Brain Doctor: The Foods Quietly Raising Your Alzheimer's Risk (It's NOT Sugar) | David Perlmutter

1. 0:00 – 1:49

   Ultra-processed foods and Alzheimer’s risk: what the data is showing

   1. RCDr. Rangan Chatterjee0:00

      What is the effect of a high ultra-processed food diet on the health of our brains?

   2. DPDr. David Perlmutter0:09

      Well, that's a great place to start. So what we know, uh, with respect to these ultra-processed foods is that, uh, they lead to metabolic mayhem. And I think, you know, you and I can unpack all of the pathways, uh, with which this, uh, metabolic mayhem is destructive in the brain. But, you know, the bottom line is there's a metabolic underpinning for Alzheimer's disease. When you look at what people eat, there's a relationship, uh, to e- evaluating what people eat and their risk for a disease for which we have no meaningful pharmaceutical treatment. And interestingly, in the Journal of Prevention of Alzheimer's, let me pause right there. Think of it, a journal of prevention of Alzheimer's. For me, that's a huge, a huge step that they would dedicate an entire medical journal to the notion of Alzheimer's prevention when, you know, so much in our world is really focused on the treatment of particular diseases. Anyhow, in January of 2025, published an article that really evaluated over a 12-year period of time, uh, in 1,375 people, followed them for 12 years as part of the Framingham Heart Study, and basically followed what they ate. And what they found was really quite, uh, important, I think, for our discussion today, that for every one serving of, uh, ultra-processed foods, whatever they were, these patients had an associated increased risk of Alzheimer's of 13%. And for those who were eating 10 or more servings per day of these ultra-processed foods, which, you know, here in America make up 60% of adult calories, think about that.

   3. RCDr. Rangan Chatterjee1:48

      Mm-hmm.

2. 1:49 – 4:36

   Alzheimer’s as lifestyle-driven and preventable: a shift in mindset

   1. DPDr. David Perlmutter1:49

      But if people consume 10 or more servings per day, their risk for Alzheimer's went up about threefold. Now, is this meaning that ultra-processed foods are causing this risk? You know, this is a, uh, a, you know, a retrospective study. Uh, it's a correlation, not causation. But if you ask me, and I think you are asking me, yes, I... and I'll, I'll break it down as to why I think, uh, these ultra-processed foods are so darn threatening. So, you know, I've been thinking about this for an awful long time and writing about it and lecturing about it because I think people need to grasp the fact that Alzheimer's doesn't just happen. You know, it's not a genetic thing by and large. It is a manifestation of our lifestyle choices and beyond food, that's for sure. The point is that should be empowering news for people, that this disease which people fear more than cancer, uh, is something over which they have a, a significant degree of control in terms of being basically the architect of their brain's destiny.

   2. RCDr. Rangan Chatterjee2:52

      Yeah. Thank you, David. There, there's so many empowering messages that I think exist in 2026 about brain health compared to even 10 years ago in 2016, right? There's so much science, there's so much research, and the reason actually I started off this conversation asking you about ultra-processed foods is because I think there's been a growing awareness for some time that heavy ultra-processed food intake is not a good thing for health. I think a lot of people know that there's a relationship between your rate of intake and obesity and things like Type 2 diabetes and maybe your risk of heart attacks, but I still don't think it's common knowledge that the overconsumption of these types of foods has a detrimental impact on the health of our brains. And your new book, which I thoroughly enjoyed reading over the past 24 hours, uh, Brain Defenders, in the chapter on diet, I'll be honest, there were some pretty alarming statistics. You quote some research, David, that was published in JAMA Neurology in 2022, where they followed more than 10,000 individuals for an average of eight years, and this is what you wrote in your book, "Compared with the participants who ate the least amount of ultra-processed foods, those who consumed higher amounts experienced a staggering 28% increased rate of global cognitive decline," meaning all areas of decline, including memory, language, and attention.

   3. DPDr. David Perlmutter4:32

      Yeah.

   4. RCDr. Rangan Chatterjee4:32

      That is a staggering increase in risk, isn't it?

3. 4:36 – 6:39

   Metabolic health, insulin resistance, and brain decline: connecting the puzzle pieces

   1. DPDr. David Perlmutter4:36

      It really is, and a- again, you know, critics would say, "Well, that's correlation. It's not causation." And I, I understand that you cannot say, uh, that, uh, you know, the ultra-processed foods are causing dementia based on this study. I can say it, and I believe it, but, you know, from a strict scientific perspective, this is a correlation. But when we add these studies together in the aggregate, the study I just quoted you on ultra-processed foods w- I don't think is in my book because it, it, it's quite recent. Uh, but having said that, um, you know, I, I think we understand that when Type 2 diabetics manifest a 3 to 4X increased risk of, of developing Alzheimer's and even pre-diabetics, we make the, we see the relationship to insulin resistance and even mild elevation of blood glucose, uh, and then we see what people absolutely understand, and that is the relationship of consumption of these ultra-processed foods to Type 2 diabetes and, as you mentioned, obesity, uh, then, a- and obesity as a risk for Alzheimer's as well. Everything really kind of falls into place. The puzzle pieces are absolutely falling into place still in a world that would like us to believe that we should live our lives come what may, and then when we develop an issue, there'll be a magic drug to fix it. That's the messaging in the Western world. Uh, I mean, I, I don't know how it is in the United Kingdom, but here in America we have- Uh, television commercials for one drug after another. And it's interesting 'cause when you, when you s- take a look at what the drugs are doing, many of these drugs are what we call monoclonal an- monoclonal antibodies, or antibodies that are directed against inflammatory proteins used in a lot of autoimmune and inflammatory conditions. And it's quite clear that metabolic disturbances increase these autoimmune and inflammatory conditions through something called immunometabolism, meaning there's a direct relationship

4. 6:39 – 17:46

   Microglia as the central mechanism: M2 ‘supportive’ vs M1 ‘destructive’ brain immunity

   1. DPDr. David Perlmutter6:39

      between our metabolic health and how balanced our immune system really is. I gave a lecture on that this past weekend, uh, in Chicago. How does immunometabolism, this notion that our metabolism plays out in our immune system, how does that manifest in the brain? And it is the f- the exactly what Brain Defenders is all about, the fact that we have in our brains immune cells called microglial cells, and they can be friend or foe. They can be supportive of our blood-brain barrier and help us make new neurons and new synapse connections between the neurons, or they can shift and become the evil twin where they destroy our synapses, they reduce our rate of growing new, uh, neurons, and they damage the important blood-brain barrier. That shift between being the good twin or the evil twin is dictated by their metabolism, and their metabolism reflects our total body metabolism. Now, I've just said a lot, but the- let me collect the two outlying dots. They are that our body's metabolism determines whether our brain's immune system is going to support a good, wonderful, healthy brain or is going to set the stage for our brain to be destroyed based upon our metabolism. And here's the empowering part about what I just said. Our metabolism, each of our metabolisms, your metabolism is based upon choices that you make every day. So that's darn empowering that you have the choice to make lifestyle, uh, changes to m- increase the, the value of your metabolism to ultimately affect your brain's destiny. So, you know, I know we, we, we have a lot of time together today to, uh, chat about a lot of different things, but having said that, what a message. I mean, it, that flies directly in the face of what we are being messaged. What we're being messaged is, as I mentioned earlier, just live your life however you want, and we will fix it. That doesn't work. Uh, we need to have the ball hit across the net to our side of the court so that our destiny really depends on how we return that serve.

