I mean, there was a time when fat was not the right thing to be eating in any form.

45:09And, you know, that was what the science was telling us. And I, you know, in mainstream medical training was parroting that. And that changed, obviously, and for good reason over time in my outreach that, you know, fat is a fundamental player for metabolism, for inflammation, for structural integrity of the neurons. a variety of things that the right fats do in our bodies. Yeah. I really like the guidelines you provided for food there, David, because ultimately, whatever diet you follow, there's a certain outcome that we're looking for, right? One of those outcomes is a well-controlled blood sugar, right?

45:55so you can get that outcome in a variety of different ways so I kind of feel this is a good time to talk about testing one of the things I really enjoyed reading at the start of brain defenders was this idea that there are two wars that we're fighting at the moment one is I think the war as to why are millions of brains around the world as you say in the book on fire but then you also said the other war we're fighting is on our attitudes, our attitudes about illness and expectation. And I thought it was a really provocative thought, but a very important thought because that's what we're up against, aren't we?

46:33We're up against a medical system that has made amazing inroads into certain conditions that many of us have grown up with and absorbed the idea that if you get sick, the medical system will be there to take care of you. And as we're realizing, for many of the conditions that now are affecting a majority of the world's population, these are chronic diseases that take years to build up in your body. As you said earlier on, David, maybe 20 to 30 years before you get a diagnosis of Alzheimer's, that process has been going on and causing havoc in your body. You know, the diagnosis is the end stage, right?

47:18That's right. Of a long process. And that really ties into what you're saying about what diet you want to follow is the diet that gives you a certain outcome on certain biomarkers. Now, David, one thing early on in my career, I did back in maybe 2012, 2013, 2014, I would go to America a lot in my vacation time to go to conferences and to learn stuff that I felt I didn't learn at medical school. A lot of the good conferences back then were certainly in America. And what I noticed from chatting to a lot of American physicians is that the American medical system is fundamentally very different from the UK one.

48:03And it's very obvious now as I look back, but what that led to is for many years, David, I was hoping that the NHS, our National Health Service, would really take on the mantle of prevention. And unfortunately, a few years ago, I realised that, you know what, I actually don't think that's ever going to happen because the DNA of the NHS is to manage disease. And I think often it does that very, very well. And the NHS's idea of prevention is once you hit the age of 40, maybe every now and again go in and get your blood pressure checked and maybe once every five years get some bloods done. That to me seems like prehistoric prevention compared to what we know.

48:49So what I did about a year ago, David, I don't know you know this yet actually, about a year ago, I thought in the UK we're in a position where people who are interested in health might listen to my podcast or your podcast or read books and go, yeah, you know, I need to check my fasting insulin. I need to check my homocysteine, my uric acid, the topic of your last book, right? Who knew? Yeah. And we'll tie this all up in a minute. But actually, they would listen to these conversations or read our books or other people's books. And then they weren't able to get that, certainly in the UK, from their NHS doctor.

49:27You just can't get, for most people, a fasting insulin or a homocysteine on the NHS. Now, there are private providers where if you were really motivated, you could put together the correct panel. But there's a lot of work on your shoulders in order to do that. So I teamed up with some amazing tech guys and created something called Do Health, which I don't think there's anything like it in the UK. And basically, we don't do like a test hundreds and thousands of biomarkers. We started small and test the 11 biomarkers that I believe are the most impactful when it comes to metabolic health. And we give daily and weekly lifestyle advice on what you can do around them.

50:15Like all of these 11 biomarkers, we know impact your metabolic health, your short-term health and your long-term risk of disease. but at the same time, they are 11 biomarkers that are all amenable to change. Those are the criteria. It's only been live for two and a half months, but the feedback, David, is absolutely incredible because A, it's very, very cost-effective for what it is, but we have basically gone, I think talking about the sort of stuff you're talking about, right? We're checking stuff like fasting insulin, homocysteine, HbA1c, ALT B12 uric acid you know and I won't do the whole list but I would say that your book your last book heavily influenced my decision to put uric acid in this panel of 11 so first of all thank you but I think what it means then is whatever diet you follow you know as long as it's generally a whole food minimally processed food diet as much as you can if you are getting these biomarkers in the correct range, right?

51:23A low fasting insulin, an HbA1c maybe under, I don't know, 5.3, 5.2, whatever it is. You know, if you're homocysteine in the normal range, then actually, you know that whatever lifestyle you're following, the key markers that influence metabolic disease are actually, you know, in good shape. And we've decided to recheck twice a year, well, three times a year. So it's like you test, you do four months of lifestyle change, and then we recheck. Because of course, this isn't just a one hit. So first of all, I want to get your take on that, David. Do you think this is the kind of approach that we now need if we really want to get on top of our brain health?

52:06And then I guess secondly, from what I've said, are there any downsides to this kind of approach? Well, let me answer the second question. First, I can't imagine any downside. You know, costs will have to be considered. But, I mean, everything that you mentioned on that short list has huge play in terms of brain health. And, you know, it impacts metabolic health in the body. And the brain isn't distant from the body. It's part of the body. It's going to be the same impact on the heart, on the liver, on bone density, which is reflective of metabolic health. Who knew? And, you know, my only time in visiting your country was several years ago when we met.