   2. RCDr. Rangan Chatterjee8:49

      Yeah, David, I've been thinking a lot about brain health over the past few months. I've had multiple conversations on this podcast with people like Professor Dale Bredesen, Dr. Tommy Wood, all kinds of professionals and researchers like yourself who are showing us from multiple angles that there is plenty we can do about this. This is not our fate. Even if our mom and our dad or our auntie had Alzheimer's, it doesn't mean it's going to happen to us. Now, what's really interesting though, as I talk about this with my friends and colleagues, and perhaps this is my age, I'm, you know, in my mid to late 40s, David, but a lot of people I speak to will say back to me, "I'm worried about my mom. I'm worried about my dad at the moment." It, it very much feels as though this is reaching epidemic levels, right?

   3. DPDr. David Perlmutter9:49

      It is.

   4. RCDr. Rangan Chatterjee9:49

      The amount of people who are struggling with cognitive decline as they get older is becoming so common that I believe many people think it is the norm, but it's not, is it? It certainly doesn't have to be the norm.

   5. DPDr. David Perlmutter10:02

      Yeah, I mean, it, uh, you know, people laugh away the idea of senior moments, and instead of Alzheimer's disease, they call it old-timer's disease. Well, I will tell you, uh, I'm not planning on being there, and I know Dale Bredesen's not planning on being there. And, uh, it, it's interesting. Let me ta- take you back a moment to what you just said, and you said, "You know, my friends in my 40s are telling me about they're worried about their parents." My statement is that your friends in your 40s should be worried about themselves because we know that the seeds are sown for Alzheimer's in terms of the metabolic threats to the brain in our 30s and in our 40s. So this is when we really need to start concentrating on an Alzheimer's prevention program because the metabolic changes that occur in the brain happen two, three, four decades prior to the clinical manifestations. When I say clinical manifestations, I mean the, the issues that people begin to recognize, loss of sense of smell being something that happens very early, a loss of certainly memory, cognitive function, uh, executive function, et cetera. But tho- those things are late players. Uh, you know, they're late to arrive at the party and, you know, my outreach now, I, you know, my outreach has really been to those people who are suffering and, uh, you know, and hopefully their family members might, you know, get ti- uh, clued in on what I'm talking about. But I realize now that to really have an impact because of the very epidemic that you describe, uh, we've got to be targeting, uh, uh, individuals at a lot younger age and make them realize that, yes, what you just said is true, that this is an epidemic in older people, but the way to prevent it is to target those individuals earlier in life. We know that, well, at least here in America, that- I mean, we have, uh, 30 m- a million, uh, Americans, adults with prediabetes. And, you know, the staggering thing about that, uh, fact is that 90% of them don't know it.

   6. RCDr. Rangan Chatterjee12:01

      Hmm.

   7. DPDr. David Perlmutter12:01

      So I really w- welcome and, uh, uh, applaud the idea that there's direct-to-consumer laboratory testing now available here, and that means that people can't blame their doctor and say, "Well, my doctor told me I needed a fasting blood sugar every year, and it was pretty good," and he or she says, "I... We'll, we'll see what you're doing next year." No, the people can be again, uh, in charge and can get their own fasting blood sugar, but beyond that, get much more detail as it relates to their metabolism.

   8. RCDr. Rangan Chatterjee12:32

      Yeah.

   9. DPDr. David Perlmutter12:32

      A fasting blood sugar is interesting, especially if it's really high, you know you've got a problem. But a predictor of fasting blood sugar elevation even before it's elevated is a fasting insulin test. And, you know, I'm very deeply, uh, involved in, uh, getting that message out-

   10. RCDr. Rangan Chatterjee12:49

       Yeah

   11. DPDr. David Perlmutter12:49

       ... that we should all know our fasting insulin levels and our hemoglobin A1Cs. And, you know, if you really wanna take it to the next level, wear a continuous glucose monitor, believe it or not, even if you're not diabetic. These are available without prescription.

   12. RCDr. Rangan Chatterjee13:02

       Yeah.

   13. DPDr. David Perlmutter13:03

       And not only shows us what our blood sugar is in the morning when we awaken, but also gives us a sense as to the dynamics of our blood sugar control during the course of the day, during, uh, the times during which we exercise, what happens during a meal, after a meal, et cetera. These are very in- uh, valuable inputs for us in terms of understanding our metabolism. And I would say if we want to rein in our metabolism, that, that keeping blood sugar where it needs to be is absolutely job one. Why do I say that? Because all the other lifestyle inroads play out in terms of blood sugar. Not getting enough sleep, exercise, uh, stress. Uh, I don't know that lack of social connection is necessarily threatening blood sugar, but I bet it is. Uh, I'm, I'm certain if we were to, to, you know, look at, uh, for a study about that, we would see it, because, you know, a lot of people talk about it as it relates to reduced risk of Alzhe- uh, Alzheimer's vis-a-vis, you know, the blue zone studies, et cetera. And I think it, it, it sort of, yeah, okay, you know, social connection's important, but let's talk about sleep and exercise. That's usually the conversation. But, you know, this ... It's one of the important pillars, so I wanna make sure we don't, uh, overlook that.

   14. RCDr. Rangan Chatterjee14:16

       Yeah. Thank you. I, I completely agree. Um, social connectivity is absolutely huge, and I think you raised a really good point, David, about this idea that we, we should be paying attention to our brain health in our 40s, not just in our 70s when things start to go wrong or we forget our grandchild's name or whatever it might be. I think I wanna come back to that point. Testing for sure. Before we go into those areas, though, one of the things I enjoyed the most about your new book, Brain Defenders, is that you really set the stage at the top of the book about this one fundamental mechanism that potentially underlies virtually all neurodegenerative conditions. You've already mentioned the microglia immunometabolism, but I really want us to just really understand that because this kind of balance between M1 microglia and M2 is something I hadn't come across before. And once you get that in your head, you can look at every single lifestyle intervention through that lens and go, "What is this doing to M1 and M2?"

   15. DPDr. David Perlmutter15:27

       Absolutely. That, that's what the book's all about. You, you hit the nail on the head. It's exactly what we're talking about. And, you know, the polarization, uh, of these microglial cells from being M2 supportive to being M1 destructive i- is a theme now that we're actually seeing elsewhere in the body. We've known that macrophages, uh, the, uh, immune cells in, you know, in the rest of the body go through the same sort of shift when they are metabolically challenged. We even know that chondrocytes that are involved in either nurturing or destroying our joints have an M2 supportive or M1 destructive configuration. So, you know, uh, but when you ... We see through the lens that you describe, the part ... The, the, the take-home message is i- empowering because we control the levers that determine whether these microglial cells are gonna be on our side or setting the stage for, uh, brain destruction. And, you know, I'm thinking of a slide that I use when I, when I, um, in my presentations, in fact, with who you mentioned, Dr. Dale Bredesen, three days ago in Chicago, and it is a, a type of brain scan, uh, that is called TSPO, and it's actually a, a brain scan, uh, that allows us to image activated threatening M1 microglia when people are alive, in vivo. And when I show the image in, in Alzheimer's, you know, the brain lights up, but then I list the diseases in which this TSPO imaging is positive, in other words, microglia have been shifted to being the evil twin, and the list is really every major neurodegenerative condition you can think of, including Parkinson's, frontotemporal dementia, multisystem atrophy, progressive su- supranuclear palsy, uh, long Covid, PTSD, major depression.

   16. RCDr. Rangan Chatterjee17:14

       Hmm.

   17. DPDr. David Perlmutter17:14

       You know, there are a lot of things included, uh, that are manifestations of this shift in the immune system. And, you know, that said, it, it sheds light not just on the neurodegenerative issues, but in the mood disorders as well, which we, we've known for many years are characterized by increased inflammation in the brain. But now we understand why there's destruction, why there's, uh, destruction of the synapses, for example, in particular parts of the brain like the prefrontal cortex, because we're turning on these immune cells that are damaging the synapses.