52:49And it's interesting because I was asked, I was summoned to visit with then Prince Charles. And we sat in High Grove, I guess it's called. And he asked me the question, what is the reason that our health is deteriorating? And the answer was very simple. ultra processed foods. And I looked him straight at that. I said, that's what's going on. And that's what you need to address. And he said, well, I don't know how I'm going to address that. And I don't think there was really any outcome of that meeting, but I think that's what we're up against. And I think, you know, the food industry has no interest in health and healthcare really doesn't spend any time in involving itself in food.

53:38So this is a huge disconnect that has It's never been present in humanity. Traditionally, food and health have always been linked. And I remember years ago, I was, somebody accused me of my practices being non-traditional because I was talking about nutrition and the brain. I said, that's really non-traditional. And actually, interestingly, it was a time when I was supposed to be the chairman of neurology at our local hospital. It was my turn. Nobody even wanted the job. and one of the individuals in the group said, well, we can't have Dr. Perlmutter do it because he's doing these non-traditional things like nutrition.

54:17And I'm thinking, humanity has always valued the food that we eat and its relationship to our health and its relationship importantly to our connection to the planet as well, which is really something I think that we no longer value and even recognize. Well, not we, but, you know, generally in the world, there's no connection between the fact that the planet is giving us this sustenance. All food comes from the earth, whether you're vegetarian or not, you know, because ultimately plants are the source of food, even for the animals that people eat, with the energy ultimately coming from the sun, for all of it.

54:58So, you know, I think I was a little bit divergent on my response to you, but I think that it is very challenging. I honor what you're doing because I think what you're doing is simplifying. There are organizations here in America that offer 400 different labs. And it's overwhelming, in my opinion. David, you raise a key point there. So I'll be honest with you. I never had any plans or desires to launch a health app. right? But I just thought there are so many people out there who want to know their biomarkers so they can make changes and see what changes are working and which changes are not working, which is why I think tracking biomarkers and rechecking them is so important.

55:48Because A, you can be making some changes to your diet and not getting the drop that you might want to see in your HbA1c. I accept there are other factors like movement and stress and sleep, but it might be that, oh, maybe the diet you're trying at the moment isn't the right one for you. Maybe, you know, maybe you're really insulin resistant and actually you need to - That's so personalized. I'm just loving what you're saying. It's so personalized because maybe that diet isn't the right diet for you. Yeah, maybe you heard about the evidence on the latest podcast you listened to and thought, great.

56:25But when that diet interacts with your biology, what is the outcome on these key biomarkers? And so I kind of feel that this is not a slight on the NHS. It's basically saying, look, let the NHS do what the NHS is really good at. Let's create something that I hope is the future of preventative health in the UK. and I specifically insisted on small amounts of biomarkers, right? Because I think it can become overwhelming. Over time, David, I'm sure we'll add to these biomarkers, but we've started where there's 11 biomarkers, there's damn good evidence for all of them. I think that's a home run. I mean, look what I did in this book.

57:07I said one biomarker. I mean, we look at a lot of biomarkers in the book. I talked about homocysteine and GFAP, P-TAL-217, you know, other things. But in terms of your diet, I just wanted to control your blood sugar. And having said that, and you make the changes and your blood sugar's recalcitrant, it's still not coming around. You know, you might need metformin. You might need a medication. So that's the point here. And I think what you alluded to is the notion of personalized medicine, that this person may have adopted a specific diet and it's not yet controlling her blood sugar. So what, you know, the uniqueness there is this notion of personalized medicine based perhaps on her genetics and other aspects of her lifestyle as well.

58:00The variables like exercise, sleep, et cetera, that, you know, that is just not enough. And she would not know it's not enough unless she is testing. Exactly. We have that ability now. We should welcome it and use this information that we have. And we can, through guidance like you're offering, be stewards of our own health and really adopt more salubrious lifestyle choices based upon the input from this information. So I think what you're talking about is an absolute home run. David, I've heard you previously talk about the fact that your homocysteine was previously elevated and that you take B vitamins to manage that.

58:42I know you write about homocysteine in the book as an important biomarker we should all be looking at. I wonder if you could just touch on why you think homocysteine is so important, but also if you could remind us, for those people who didn't hear my first conversation with you, why is uric acid an important biomarker to look at as well?

59:21Dr.

59:34Rangan Chatterjee and Dr David Perlmutter. you know, the notion of a supplement means it's something added to, to supplement because of a deficiency or a need. That's why we take certain supplements. And so in my case, I had a need. I had an elevated homocysteine. I'll describe what that means in just a moment. But the reason that I have an elevated or had an elevated homocysteine is because of my unique genetics. I carry something called an MTHFR polymorphism. Now that's a mouthful. It simply means that I don't handle B vitamins in a good way when I consume B vitamins either in a supplement or getting them in food or perhaps even the ones created by my gut bacteria, such that I'm not able to methylate.

1:00:25It's a biochemical change that activates, let's say, and makes them worthwhile, while the certain B vitamin, B6, B12, and folic acid. So I have to add, and that is the reason that my homocysteine level is elevated. So I take these, I take folate, I take rather methylated folate, B12 sublingually and a B complex and every once in a while a B12 shot. And lo and behold, my homocysteine level has come down. I don't feel any different. I feel happier, right? And more confident. but I can't feel, so I'm like, oh gosh, I've been taking these vitamins, now I have more energy and my life is great. That's not what you're looking for.