5. 17:46 – 21:22

   Inflammation as the trigger and amplifier: the feed-forward ‘spreading’ cycle

   1. RCDr. Rangan Chatterjee17:46

      Yeah. Just to check I've got this clear so far, David. The microglia are the brain's resident immune cells. When they become damaged for a variety of reasons, you know, insulin resistance, toxins, infections, whatever it might be, they change shape and function. Ultimately, that causes a disruption in mitochondrial function, and that then leads to neuroinflammation, which sits at the heart of many of these different kinds of neurodegenerative conditions. Is that an oversimplification or have I roughly-

   2. DPDr. David Perlmutter18:24

      No, I'm gonna actually, uh, I'm gonna actually simplify even further.

   3. RCDr. Rangan Chatterjee18:27

      Okay.

   4. DPDr. David Perlmutter18:29

      When there's a shift from M2 to M1, as you correctly stated, there's a phenotypic ship, a shift. In other words, they sh- change their shape. There's a functional shift, as you described, and there's a metabolic shift away from using the mitochondria to produce energy to another type of energy production that we call glycolysis. But importantly, one of the major inroads or, uh, threats that shifts the mito- uh, mi- uh, the microglia is inflammation. The chemicals of inflammation called cytokines target the M2 microglia and shift them to becoming the evil twin. Those inflammatory cytokines can come from anywhere in the body. When you get your arms around that, you realize then, oh, they can come from a leaky gut. When we have a bowel disturbances, for example, that leads to increased inflammation in the body, these chemicals make their way to the brain and now help us understand why there is such a constant correlation between neurodegenerative conditions like Parkinson's and bowel disorders. Further, and here's where the story gets really interesting, these inflammatory cytokines are produced once those microglia shift to becoming the evil twin. So once we shift from being supportive and loving M2 microglia to the threatening M1 configuration, it, as you mentioned, increases neuroinflammation. What does that neuroinflammation do? It further targets those good M2 microglia and shifts them over to being zombies. Think about that. So this explains now, we understand why a football player who no longer is playing football but yet has been diagnosed with CTE, chronic traumatic encephalopathy, gets worse over time, why Alzheimer's patients worsen over time, why Parkinson's patients continue to worsen over time long after they've had their head trauma, long after they've had their exposure to a toxic chemical. We can talk about that a little bit later. I think we're, we're [laughs] teeing up an awful lot to talk about. But that said, it's because this spreads th- through the brain like a cancer. These M1 threatening microglial cells target th- the support of M2 microglial cells and with time become dominant. So, uh, what you said is very true, but I think the important thing is that there is a shift in their metabolism away from the mitochondria doing the heavy lifting as it relates to energy production to a different form of energy production called glycolysis. So in a very real sense, we should be targeting mitochondria, as we talk about in Brain Defenders, uh, if we wanna do something very, very important, and that's the take-home message of our time together today, and that is that the microglia can shift back to being good, and that's our mission.

6. 21:22 – 26:29

   Why diet changes alone may not fully reverse damage: multi-pronged interventions

   1. RCDr. Rangan Chatterjee21:22

      Yeah. Most of the messages are deeply empowering. The message is it's never too late. Having said that, going back to your chapter on diet when you were, you know, quoting some of the research that exists out there on the relationship between diet and brain health, I mentioned one of the studies that you wrote about. Um, there was another one you spoke about, this 2024 study published in Neurology led by a researcher from Harvard Medical School, where they investigated the relationship between ultra-processed food consumption and brain health outcomes. And yes, you know, as many other studies, that study, you know, concluded that there was a significant association between higher ultra-processed food intake and an increased risk of cognitive impairment. But I'll tell you what was really striking for me, David, a couple of paragraphs later you write that, "Interestingly, when some of those patients adopted the Mediterranean diet, the DASH diet," that Dietary Approaches to Stop Hypertension, "or the Mediterranean DASH diet, after the initial survey, the brain-altering effects of the UPFs persisted. This means switching to a healthier diet can't always reverse the damage done." You just mentioned that, didn't you? That we want M2 microglia. If for a variety of reasons they start to shift to M1, that's problematic for our brain, but then it's a feed-forward cycle where those M1 microglia themselves start to cause more M2s to go to M1. Could that be one of the reasons why when we change our diet, eat, let's say, after 20 or 30 years of a poor diet, that actually some of those brain-altering effects might, um, might have persisted?

   2. DPDr. David Perlmutter23:17

      Yeah. And I think, you know, w- when we look at what has been the goal of pharmaceutical intervention for Alzheimer's disease, their goal, I mean, in an ideal world, would have been improvement in cognitive function. But then they settled on, well, let's just see if we can stabilize people so they don't decline. You know, that's a reasonable goal for a patient with early Alzheimer's. Uh, but they even failed at that. So I, I think that, uh, the idea of reestablishing cognitive function and, and, and improvement is going to require a, a much more comprehensive approach, and we outlined a lot of things in the book, uh, that need to be added Diet is certainly one important pillar. A diet is really critical as it relates to reducing inflammation, but if we, uh, wanna really boost, uh, the growth of new brain cells and the, the formation of new synapses, we have to, uh, target exercise as well such that we will increase, uh, the production of brain-derived neurotrophic factor in the brain or fertilizer, if you will, that helps also nudge these microglial cells, uh, back from being M1 destructive-

   3. RCDr. Rangan Chatterjee24:24

      Yeah

   4. DPDr. David Perlmutter24:24

      ... to being M2 supportive. You know, if you look at Dr. Dale Bredesen's work, he talks about 36 things, uh, that need to be at least considered, if not targeted, to bring about, uh, actually improvement in brain function. So, you know, the mission here is to indicate that there are multiple inroads-

   5. RCDr. Rangan Chatterjee24:42

      Yeah

   6. DPDr. David Perlmutter24:42

      ... that threaten these microglial cells. We know that their metabolism is key, so metabolic health is certainly important. Inflammation is very important as well. Infections need to be considered. Uh, toxic, uh, uh, issues like metals, et cetera, need to be considered. All of these things es- uh, attack the M2 microglial, so there are receptors on these microglia, uh, that then, uh, instigate the change in their internal metabolism that leads to their shift to becoming M1.

   7. RCDr. Rangan Chatterjee25:11

      Yeah.

   8. DPDr. David Perlmutter25:11

      But I think your point is well taken that, uh, and Dale Bredesen makes it very clear that we need a multi-pronged approach if we're going to do more than stabilize but if we're gonna, uh, lead to improvement. Now, as we say that, uh, that is something that can be achieved. I actually quote his work in the book and, uh, uh, present a couple of his case studies where in, uh, in which patients clearly improved, uh, and demonstrated not only improvement in their cognitive function but improvement in the size of their brain's memory center-

   9. RCDr. Rangan Chatterjee25:45

      Yeah

   10. DPDr. David Perlmutter25:45

       ... the hippocampus on brain imaging. That is black and white. These are read by independent, uh, ra- radiologists who didn't know that there was an intervention and clearly described enlargement post-treatment of the hippocampus in these treated individuals. So the idea that the brain can't improve and cognitive function can't improve, I think is outdated. Uh, I, I think it takes a lot of work. But I think the beauty of what we're talking about now is it takes us away from hoping and relying upon something called monotherapy. Western medicine is built upon this idea of one drug for one illness, and in Alzheimer's it just doesn't hold up.

   11. RCDr. Rangan Chatterjee26:29

       Yeah.

7. 26:29 – 35:37

   From monotherapy to systems thinking: Parkinson’s, mitochondria, and GLP-1 lessons

   1. DPDr. David Perlmutter26:29

      And, you know, in Parkinson's it doesn't hold up. We don't have any medications right now to treat Parkinson's disease, and that may be surprising for some of your viewers. But the reality is all of the medications that are approved for Parkinson's treatment are treating the symptoms. They're treating the smoke. They're not treating the fire. I 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, uh, as it relates to, uh, addressing the tremor are valuable, allow people to continue on with their lives. But the disease continues to progress underneath that, uh, symptom-based approach, uh, readily. And, uh, maybe this sounds a little bit divergent but, uh, in 2024 a fascinating study, and I talk about it in the book, uh, was, uh, published in the New England Journal of Medicine. 135 Parkinson's patients were randomized to receive a GLP-1 Ozempic-like drug-

   2. RCDr. Rangan Chatterjee27:32

      Mm-hmm

   3. DPDr. David Perlmutter27:32

      ... or a placebo for one year, and the results were dramatic. Uh, the group receiving the placebo, uh, continued to decline as we would see in Parkinson's, but the group receiving the GLP-1 drug stabilized it, in fact, slightly improves on what is called the Unified Parkinson's Disease Rating Scale, a, a standardized way of assessing how a Parkinson's patient is able to function, uh, in, in their daily life. So this is the very first time, uh, well, I'm gonna actually say it's the second time. It's... I, I'll tell you the first time in a moment. The, uh, uh, that the actual underlying metabolic issue, uh, in Parkinson's was addressed and look what they found. Now, I'll tell you about the first, uh, was, uh, actually our study, uh, in the 1980s using intravenous glutathione published in the Journal Movement Disorders. Intravenous glutathione was given a- 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, um, GLP-1 was specifically chosen, uh, because of its ability to make its way into the brain. And in fact, now it's not available, uh, on the market here in America because it's been associated with, uh, some, uh, changes in the pancreas. But that said, what do GLP-1 drugs do? Well, they don't just lower our appetite. They don't just control our blood sugar. The blood sugar control being why they were originally developed and now we're seeing, uh, you know, a variety of other outcomes in people taking the GLP-1 drugs. But one study that I did describe, uh, in Brain Defenders just, uh, 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 d- a problem with our cells' energy-making machinery, our mitochondria. And 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 used 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 are, people are, are, are getting wrong and people can improve because that's very empowering. That's the take-home message. People do these things and can ha- and have better health. But, you know, as are you, I am open to anything that is, uh, fulfills the, the notion of risk-benefit ratio. And if the benefit of GLP-1 drugs in an Alzheimer's patient seem to be, uh, very favorable in the face of, uh, not such a significant risk, I'm all in. You bet I am. That's gonna be part of the toolbox. Uh, I, I think it's, you know, our duty as physicians to keep an open mind and put in our toolbox whatever, uh, is, satisfies risk-benefit ratio. So, uh, that said, we will see, uh, what happens with GLP-1s and the brain. We know that, uh, recently, uh, the study on oral Ozempic, semaglutide, was published in Alzheimer's patients interventional trial and did not meet its endpoints, uh, in terms of improving, uh, or slowing their rate of decline.

   4. RCDr. Rangan Chatterjee31:44

      Yeah.

   5. DPDr. David Perlmutter31:44

      That said, perhaps it was 'cause it was oral and, uh, semaglutide, uh, coupled that didn't make its way to the brain. Uh, but we will see. You know?

   6. RCDr. Rangan Chatterjee31:53

      Yeah.

   7. DPDr. David Perlmutter31:53

      Our researchers are hard at it, uh, 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 mito- microglial cells themselves.

   8. RCDr. Rangan Chatterjee32:05

      Yeah. I have been using Bon Charge wellness products for over five years. From blue light glasses to red light therapy, Bon Charge make it really easy to get healthy while staying at home. Now, one of my current favorites is their Demi Red Light Therapy device. There are just so many studies now showing the potential benefits of red light therapy, including better eye health, pain relief, reduced inflammation, enhanced recovery, improved sleep, and even better skin. In fact, when it comes to skin, I have many friends and family members who absolutely love the Bon Charge red light face mask, super light and portable, and after using it for just 10 minutes a day, are reporting more radiant and glowing skin. So if you're looking to take charge of your health at home, I would highly recommend you check out Bon Charge. They are giving my audience 20% off all of their products. Just go to boncharge.com/livemore and use the coupon code LIVEMORE to save 20%, or click on the link in the description box below or scan the QR code on screen. 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, right? 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. You 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, um, Dale's work, and, you know, I, I've, like you, been a friend of Dale's for many years, and I, 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 re- reverse, and we worked on patients together for a few days. It was very, very inspiring to look at that research. This 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, you know, 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. We're gonna 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

8. 35:37 – 41:27

   Simplifying diet guidance: focus on outcomes and blood sugar control

   1. RCDr. Rangan Chatterjee35:37

      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"?

   2. DPDr. David Perlmutter35:54

      I've done my very best recently to simplify the, the notion of dietary recommendations because there are so many diets. There's probably a diet for every letter in the alphabet. Uh, whether it's paleo or primal or MIND diet or MED diet or green MED diet. Uh, a- and I think it's, it's very challenging for patients to think they need to adopt a certain diet and follow it to the letter, uh, in order to achieve an outcome. So in this time around, and this is, uh, book number 16, I look not at the diet, but at the outcome. And I said, uh, that really, I don't care what diet, uh, you wanna ... What name you wanna attach to your diet. Let's look at what that diet should do. And to be, you know, to be very simple about it, 'cause I think that's what people really need because, you know, when you try to adopt a certain diet and you have to have an app or follow a 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-"

   3. RCDr. Rangan Chatterjee36:53

      Mm

   4. DPDr. David Perlmutter36:55

      ... that offers up your body a lot of dietary fiber, in other words, is mostly plant forward, a diet that is colorful, so we're gonna 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, uh, grams per kilogram, ideal, uh, body weight, and I also describe in depth as you, as you saw what are the good fats. That's it. So, uh, I, I wanted to open the door, uh, to people to embrace their, uh, ethnicity in terms of their food choices, uh, or not. Whatever they, they choose. Um, you know, th- thinking about that, the idea of a Mediterranean diet, if you ... When, when you travel around the Mediterranean, you really see that they're not doing the Mediterranean diet anymore. Uh, I just got back from there, and it's, it's, you know, this, uh ... W- we originally called it the standard American diet, the S- 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.

   5. RCDr. Rangan Chatterjee38:03

      Mm.

   6. DPDr. David Perlmutter38:03

      And it, you know, it explains why there's 53 million, uh, Alzheimer's patients, uh, in, in the world right now, and that number will triple by, you know, in, by 2050.

   7. RCDr. Rangan Chatterjee38:13

      Yeah.

   8. DPDr. David Perlmutter38:13

      So, uh, you called it out as a, uh, an epidemic, and it is. And it's, 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. Our metabolism has changed, and I would s- you know, 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, uh, 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. W- w- we'll put a pin in that and deal with that later, but, uh, you know, getting back to, to what you've been talking about. So I, I, I'm trying my best to simplify these dietary recommendations, uh, such that people can look at their diets in terms of how I am metricizing my body. In other words, what's the outcome of the food I'm eating on my blood sugar?

   9. RCDr. Rangan Chatterjee39:15

      Yeah.

   10. DPDr. David Perlmutter39:15

       That is a leap.

   11. RCDr. Rangan Chatterjee39:17

       Yeah.

   12. DPDr. David Perlmutter39:17

       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, uh, 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, are eating inappropriately. So-

   13. RCDr. Rangan Chatterjee39:35

       Yeah

   14. DPDr. David Perlmutter39:36

       ... 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, the pharmacy and buy a finger stick. That di- uh, it's available to anybody, and I know it's not pleasant sticking your finger, but do it once a month and see where you are. But, um, it's, it's really that important.