1:01:11You're, again, getting back to the idea of looking at your biometrics like you described with your testing. So homocysteine has been, elevated homocysteine has been directly correlated with dramatic increased risk for Alzheimer's, even cardiovascular disease as well. We've known for a long time that homocysteine poses a threat because it is converted in the body to something called homocysteic acid. Homocysteic acid does two things that are very important. It damages the lining of blood vessels, hence the cardiovascular risk from elevated homocysteine, and it is a mitochondrial toxin, home run.

1:01:49So elevated homocysteine is threatening mitochondria and therefore threatening whether your microglial cells our friend or foe. That's why Dr. Chatterjee is adding homocysteine to his very short panel of critically important blood markers. And I applaud you for it because I went to a cardiologist yesterday. I do see a cardiologist. I had atrial fibrillation in the past, did well after a cardioversion, after a ablation procedure, home run. But I mentioned homocysteine and he said, I'm going to have to send you to a different cardiologist who knows about that kind of stuff. And I was grateful that he would refer me.

1:02:35But homocysteine is a player. I mean, it really is a player. If 28 % of people in Western cultures have this MTHFR genetic variant like I do, 28 % of people are at great risk for having an elevation of this homocysteine that is a brain threat, then darn it, they need to know about that and fix it by taking simple B vitamins. Yeah. David, I just want to comment on a couple of things there. First of all, there's this idea that, well, you may have checked your B12 levels, right? But in some ways it wasn't necessary in the sense that your homocysteine was elevated. We know that an elevated homocysteine increases your risk of dementia and, as you say, other conditions as well.

1:03:27So therefore, you need to do certain things like take methylated B vitamins to bring the homocysteine down, irrespective of your B vitamin levels. It's a subtle difference there. You're taking the nutrients to drive the biomarker down, and by driving that biomarker down, you're reducing your risk of getting sick. Yeah, let me simplify that if I can. Sure. If you have your B vitamin levels checked and they're normal, it's not good enough because you might not be deficient in those B vitamins. You might be deficient in the methylated B vitamins, which you can't really test for, but the homocysteine is a proxy for that.

1:04:11Maybe that made it more complicated. No, no. I think it's great because it's not the way I think people think about nutrients, right? So I think that's really useful. I do want to talk about uric acid, but a thought just came up for me, David, which is, I believe that you are in your 70s now. Is that correct? You're 71. 71. Okay. I remember meeting you in London two or three years ago. You were sharp, bright, right on the money. you gave a great talk. We did a lovely podcast together. I see you now at 71 having written, I think you said, what is it? 18th, 16th book? You know. This is number 16.

1:04:52Your 16th book. I think for many of us, it's inspiring. I think a lot of us would go, if I could have the sort of cognition and brain that David Pilmutter appears to have at the age of 71, I'd be very happy with that. And I think that's very relevant in the context of what we're talking about, which is our brain health getting worse as we get older. What do you attribute your apparent exceptional brain health to? I think you just mentioned it a moment ago, you said curiosity. And curiosity has been powerfully motivating for me throughout my lifetime. I'm really trying to understand, okay, there's a paper written that shows this correlation, but why?

1:05:35What's underlying it? And I think satisfying that curiosity has been the development of this idea that all of our inputs for things like Alzheimer's risk converge on the brain's immune system. So that's, you know, connecting dots has been something really central in my life, as has been the idea of compassion that I learned from my father, a brilliant neurosurgeon, brain surgeon who, as fate would have it, died of Alzheimer's. That was a powerful event in my life, and it solidified my desire to learn more. Robert Kennedy Sr. said years ago that some people see things as they are and ask why, others see things as they could be and ask why not.

1:06:28And I love it. I just love it. Because, you know, medicine has traditionally put constraints on outliers like you and me and, you know, many of the people who've been on your podcast and on my podcast. And I think we're starting to get to a place where we're starting to value a little bit the idea that, you know, maybe people are onto something. And I think the notion of lifestyle influencing brain health is really gaining a lot of traction right now. So I keep my brain aggressively engaged, not as, I don't do that as I exercise. I mean, in other words, I dedicate time to exercising each day. I don't say I'm gonna do X amount of reading and writing each day because it's good for my brain.

1:07:14That's just part of what I do. So it's not one of my lifestyle choices. I don't know if I made that clear. As are the foods I eat, the sleep I get, you know, metricizing all these things. So I'm grateful to hear you say that you think I'm still in the batter's box. That's encouraging. Let's get together when I'm 81 and we'll reassess where we are. Yeah. David, what I hear from you there are so many sort of beautiful things about curiosity, compassion. Thank you for sharing about what happened to your father and how influential that has been in terms of what you do today. But it sounds to me as though so much of what you do is an expression of who you truly are.

1:08:04And I think this is where we often go wrong with behavior change. My philosophy on behavior change is that yes, at the start, it can be tricky, right? But I think the missing link in behavior change for many people is that at some point, I actually think behavior change or adopting healthy behaviors becomes quite easy and effortless. When it truly is an expression of who you are, when there's full alignment with the person who you are and the person who you are being out there in the world are one and the same, I kind of feel that your behaviors follow suit. So I obviously don't know the intricacies of your life, but you write about empowering us to have better brain health.

1:08:54You've treated so many patients and helped them. And it strikes me as though you can't really write about this stuff and be curious about this stuff and not also do it yourself. There would be a complete misalignment between what you were writing and your behavior. So it strikes me that you do have a wonderful lifestyle. and you're engaged, you're curious, you enjoy what you do. And so it all kind of fits together instead of it being that I'm trying to make lifestyle change in conflict with the person who I believe myself to be. Well, I really want to not be that person, do as I say, not as I do.

1:09:38And many of the things that I choose to do, then I articulate. if they're effective and achieving a goal. But going back to what you were speaking about earlier, I focus not on who I am as much as who I want to be. And so there's still plenty of work to be done. And that's what life is about, is doing that work and focusing on those goals. You know, the Dalai Lama said, if you want somebody to be happy, want others to be happy, treat them with kindness. And if you want to be happy, treat others with kindness. So I think that maybe it's self-serving then, and that's okay. That if you do this work and you see the outcome, that it's good for you.

1:10:34And therefore, that's self-serving. And I'm the first to admit that. We wrote a book, my son and I, two or three books ago, called Brainwash. And it really focused on something you just touched on, and that is our decision-making. What do we decide to do once we have information? Are we able, you know, you said then it gets easier. And we focused on the hardware of decision-making, if you will. What are the mechanics of decision-making? And really tried to distill that down to two important brain areas, the amygdala, which leads to our rapid decision-making that is really pretty self-centered, doesn't look at future consequences, doesn't look at impact on other people, on the planet, etc.

1:11:21I want to do it. I want to do it now. And that's it and the story. Versus bringing into the decision-making process an area of the brain called the prefrontal cortex, which for our discussion can be looked upon as the adult in the room. That is measured, says, hang on a second, how is this going to play out in terms of your life moving forward? How does it affect other people? Is empathy involved, et cetera? The prefrontal cortex, as we reach our teenage years, begins to exercise control over the more impulsive amygdala-type brain activity. It exercises what we call top-down control, or what I like to say, the adult comes into the room.

1:12:04The pathway that connects and allows that top-down control, called the anterior cingulate, is threatened by inflammation. And that has huge implications. What causes inflammation in the human body that would then lead us to be more impulsive, less empathetic, and more self-centered? ultra processed foods. So the pervasive consumption of pro-inflammatory foods globally is segregating us away from the gift that we have of this wonderful prefrontal cortex, allowing us to conceive of the future and consequences and be empathetic beings and locking us into being this narcissistic, self-centered, instantaneous decision-making apparatus called the amygdala.

1:12:54It has its upsides. We need to make rapid decisions at times instantaneously and not think about things. When you're backing up your car and in the rear view mirror, in the camera, I used to do something called the rear view mirror for some of you younger people. That was anyway. But you see a kid on a tricycle, you don't think about it. You step on the brake instantly. That's an amygdala response. But to live your life in fight or flight and making decisions based upon the amygdala doesn't have good outcomes, even as it relates to your lifestyle choices. So what I've just done is created a feed-forward process whereby when we eat what you are so focused on, these ultra-processed foods, increased inflammation in the body, it takes us away from better decision-making.

1:13:41What does that do? We continue to eat those foods. We continue to stay up late. We continue to lack exercise, sedentarity, and that just builds a situation whereby we're paving, in my world, the way for brain degeneration. But the simple part that you, I think, touched upon is that any inroad that can allow us to re-explore and value and utilize this prefrontal cortex as playing a role in our decision-making and exercise this top-down control will ultimately allow many other lifestyle choices to come online and pave the way for a better life. So it really does come down to the nuts and bolts of our decision-making apparatus.

1:14:26Yeah, that is so interesting as to the impact of inflammation and ultra-processed food consumption on our ability to make the right decision. So maybe it's, yeah, at first it might be a bit tricky whilst you're changing over your behaviors. But as the inflammation starts to come down, you know, your decision-making will start to improve. and you may well find it easier and easier over time to make certain changes. David, let's come back to uric acid. That was the topic of your last book. Why is uric acid an important marker for us to look at when we're trying to assess our metabolic health? The next sentence I think is very important.

1:15:11Uric acid tells your body winter is coming. What does that mean? It means that elevation of uric acid does things to pave the way for your survival during times of caloric scarcity, meaning increased fat production, down-regulating mitochondrial function, increasing blood pressure as a hedge against not even finding water. So this is a genetic change that happened in Proconsul, one of our primate ancestors, around 8 million years ago. A change such that uric acid would be increased when our ancestors, our primate ancestors, ate a certain food that would be present in the late fall when winter is coming.

1:16:01Something is in the food in the late fall that triggers the body's production of uric acid that sets into motion this survival pathway. And what is that trigger? It is fructose, fruit, sugar. When does fruit ripen? It ripens in the fall before winter. It's a beautiful bit of chronobiology, isn't it? That we're in harmony with the planet. The plants finally ripen their, the starch turns to sugar, fruit gets sweet. We love sweet. We're hardwired to love sweet. We eat the fructose and fructose is directly metabolized to uric acid. That is a powerful signal to our metabolism to prepare us for winter.