   15. RCDr. Rangan Chatterjee39:57

       Yeah.

   16. DPDr. David Perlmutter39:57

       Again, the fiber for the microbiome, the polyphenols, we should have a ... We could talk about that in terms of why that's important for the brain. Uh, the right kind of fat gets back to your original question, what has changed? I think one of the biggest change, uh, that, uh, I emphasize now that really was not emphasized earlier in, very, very early in my career, frankly, respectfully, before you were born.

   17. RCDr. Rangan Chatterjee40:21

       [laughs]

   18. DPDr. David Perlmutter40:22

       Uh, and that is, you know, the, the position on fat. I mean, there, there was a time when fat was, uh, not a, uh, the right thing to be eating in any form, and, you know, that was what the science was telling us. And I, you know, in mainstream medical training w- was parroting that, and that changed obviously and for good reason, uh, over time, uh, in my outreach that, you know, fat is a fundamental player, uh, for m- metabolism, for inflammation, for structural, uh, integrity-

   19. RCDr. Rangan Chatterjee40:52

       Yeah

   20. DPDr. David Perlmutter40:52

       ... of the neurons. You know, a, a variety of things that, that the right fats do in our bodies.

   21. RCDr. Rangan Chatterjee40:57

       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? You know, one of those outcomes is a well-controlled blood sugar, right? [laughs] So you can get that outcome in a variety of different ways. So I, I kinda feel this is a good time to talk about testing. Um,

9. 41:27 – 53:55

   Testing as empowerment: fasting insulin, HbA1c, CGMs, and personalized prevention

   1. RCDr. Rangan Chatterjee41:27

      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? We'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?

   2. DPDr. David Perlmutter42:40

      That's right.

   3. RCDr. Rangan Chatterjee42:41

      Of a long process. And that really ties into what you're saying about what diet you wanna 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, uh, American physicians is that the American medical system is fundamentally very different from the UK one. And 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 realized that, you know what, I, I actually don't think that's ever gonna 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. So what I did about a year ago, David, um, I don't think 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, 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?

   4. DPDr. David Perlmutter44:35

      Who knew?

   5. RCDr. Rangan Chatterjee44:36

      Yeah. And we'll c- 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. You 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, you know, that'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 Due Health, which I don't think there's anything like it in the UK, and basically we don't do like a, you know, 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. Like all of these-

   6. DPDr. David Perlmutter45:38

      Nice

   7. RCDr. Rangan Chatterjee45:38

      ... 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, right?

   8. DPDr. David Perlmutter45:51

      Right. Yeah.

   9. RCDr. Rangan Chatterjee45:52

      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 are basically gone... I, I think talking about the sort of stuff you're talking about, right? We're, we're checking stuff like fasting insulin, homocysteine, HbA1c, ALT, B12, uric acid. You know, and I, I, 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. Um, but I think what it means then is whatever diet you follow to... You know, as long as it's, you know, generally a whole food, minimally processed food diet as much as you can, if you are getting these biomarkers in the correct range, right? A low fasting insulin, an HbA1c maybe under, I don't know, 5.3, 5.2, whatever, whatever it is. You know, if your 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 y- 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 wanna get your take on that, David. Do you think this is the kind of approach that we now need if we really wanna get on top of our brain health? Um, and then I guess secondly, you know, from what I've said, are there any downsides to this kind of approach?

   10. DPDr. David Perlmutter47:35

       Well, let me answer the second question first. W- I, I can't imagine that any downside, you know, cost will have to be considered, but I mean, everything that you mentioned on that shortlist, uh, has huge, uh, play in terms of brain health. And, you know, it, it, 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 for, uh, which is reflective of metabolic health. Who knew? And, you know, m- my only time, uh, in visiting your country was several years ago when I, when we met. And it's interesting 'cause I was asked... I was summoned to visit with, um, then Prince Charles, and w- w- we sat, uh, at, in, uh, at Highgrove, I guess it's called, and, um, he, 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 in the eye and I said, "That's what's going on, uh, and that's what you need to address." And he said, "Well, I don't know how I'm gonna address that." And I don't think there was really any outcome of that meeting, but, uh, I, I think that's what we're up against, and I think, um, you know, the food industry has no interest in health, and healthcare really doesn't spend, uh, any time involving itself in food. So this is a huge disconnect that has never been present in humanity.

   11. RCDr. Rangan Chatterjee49:06

       Yeah.

   12. DPDr. David Perlmutter49:06

       Traditionally, uh, food, uh, and health have always been linked. And it's, uh... I remember years ago, I was... uh, somebody accused me of my practices being non-traditional because I was talking about nutrition and the brain. They said, "That's really non-traditional."

   13. RCDr. Rangan Chatterjee49:23

       [laughs]

   14. DPDr. David Perlmutter49:23

       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, uh, individuals in the group said, "Well, we can't have Dr. Perlmutter do it because he's doing these non-traditional things like nutrition." Huh. And I, m- you know, I'm thinking, you know, humanity has always valued-

   15. RCDr. Rangan Chatterjee49:44

       Yeah

   16. DPDr. David Perlmutter49:45

       ... the food that we eat a- and its relationship to our health and its relationship, importantly, to our connection to the planet as well, which, uh, is really something I think that we-

   17. RCDr. Rangan Chatterjee49:56

       Yeah

   18. DPDr. David Perlmutter49:56

       ... we no longer value and even recognize. Well, not we, but, uh, you know, the, generally in the world there's no connection between the fact that the, the planet is giving us this sustenance. All food comes from the Earth, whether you're a 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, uh, for all of it. So, um, uh, you know, I think I was a little bit divergent on my response to you, but I think that, um, it is very challenging. I honor what you're doing because I think what you're doing is simplifying. You know, there are, uh, uh, organizations here in America that offer 400 different labs.

   19. RCDr. Rangan Chatterjee50:39

       Yeah.

   20. DPDr. David Perlmutter50:39

       And, uh, it's overwhelming in my opinion.

   21. RCDr. Rangan Chatterjee50:41

       Well, yeah, David, uh, you, you raise a key point there. So I, I, I'll be honest with you. I never had any, uh, 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 because, A, you could be making some changes to your diet and not getting the drop that you might wanna 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-

   22. DPDr. David Perlmutter51:33

       Ah

   23. RCDr. Rangan Chatterjee51:33

       ... and actually you need to drop-

   24. DPDr. David Perlmutter51:34

       That's so personalized. I, I, I, I'm just loving what you're saying. It's so personalized because maybe that diet isn't the right diet for you.

   25. RCDr. Rangan Chatterjee51:42

       Yeah, maybe you heard about the evidence on the latest podcast you listened to and thought, "Great," but when that diet interacts with your biology, what is the outcome on these key biomarkers? And so I kind of feel that it... th- 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, we've started where there's 11 biomarkers. There's damn good evidence for all of them.

   26. DPDr. David Perlmutter52:26

       I, I, I think that's a home run. I mean, I mean, look what I did in this book. I said one biomarker. I, I mean, we, we look at a, a lot of biomarkers as you... in the book.

   27. RCDr. Rangan Chatterjee52:35

       Yeah.

   28. DPDr. David Perlmutter52:35

       I talked about homocysteine and, and, uh, GFAP, uh, pTau217, you know, other things. But, uh, in terms of your diet, I just wanted to control your blood sugar. And having said that, and you make the changes and, uh, your blood sugar's recalcitrant, uh, it's still not coming around, you know, you might need metformin. You might need a medication.

   29. RCDr. Rangan Chatterjee52:59

       Yeah.

   30. DPDr. David Perlmutter53:00

       So, uh, uh, that's, that's the point here. And I think what, 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, uh, blood sugar. So what, uh, you know, the uniqueness there is this notion of personalized medicine-
10. 53:55 – 1:13:16

    Homocysteine: a practical biomarker tied to genetics and mitochondrial toxicity

    1. RCDr. Rangan Chatterjee53:55

       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. I 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?

    2. DPDr. David Perlmutter54:26

       Okay, let's start with homocysteine. And my homocysteine as of yesterday was 8.2, and that makes me very happy. So [laughs] you know, it's been said that why should I take supplements? After all, I can't measure that they're doing any good. And I always, uh ... You know, people have, uh, asked me that question when I give a lecture, uh, whatever, and I, and I, I always challenge that because, um, you know, the notion of a supplement means it's, it's so- something added to, to supplement because of a deficiency or a need. That's why we take certain supplements. And, uh, 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.

    3. RCDr. Rangan Chatterjee55:19

       [laughs]

    4. DPDr. David Perlmutter55:20

       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, my gut bacteria, such that I'm not able to methylate. It's, it's a biochemical change that activates, let's say, and makes them more worthwhile, the B vi- certain B vitamin, B6, B12, and folic, folic acid. So I have to add ... And that is the reason that my homocysteine level is elevated. So I take these. I take, uh, folate, I take, uh, rather fo- uh, methylated folate, uh, 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 don't ... I can't feel, sort of like, "Oh gosh, I, I've been taking these vitamins. Now I have more energy and, you know, uh, my life is great." Uh, that's not what you're looking for. You're, again, getting back to the idea of looking at your biometrics like you described with your testing. So homocysteine has been ... uh, elevated homocysteine has been directly correlated with dramatic increased risk for Alzheimer's, uh, 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 homocysteaic acid. Homocysteaic 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. So elevated homocysteine is threatening mitochondria and therefore threatening whether your microglial cells-

    5. RCDr. Rangan Chatterjee57:07

       Mm-hmm

    6. DPDr. David Perlmutter57:07

       ... are friend or foe.

    7. RCDr. Rangan Chatterjee57:09

       Yeah.

    8. DPDr. David Perlmutter57:09

       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, I went to a cardiologist yesterday. I do see a cardiologist. I had atrial fibrillation in the past, did well after a cardioversion-

    9. RCDr. Rangan Chatterjee57:27

       Okay

    10. DPDr. David Perlmutter57:27

        ... after a, uh, yeah, uh, uh, ablation procedure. Home run. But, um, we ... I mentioned homocysteine and, uh, he said, "I'm gonna have to send you to a different, a cardiologist who knows about that kind of stuff." And I was grateful that he would refer me. Uh, but homocysteine is a player. I mean, it really is a player. If 28% of people, uh, in Western cultures have this MTHFR genetic, uh, variant like I do, 28% of people are at great risk for having a, an elevation of this homocysteine that is a brain threat-

    11. RCDr. Rangan Chatterjee58:06

        Mm

    12. DPDr. David Perlmutter58:07

        ... then darn it, they, they need to know about that and fix it by taking simple B vitamins.

    13. RCDr. Rangan Chatterjee58:12

        Yeah. David, I just wanna comment on a couple of things there. First of all is 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. So therefore you need to do certain things like take methylated B vitamins to bring the homocysteine down irrespective of your B vitamin levels, right? It's a, it's a, it's a subtle difference there. You're, you're taking the nutrients to drive the biomarker down, and by driving that biomarker down, you're reducing your risk of getting sick.

    14. DPDr. David Perlmutter59:01

        Yeah, let me, let me simplify that if I can.

    15. RCDr. Rangan Chatterjee59:03

        Sure.

    16. DPDr. David Perlmutter59:04

        If you have your B vitamin levels checked and they are normal, it's not good enough because you're not ... 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. Maybe that made it more complicated. I don't know.

    17. RCDr. Rangan Chatterjee59:23

        No, no. I think, I think it's great-

    18. DPDr. David Perlmutter59:24

        Uh-huh

    19. RCDr. Rangan Chatterjee59:24

        ... 'cause it's not the way I think people think-

    20. DPDr. David Perlmutter59:27

        Yeah

    21. RCDr. Rangan Chatterjee59:27

        ... about nutrients, right? So I think that's really useful. I do wanna 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?

    22. DPDr. David Perlmutter59:39

        71.

    23. RCDr. Rangan Chatterjee59:40

        You're 71.

    24. DPDr. David Perlmutter59:41

        I'm 71.

    25. RCDr. Rangan Chatterjee59:41

        Okay. I remember meeting you in London two or three years ago. You were sharp, bright, right, right on the money. You gave a great talk. We, 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.

    26. DPDr. David Perlmutter1:00:01

        This is number 16, correct.

    27. RCDr. Rangan Chatterjee1:00:02

        Your 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 Perlmutter appears to have at the age of 71-"

    28. DPDr. David Perlmutter1:00:15

        Right

    29. RCDr. Rangan Chatterjee1:00:15

        ... 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? Have you tried to meditate before? Perhaps you've heard about some of the benefits, like reducing stress and increased focus, and you've given it a go and thought it's not the practice for you. Well, I believe that may well be because you have not tried the right approach. The Way is the only meditation app with a single long-term pathway. You're not forced to make loads of choices each day. Instead, you're guided on an enjoyable and progressive journey that deepens your practice step by step. Since I partnered with The Way, I have had so much positive feedback. One listener said, "Dr. Chatterjee, I came to The Way through your podcast. I have tried other meditation apps in the past with limited success, and like the idea of following a single guided path. I'm nearly two months in now and loving it. Henry's gentle and concise approach is very calming, and The Way is now a part of my morning routine." You see, that's the sentiment that so many people report when they start meditating with The Way. For listeners of my podcast, The Way is offering 30 free days to establish your own meditation practice. All you have to do is click on the QR code on screen or go to thewayapp.com/livemore to get started. I'm delighted to announce that AG1, the daily health drink that has been in my own life for over six years now, have updated and improved their formulation based upon the latest science, and to celebrate by giving my audience a very special offer. Some of the upgrades include more magnesium, which supports muscle function and improves the ability of your nervous system to relax, and also five strains of bacteria instead of just two to reflect the latest advances in microbiome science. It also contains key nutrients like vitamin C, biotin, niacin, vitamin B6, riboflavin, thiamine, zinc, and folate in bioavailable forms the body can easily and readily utilize, maximizing their potential benefits. Nutrition can often seem really complicated. What diet should we be following? What supplements should we be taking? And I think that's one of the main reasons I really like AG1. They make it really simple for you to be the best version of you. Over 70 ingredients, one scoop once a day for less than a cup of coffee. So if you want to support your health seven mornings a week, get started with AG1, and right now we have a very special limited time offer. Your first month subscription will be only £59, saving you £20 off the regular price. On top of that, you'll get a free welcome kit, a shaker bottle, a scoop, five travel packs, and a bottle of vitamin D3 and K2 drops. To claim this limited time offer, head to drinkag1.com/livemore.

    30. DPDr. David Perlmutter1:03:40

        I think you just mentioned it, uh, a moment ago. You said curiosity, and curiosity has been powerfully motivating for me throughout my lifetime. Uh, really trying to understand, oh, okay, you know, there's a paper written that shows this correlation, but why? What'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, uh, the idea of compassion that I learned from my father, uh, a, a brilliant neurosurgeon, brain surgeon, who, uh, as fate would have it, died, uh, of Alzheimer's. Uh, that was, um, that was a powerful, uh, event in my life, and it, it solidified my desire to learn more. Uh, Robert Kennedy Senior, uh, 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, and I love it. I just, I just love it.
11. 1:13:16 – 1:16:08

    Uric acid and fructose: the ‘winter is coming’ metabolic switch

    1. RCDr. Rangan Chatterjee1:13:16

       that was the topic of your, your last book. Why is uric acid an important marker for us to look at when we're trying to assess our metabolic health?