1:16:43There would be selection of those individuals who had higher uric acids for survival because they made more body fat and they had a depot for caloric reservoir so they could survive during times of caloric scarcity when others who didn't have high uric acid would die. Where are we today? We're in that same situation where we still have the lack of uricase enzyme, the enzyme that breaks down uric acid such that we as humans accumulate uric acid higher than any other mammal. And that uric acid is directly leading to fat formation by changing cellular metabolism. It's directly involved in damaging mitochondrial function.

1:17:30It is elevating our blood sugar and elevating our blood pressure as well, inhibiting nitric oxide and as such leading to inability of blood vessel to relax. By its inhibition of nitric oxide, it is downregulating the effectiveness of insulin. So where is the fructose coming from? Well, fructose is the number one natural additive sweetener to food. You know, more than 80 % now of foods in America's grocery stores have added sweetener. And by and large, that sweetener is fructose or a combination of fructose with other sweeteners. Why? Because it's really sweet and it's really easy to make and it's cheap.

1:18:15So we make fructose from corn, high fructose corn syrup, that is just across the board ubiquitous in foods to make them palatable and tapping into this ancient desire survival mechanism that we have for sweet foods. So we recognize that uric acid, when elevated, is a powerful metabolic destabilizer, that higher uric acid levels are linked to all-cause mortality. They're linked to development of dementia. And they're certainly linked to development of metabolic issues like diabetes. So I think it's reasonable to understand what is your uric acid level. And I think you mentioned you're gonna include that in your 11 item panel.

1:18:58And you absolutely should. You know, people, it takes us to an interesting discussion of in the normal range. What does that mean? Oh, I got my labs back and everything was in the normal range. Oh, but the labs I got last time, I had something that was out of range. And my doctor said I should be careful. It was my B12 level was too high. And, you know, I don't know why I'm focusing on that. And vitamin D level was out of the normal range. Well, I think that clearly what you're going to do if you're not already doing is recontextualize this notion of normal range. Normal range is average. It's two standard deviations from the mean, looking at large population sets, large data sets, and what is average.

1:19:43And what is average is not necessarily what is best. We want people, you want people to be in the optimal range. In other words, what is best? Blood sugar of 100 is not good enough. No way. That's just not good enough for your messaging and my messaging. We want people who are listening to us today and will continue to listen to you and pay attention to your app to really focus on what is optimal, not just what's good enough. Yeah, absolutely. Thank you for sharing the importance of uric acid. And I completely agree. You know, there are normal ranges, there are optimal ranges. And certainly with DoHealth, we're helping educate people as to where they are now, where they could get to, and we're going to help them along the way to get there.

1:20:29David, I want to go back to the central message of Brain Defenders, which is we want to, as much as possible, keep our microglial cells in the M2 form and not have them go to the destructive M1 form. We've touched in terms of practical applications to people, we've spoken about some dietary principles. I wonder if we could go through some sort of practical take homes for people, but through the lens of M2 and M1. So for example, people know that exercise is good for their well-being how exactly is exercise good for the brain and what does exercise do to our microglial cells i'm going to answer that question in one moment but i just want to get a little bit broader perspective because i'm often asked what is the one thing the number one thing you can recommend for people uh to help them chart their brain's destiny for the better.

1:21:28And that one thing is to embrace the idea that you are in charge with regard to these choices, with respect to your lifestyle choices. Yes, sleep, yes, exercise, yes, diet. These are all connections, social connectivity, important. The most important thing is to recognize that you're in charge. You control your brain's destiny. Now, as it relates to exercise, we've known for an awful long time, people have said, yes, exercise, good for your heart, good for your brain. And it brings to mind just one other thing that's, I think, divergent. And that is that nobody talks about a brain-smart diet, but for how many years have we heard about heart-smart diet, right?

1:22:09There's even, I think, a label that goes on certain foods. This is a heart-smart food. Why not the brain? It's the same thing. We're talking about inflammation, free radical stress, and it's the very same diet. It's no different. But let's get back to exercise. I've had a cup of coffee, as you can see. We have to look upon the muscles, which are the active player in exercise, obviously, and the brain. But look upon the muscles as being an endocrine gland. And that will raise eyebrows. You know, people consider the endocrine gland, well, the adrenals, you know, the pituitary, the ovaries. These are our endocrine glands.

1:22:48And by definition, the endocrine gland is a part of the body that creates messengers that go elsewhere in the body and do certain things, right? The pituitary sends out things like growth hormone that do certain things. Adrenal corticotropic hormone from the pituitary challenges our adrenal glands to do certain things. But the muscles indeed do exactly that. They secrete chemicals when they are active that do really good things throughout the body. They are cathepsin B, ericin, interleukin-6. Oddly enough, we tend to think about that as being a pro-inflammatory cytokine, but actually does some great things.

1:23:27These chemicals go throughout the body and even into the brain and do good things for us. Importantly, something called ericin gets into the brain and stimulates the brain to produce something called BDNF. I spoke about BDNF, brain-derived neurotrophic factor, earlier. You really want to have a lot of BDNF in your brain because BDNF nurtures the neurons, nudges the microglia back to being supportive, and therefore nurtures the formation and preservation of our synapses, and yes, even the blood-brain barrier. So we want this BDNF to be present. We know that there are higher levels of BDNF when we exercise, and that was demonstrated way back in 1988 by Dr.