    2. DPDr. David Perlmutter1:13:28

       The next sentence I think is very important. Uric acid tells your body winter is coming. What does that mean? It means that, uh, 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, a hedge against, uh, not even finding water. So this is a, a, a genetic change that happened in Proconsul, our, one of our primate ancestors, around eight million years ago, a change such that uric acid would be increased when our ancestors pr- our primate ancestors ate a, a certain food that would be present in the late fall when winter is coming. Something 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, in the fall before winter. It's a beautiful, uh, bit of chronobiology, isn't it, that, uh, you know, we're in harmony with the planet. The plants have finally ripened their... You know, 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. There would be selection of those, uh, individuals who had higher uric acids for survival because they made more body fat, and they had a, a depot for caloric, uh, a caloric reservoir so they could survive during times of caloric scarcity, when others who didn't have high uric acid would die. Well, 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, uh, accumulate uric acid higher than any other mammal, and that uric acid is directly leading to fat formation, uh, by changing, uh, cellular metabolism. It's directly, uh, involved in damaging mitochondrial function. Uh, it is e-elevating our blood sugar and elevating our blood, uh, pressure as well, uh, inhibiting nitric oxide and as such, uh, leading to inability of blood vessel to relax. By its inhibition of nitric oxide, it, it is, uh, down-regulating the effectiveness of insulin.

12. 1:16:08 – 1:19:00

    Decision-making, inflammation, and behavior loops: why UPFs keep people stuck

    1. DPDr. David Perlmutter1:16:08

       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.

    2. RCDr. Rangan Chatterjee1:16:34

       Mm-hmm.

    3. DPDr. David Perlmutter1:16:35

       So we make fructose from corn, high f- co- high-fructose corn syrup that is just, you know, across the board ubiquitous in, in foods to make them palatable and tapping into this ancient desire survival mechanism that we have, uh, for sweet foods. So we recognize that, uh, 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, and to understand what is your uric acid level, and I think you mentioned you're gonna include that in your 11, uh, item panel-

    4. RCDr. Rangan Chatterjee1:17:18

       Yeah, it, it's one of them. Yeah

    5. DPDr. David Perlmutter1:17:18

       ... and you absolutely should. Uh, you know, people, it takes us to an interesting discussion of in the normal range.

    6. RCDr. Rangan Chatterjee1:17:26

       [laughs]

    7. DPDr. David Perlmutter1:17:26

       What does that mean? Oh, I got my labs back, and everything was in the normal range. Oh, but the l- 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. [laughs] And you know, I, I don't know why I'm focusing on that, and vitamin D level was out of the normal range. Well, I, I think that clearly what you're going to do, if you're not already doing, is, is recontextualize this notion of normal range. Normal range is average. It's two standard deviations from the mean, uh, looking at large population sets, large data sets, and what is average, and what is average is not necessarily what is best. We want people, and you want people to be in the optimal range, in o- in other words, what is best. Blood sugar of 100 is not good enough. No way.

    8. RCDr. Rangan Chatterjee1:18:15

       Yeah.

    9. DPDr. David Perlmutter1:18:15

       That's just not good enough for, for your messaging and my messaging.

    10. RCDr. Rangan Chatterjee1:18:19

        Yeah.

    11. DPDr. David Perlmutter1:18:19

        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.

    12. RCDr. Rangan Chatterjee1:18:30

        Yeah, absolutely. Thank you for sharing the importance of uric acid, and I completely agree. You know, there, there are normal ranges, there are optimal ranges, and certainly with DueHealth, we're- Helping educate people as to where they are now, where they could get to, and we're gonna help them along the way to get there. David, I wanna 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

13. 1:19:00 – 1:29:41

    Exercise as a brain intervention: muscles as an endocrine organ and BDNF support

    1. RCDr. Rangan Chatterjee1:19:00

       not have them go to the destructive M1 form. We've touched, in terms of practical applications to people, we, 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 wellbeing. How exactly is exercise good for the brain, and what does exercise do to our microglial cells?

    2. DPDr. David Perlmutter1:19:33

       I'm gonna answer that question in one moment, but I just wanna get a, 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, for the better? And that one thing is to embrace the idea that you are in charge with regard to the, these choices with y- with respect to your lifestyle choices. Yes, sleep. Yes, exercise. Yes, diet. These are all connection, social connectivity important. But the most important thing is to recognize that you're in charge. You control your brain's destiny. Now, as it relates to exercise, uh, we've known for an awful long time people have said, yes, exercise good for your heart, uh, good for your brain. And, uh, it, 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 h-how many years have we heard about heart-smart diet?

    3. RCDr. Rangan Chatterjee1:20:28

       Yeah.

    4. DPDr. David Perlmutter1:20:28

       Right? There'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, uh, and, y- you know, uh, it's, it's the very same diet. It's no, 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, uh, the ovaries. These are our endocrine gra- glands. And by definition, the endocrine gland is, is a part of the body that creates messengers that go elsewhere in the body and do certain things, right? Uh, the pituitary sends out things like growth hormone, uh, uh, that do certain things. Adrenal, uh, 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. Uh, they are, you know, cathepsin, uh, B, uh, irisin, uh, interleukin-6. Oddly enough, we tend to think about that as being a pro-inflammatory cytokine but actually does some, some great things. These chemicals go throughout the body and even into the brain and do, uh, good things for us. Uh, importantly, something called irisin 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, uh, way back in 1988 by a Dr. Erickson, University of Pittsburgh-

    5. RCDr. Rangan Chatterjee1:22:35

       Mm

    6. DPDr. David Perlmutter1:22:35

       ... who correlated exercise in a one-year interventional trial versus simply just doing some, uh, 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 it exercise caused growth and also improved memory performance as a consequence of exercise. Since that time, multiple, multiple studies have come out, uh, 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, uh, batted around as being the ideal, uh, amount of steps to take in a given day. I think there are benefits to both aerobic exercise, uh, as it relates to producing that BDNF and also resistance exercise simplistically to increase the, the size of the pharmacy. So there's more muscle mass there to create these really-

    7. RCDr. Rangan Chatterjee1:23:40

       Mm

    8. DPDr. David Perlmutter1:23:40

       ... 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. Bo- all of the above, which you really wanna have... I, I actually say there should be three, and, um, [chuckles] just to be, uh, kind of conjectural, and that is I think we definitely wanna have flexibility, uh, exercises as well. Why? 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 gonna exercise anymore and, you know, that whole program, uh, 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, uh, resistance training. So what do I do? I, I go to the gym three times a week and do weights. Uh, I, I tend to like the machines, but I do some free weight, uh, work as well with dumbbells, uh, on a, uh, incline, uh, board, incline bench. Uh, I'm particularly fond of the Ab Machine. Um, and, uh, and then I, 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, uh, flexibility and, yes, balance. On the other days, I either run or walk or, uh, use an elliptical machine. But right now I've gotten a new stationary bike that I am totally thrilled with. Um, it, it gamifies exercise. In other words, I'm on the stationary bike and I'm ha- having to do these various games which are fun, and I wanna win, and at the end they show you the leaderboard. And, you know, I've gotten up to, I think, number three on the leaderboard for ... No, on number four, and I'm the old man. So I did an Instagram post saying, "Hey, for you who are using the Aviron, uh, stationary bike or treadmill, that David P., that's me. I'm number four on the leaderboard."

    9. RCDr. Rangan Chatterjee1:25:42

       [laughs]

    10. DPDr. David Perlmutter1:25:42

        "Don't let the 71-year-old guy catch you." [laughs] But anyway, so for me, gamifying, uh, has been very helpful.