1:24:13Erickson, University of Pittsburgh, who correlated exercise in a one-year interventional trial versus simply just doing some mobility work, but actual aerobic exercise with not only increased BDNF, but also increased size on MRI scanning of the brain's hippocampus, showing that exercise caused growth and also improved memory performance as a consequence of exercise. Since that time, multiple studies have come out, studies demonstrating a correlation between the number of steps you take on a daily basis and your risk and or rate of cognitive decline. Simply taking steps, the magic number was oddly enough close to that 10 ,000 that we often hear batted around as being the ideal amount of steps to take in a given day.

1:25:02I think there are benefits to both aerobic exercise as it relates to producing that BDNF and also resistance exercise simplistically to increase the size of the pharmacy. So there's more muscle mass there to create these really supportive chemicals for total body health and for brain health as well. So, and I actually describe this in the book, that really what has been demonstrated in research that looked at what is best, aerobics or resistance, answer both, all of the above. that you really want to have, I actually say there should be three. And just to be kind of conjectural on that is, I think we definitely want to have flexibility exercises as well.

1:25:50Why? Because I think we need to remain flexible. So we reduce our risk of injury. If you become injured, then all bets are off. You're not going to exercise anymore. And that whole program is postponed. So I think flexibility, stretching, really important. I like balance exercising as well, keep you from falling, again, hurting yourself. But the main players are the aerobic and the resistance training. So what do I do? I go to the gym three times a week and do weights. I tend to like the machines, but I do some free weight work as well with dumbbells on an incline board, incline bench. I'm particularly fond of the ab machine.

1:26:33And then I use a variety of other machines, but I stretch first and I actually use a power plate. I think their data is solid in terms of improving flexibility and yes, balance. On the other days, I either run or walk or use an elliptical machine. But right now I've gotten a new stationary bike that I am totally thrilled with. It gamifies exercise. I'm on the stationary bike and I'm having to do these various games, which are fun and I want to win. And at the end, they show you the leaderboard. And I've gotten up to, I think, number three on the leaderboard, but no, number four, and I'm the old man.

1:27:13So I did an Instagram post saying, hey, for you who are using the Averon stationary bike or treadmill, that David P, that's me. I'm number form later for don't let the 71 year old guy catch you but anyway so for me gamifying uh has been very helpful because 30 40 minutes go by quickly because you know a machine like that can be boring that's why i like to be outside and run because then i can see things breathe fresh air you know see people wave at them and uh experience nature yeah but uh so that's what my program looks like and i'm sticking to it yeah david thank you for sharing what you do I think obviously I can't know this for sure but I would imagine there are going to be some people listening to this conversation who are thinking I wish my mum or dad in their 70s was doing what David is doing and the reason I say that I just want to really highlight this point that yes we've used some technical language at points during today's conversation right really tried to help people understand the science that exists behind your recommendations and everything you talk about and brain defenders.

1:28:26But on a human level, this is very, very real. People's lives are being so devastated by family members having cognitive decline. A, you know, on a sort of individual intersocial level, it can be very frustrating to see that happen to a loved one. there can be significant financial implications for families when it comes to how do you look after people with cognitive decline? Do they need to sell their house, go into some kind of facility? These things are incredibly worrying for people, yet the central message behind so much of what we're talking about today, and frankly what both me and you have covered on our various platforms for many years, is that it really doesn't need to be that way.

1:29:16There are things, it's not as difficult as you think it is, there are things that you can do that are going to really make a difference. But I do think, David, there may be a generational issue here in the sense of, you said before, right? We spoke about this war on our attitudes. I saw a good mate of mine this weekend. And his mother, unfortunately, is starting to decline cognitively. And she's going to see her conventional doctor. And really, you know, as well as I do, that you go to your conventional doctor, you're generally told that there's not much you can do about this. There is an inevitable decline.

1:29:58You know, yes, they might put you on a waiting list for things and check your blood pressure and your blood sugar, but there's not much practical guidance. And I was chatting to my buddy and he said, wrong in everything you're talking about, I'm trying to share with mum, but she's not listening. She drinks half a bottle of wine every night and has them for many years. That's just part of her lifestyle. She's unlikely to change now. And I think, David, there's a really key point here, isn't there? Which is, look, I'm learning this information at an earlier stage in life than perhaps you did because the science is there, right?

1:30:37So I'm able to really implement a lot of this stuff in my 40s and hopefully that will continue for decades, right? But there is a generation and maybe you're part of that generation, but perhaps because of the way that you think, your curiosity, your practice, you've ended up in a different state of health compared to many of your peers. But I think my friend's mother, there are so many people out there like that. They think this is inevitable. And what advice would you give to people like my friends who say, Rangan, I'm listening to this information, I'm reading the stuff, but I can't get my parents to put the advice into action?

1:31:20I think it's very challenging because my generation and his mother, again, we were brought up to think that our lifestyle choices didn't matter. do whatever you want that you like, you know, cater to your desires. And modern medicine's got the fix. And don't worry about it. They'll fix your heart. They'll fix your brain. You know, and that's just an incredible mismessaging that, you know, really characterizes what you're talking about here. You're right in your observation of people in my generation, because they're very difficult to convince and to prevail upon in terms of, you know, what your friend is up against with his mother.

1:32:04And, you know, that's pervasive. What I would say to that individual is, look, do the best you can, but let's talk about you. Because I really think that it's, the bigger play here is the 40-year-old and 50-year-olds, 30-year-olds, that, you know, John Kennedy, President Kennedy said during his inaugural address that the time to fix the roof is when the sun is shining. Not to say we ignore these individuals, we do the very, very best we can, but frankly, you know, a lot of times there's just not going to be any response from the child to the parent, on the part of the parent, because the parent's going to go, like you say, to their trusted doctor who may likely not be dialed in in terms of what you and I have discussed today and the value of what we've talked about today.

1:32:58It's incredibly valuable. It is the top tier ahead of any pharmaceutical or other type of intervention. What we've discussed today are the keys to the kingdom. Yeah. And it's not monetized. That's why we don't hear about it very much. Yeah. I mentioned alcohol there with my friend's mother. What does chronic alcohol consumption do to that M2-M1 balance? Well, the threat of Alzheimer's with respect to alcohol consumption is a U-shaped curve. That those who do not consume any alcohol have a slightly higher risk in comparison to women who drink one glass of wine per day or men consuming two glasses of wine today.

1:33:41and then the risk goes up with more alcohol consumption. So there's a U-shaped curve with an ideal range of alcohol consumption. I think more recent literature would indicate that really isn't true globally as it relates to alcohol, that, you know, call it what it is, alcohol is a neurotoxin and it threatens brain cells. Is there an upside to the polyphenols in red wine? Yeah, there is, but there's also non-alcoholic red wine and other wonderful sources of polyphenols that don't require alcohol. But I get that there's an upside to alcohol in terms of what it does for people socially, been part of their culture, but it's not a half a bottle, it's a glass.

1:34:27So I think it's making these subtle adjustments so that you can still feel good about life and participate and minimize a risk. Yeah. David one thing we've not talked about is genetic testing and again I think a big theme throughout our conversation today is how our approach to medicine has changed over the years right there's normal blood tests versus optimal there's getting involved when you have symptoms versus practicing true prevention and when I was at medical school Edinburgh Medical School between 1995 and 2001. I'm pretty sure we were told about APOE4 testing, but the general view was you don't do it, right?

1:35:17There's no point knowing your genetic status because there's nothing you can do, right? So why would you want to live your entire life with fear when there's nothing you can do? Now, of course, our understanding has moved on dramatically since then. So I wonder, David, if you could first of all explain what is APOE4? What does having one or two alleles do to your risk of getting Alzheimer's? And then I'd love to get your perspective as to whether you're a fan of getting tested or not. Let me first answer that I'm absolutely a fan of being tested. We know that individuals who carry APOE4 alleles, so this is a genetic allele that comes and you have two shots at it.

1:36:01It comes in three varieties, APOE2, APOE3, and APOE4. As it relates to Alzheimer's, APOE2 is protective, APOE3 is about neutral, and APOE4 is associated with increased risk. And as I mentioned before, you have two shots at this so that you can have any combination you can think of between 2, 3, and 4. You can be a 4-4, which poses a significant, it's associated with a significant risk for Alzheimer's disease through multiple pathways that I'll mention in just a moment. But it's been indicated that carrying APOE 4-4, and there are a significant number of people in America who are carriers of APOE 4-4, that your risk may increase for Alzheimer's by as much as eightfold, even as high as some reports as high as 12-fold risk, but not determinant.

1:36:58It's a predisposition, but not a determinant. I'll double-click on that in just a moment. Having one allele, in other words, having a 3-4 or a 2-4 combination is also associated with an increased risk of Alzheimer's by anywhere between three and five-fold. So a really significant increased risk. Now, why is APOE4 associated with such an increased risk? What does it do? We know that it involves multiple pathways. It involves downregulation of mitochondrial function, and as such, seems to target microglial cells. But in work done by a British researcher, Dr. Sarah Marzai, at what is called the Marzai Clinic, I had her on my podcast recently, she actually created microglial cells that expressed either no APOE, APOE2, 3, or 4, and then injected them into the Alzheimer's mouse model brain, who lacked microglial cells, and demonstrated dramatically that those who had APOE2 and had dramatic reduction of inflammation, sort of middle-of-the-road inflammation, APOE3, but dramatic increase in cell loss and beta-amyloid accumulation in those carrying the APOE4 allele, the microglial cells that she had engineered and injected into their brains.

1:38:25So again, while we've kind of labored over what are the exact pathways by which APOE4 is ultimately increasing risk of Alzheimer's, it looks as if now that's converging on the microglial cells, which is really kind of interesting because we can offer offsets to that through the techniques that you and I have talked about today. What I'm saying is people can have APOE4 allele and then engage these various other lifestyle changes and other practices beyond lifestyle to actually offset and i.e. reduce their risk that would otherwise have been significantly amplified. Again, I want to say that we should look upon carrying the APOE4 allele as not a determinant, but as a predisposition.

1:39:12It is clearly a risk marker. It's a risk marker like MTHFR. Again, 28 % of people, like me, like I am, have this MTHFR and therefore elevated homocysteine, another risk factor for Alzheimer's. That similarly can be offset, in my case, by taking methylated B vitamins. So I think there's been a huge change in the messaging of, well, not necessarily with respect to mainstream, but with people who understand that notion of this APOE4 being a predisposition, but not a determinant. That, okay, these are the cards you've been dealt. How are we going to play the hand? Yeah, it's such a key point, David.

1:39:55This idea of knowing your risk. I mean, look at this a different way, right? The amount of times in my career, let's say a middle-aged man would not pay attention to their lifestyle until they came in for a check and their blood pressure was found to be significantly elevated. And often that might happen at a time when maybe their own father had a heart attack or a buddy of theirs from school had some angina or something like that. right so getting the right test for some people yes it makes them anxious but for a lot of people it is the stimulus that they need to then engage with changes right so someone might hear this podcast i go yeah yeah it's important i look after my brain health you know but my life's pretty good you know i don't feel i've got any symptoms yet my lifestyle is generally okay if they did a genetic tests and came back as a, let's say, a 3-4.

1:40:56Maybe they don't have two ApoE4 alleles, maybe they just have one. They then know if they're educated in the correct manner that, oh, okay, if I look at all my risk, I have a genetic predisposition here, which means it's even more important that I lock in on these lifestyle changes. If I've got ApoE4-4, like double, you know, yeah, you don't want to get anxious about it. You want to go, okay, right, there's nothing I can do about that. What can I do to reduce my risk? And I think that's an empowering message. Now, could one argue, David, that the recommendations that we would make to you for your brain health are the same irrespective?

1:41:43So, for example, if someone was listening and And they said, David, listen, I'm going to get brain defenders and I'm going to do everything in that book. Why should I go to the trouble and expense of getting an APU4 test? You know, does getting that allele back practically make any difference in terms of what I do? I think the answer is that I cannot imagine anyone doing everything I talked about in the book. So there's a hierarchy. And I think that if you were carrying APOE4, you would be much more dedicated and really be involving yourself, not just in the standard recommendations that I made that people are probably aware of, but I wanted to reinforce, but even some of the leading edge things that we talk about in the book.

1:42:30And beyond that, I think being much more aggressive in terms of following your cognitive function. You know, we have the ability to look at cognitive function in very sensitive ways these days. And that would guide you in terms of at what level should I be engaging this program that I describe? Yeah, there's so much you've covered in the book, David. We haven't even scratched the surface today. I really appreciate the stuff at the end where you talk about some of these novel therapies, but also where you think this field is going. I also just want to say, I read a lot of health books. and this I think is beautifully written.

1:43:07It's very concise. It's to the point as to where the science is and there's so many practical tips in it that I think people could just pick it up, scan and immediately know what they have to do. So thank you for once again writing a wonderful book. For that person who has realized throughout this conversation that they've neglected their brain health for the majority of their life. They've not paid attention to their diets, their exercise, their sleep, their stress, but something shifted within them and they want to make a change, but they're worried that it's too late. What would you say to them?

1:43:49If anybody is cognitively intact enough to have that mental conversation, I'm worried that it's too late, they're in great shape. They are in great shape and ready to take full advantage. and redirect their brain's destiny. So absolutely have at it. Yeah, great advice. Very empowering. David, the book's called Brain Defenders. Thank you so much for coming back on the show. My absolute pleasure. Thank you.

1:44:19Really hope you enjoyed that conversation. As always, do have a think about one thing that you can take away and apply into your own life. But also have a think about one thing that you can teach to somebody else. This will not only help them, it also helps you learn and retain the information. Now, as this is the last episode of the season, I want to say a heartfelt thank you to all of you who listen each week. And if I may, ask you two quick favours. If you have ever received value from this podcast and have never got round to leaving a review for the show on Apple Podcasts or Spotify, I would really appreciate it if you could take a moment right now to do so.

1:45:06It will only take you about one minute and it makes a massive difference for the show. Secondly, if there is anyone in your life who you feel would benefit from listening to this episode or this podcast in general, please do spread the word. My team and I work really hard each week to make this show in order to help people improve their lives. And of course, the more people who listen, the more people who can experience the benefits. So my request is this, over the summer, can you, would you share this show with five people in your life who do not currently listen? If all of you were to do this, I honestly feel we can create a powerful, positive ripple effect where we help more people feel happier and healthier.

1:45:57No pressure, of course. If you don't want to share for whatever reason, that is completely fine as well. Now, before I sign off, I am really excited to share that I am bringing my Thrive Tour, Transform Your Health and Happiness, to Canada and Europe this September and November. It's a live, interactive, uplifting show that over 20 ,000 people came to last year across the UK and Australia. I'll be sharing powerful stories, life-changing insights, and simple tools that will inspire you to feel better, think clearer, and live with more intention and joy. To get your tickets right now and see all of the dates and venues, go to drchatterjee.com forward slash live.

1:46:46I really hope that you can join me. Thank you so much for listening each week. I hope you managed to have a relaxing and nourishing summer. And I will see you back here in September for the new season. And as a little teaser, I have some phenomenal guests lined up already. Always remember, you are the architect of your own health. Making lifestyle change is always worth it. Because when you feel better, you live more.