    11. RCDr. Rangan Chatterjee1:25:50

        Yeah.

    12. DPDr. David Perlmutter1:25:51

        'Cause 30, 40 minutes go by quickly 'cause, you know, a machine like that can be boring. That's why I like to be outside and run, 'cause then I can see things, breathe fresh air, you know, see people, wave at them, and, uh, experience nature.

    13. RCDr. Rangan Chatterjee1:26:04

        Yeah.

    14. DPDr. David Perlmutter1:26:04

        But, um, so that's what my program looks like, and I'm sticking to it.

    15. RCDr. Rangan Chatterjee1:26:07

        Yeah. David, tha- thank you for sharing what you do. I think, obviously I can't know this for sure, but I would imagine there are gonna 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, uh, I just wanna 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 in Brain Defenders. But 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, 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. There are things, it's not as difficult as you think it is. There are things that you can do that are gonna 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-

    16. DPDr. David Perlmutter1:28:08

        Mm

    17. RCDr. Rangan Chatterjee1:28:08

        ... you know as well as I do that you go to your conventional doctor, you're, you're generally told that there's not much you can do about this. There is an inevitable decline. You 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, "Rangan, everything you're talking about I'm, I'm trying to share with Mum, but she's not listening. You know, she drinks half a bottle of wine every night and has done for many years. That's just part of her lifestyle. She's unlikely to change now." And I think, David, there's a, 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? So 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, you know, what advice would you give, like, to people like my friend 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"?

14. 1:29:41 – 1:42:49

    Alcohol, aging parents, APOE4 genetics, and the ‘it’s never too late’ close

    1. DPDr. David Perlmutter1:29:41

       I think it's very challenging because my generation and his, his mother, uh, 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, your desires, and modern medicine's got the fix, and don't worry about it. They- they'll fix your heart, they'll fix your brain. Uh, you know, and, and that's just an incredible, uh, mis-messaging that, uh, it, it, you know, really characterizes what you're, you're talking about here. You're right in your observation of people in my generation because they, uh, they're very difficult to convince, uh, and to, to prevail upon in terms of, um, you know, what your friend is up against with his, his mother and, uh, you know, that's- that's pervasive. Uh, what I would say i- to that individual is, look, do the best you can, but let's talk about you because I, I really, uh, am ... think that it's, uh, the, the bigger play here is the 40 and 50-year-olds, 30-year-olds.

    2. RCDr. Rangan Chatterjee1:30:43

       Mm.

    3. DPDr. David Perlmutter1:30:43

       Uh, that, uh, you know, John Kennedy, uh, 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.

    4. RCDr. Rangan Chatterjee1:30:56

       Mm-hmm.

    5. DPDr. David Perlmutter1:30:56

       But frankly, you know, a, a lot of times there's just not gonna 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 s- have discussed today and the-

    6. RCDr. Rangan Chatterjee1:31:16

       Mm-hmm

    7. DPDr. David Perlmutter1:31:16

       ... value of what we've talked about today. It's incredibly valuable. It is the top tier, ahead of any, uh, pharmaceutical or other type of intervention. What we've discussed today are the keys to the kingdom.

    8. RCDr. Rangan Chatterjee1:31:29

       Yeah.

    9. DPDr. David Perlmutter1:31:30

       And it's not monetized. That's why we don't hear about it very much.

    10. RCDr. Rangan Chatterjee1:31:35

        Yeah. I mentioned alcohol there with my friend's mother. What does chronic alcohol consumption do to that M2, M1 balance?

    11. DPDr. David Perlmutter1:31:47

        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-

    12. RCDr. Rangan Chatterjee1:31:56

        Mm-hmm

    13. DPDr. David Perlmutter1:31:56

        ... in comparison to women who drink one glass of wine per day or men consuming two glasses of wine today, and then the risk goes up with, uh, 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, uh, 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, uh, polyphenols in red wine? Yeah, there is, but there's also non-alcoholic, uh, red wine and other wonderful sources of polyphenols that, you know, don't require alcohol. Uh, but I get that, you know, 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. So, um, you know, I, I think it's making these subtle adjustments so that you can still feel good about life-

    14. RCDr. Rangan Chatterjee1:32:53

        Mm-hmm

    15. DPDr. David Perlmutter1:32:53

        ... and participate and minimize a risk.

    16. RCDr. Rangan Chatterjee1:32:57

        Yeah. David, one thing we've not talked about is genetic testing, and again, I think a, a big theme throughout our conversation today is how our approach to medicine has changed over the years, right? So there's normal blood test versus optimal. There's getting involved when you have symptoms versus practicing true prevention. And when I was at medical school-

    17. DPDr. David Perlmutter1:33:24

        [laughs]

    18. RCDr. Rangan Chatterjee1:33:24

        ... at 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? There's no point knowing your genetic status because there's nothing you can do, right? So why would you wanna 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, you know, 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.

    19. DPDr. David Perlmutter1:34:09

        Let me first answer that I'm absolutely a fan of being tested. We know that, uh, individuals who carry, uh, APOE4 alleles, so this is a genetic allele that comes... and you have two shots at it. It comes in three varieties, APOE2, APOE3, and APOE4. As it relates to Alzheimer's, APOE2 is protective, APOE3 is about neutral, and APOE4 is, uh, 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 two, three, and four. Uh, you can be a 4-4, which poses a significant... is associated with a significant risk for Alzheimer's disease through multiple, uh, pathways that we'll, I'll mention in just a moment. But it's been indicated that carrying APOE4-4, uh, and there are, you know, a significant number of people in, in America who, uh, are carriers of APOE4-4, uh, that your risk may increase for Alzheimer's by as much as eightfold, even as high as some st- uh, reports as high as twelvefold risk, but not determinant. It's a predisposition, but not a determinant. I'll double-click on that in just a moment. Um, having one allele, in other words, having a 3-4 or a 2-4 combination, is also associated with a, a, an increased risk of Alzheimer's by anywhere between three and fivefold, so a, a really significant increased risk. Now, why is AP- APOE4, um, associated with such an increased risk? What does it do? We know that it involves multiple pathways. Uh, it involves the down-regulation of mitochondrial function, uh, and as such seems to target microglial cells. But in work done by, uh, a British researcher, Dr. Sarah Marzi, at what is called the Marzi 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, uh, APOE2 and a, uh, had dramatic reduction of inflammation, sort of middle-of-the-road inflammation APOE3, but dramatic increase and cell loss and, and beta amyloid accumulation in those carrying the APOE4 allele, the microglial cells that she had engineered and injected into their brains. So again, while we've kind of labored over what are the exact pathways by which APOE4 is ultimately increasing risk of Alzheimer's, um, it looks as if now it's converging on the microglial cells, which is really, uh, kind of interesting because- We can offer offsets to that through th- 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 wanna say that we should look upon carrying the ApoE4 allele as not a determinant, but as a predisposition. It is clearly a risk marker. It's, it's a risk marker like MTHFR. Again, 28% of people like me, like, like I am, uh, have this MTHFR, and therefore elevated homocysteine, another risk factor for Alzheimer's that similarly can be offset-

    20. RCDr. Rangan Chatterjee1:37:49

        Yeah

    21. DPDr. David Perlmutter1:37:49

        ... in my case, by taking, uh, methylated B vitamins. So I think there's been a huge change in the messaging of, of, well, not, 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 gonna play the hand?

    22. RCDr. Rangan Chatterjee1:38:11

        Yeah. It, it's such a, it's such a key point, David, this 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, right? And often that might happen at a time when maybe their own father had a heart attack or a buddy of theirs from school, you know, 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 and 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's generally okay." If they did a genetic test and came back as a, uh, let's say a three-four, maybe 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 four, like double, you know, yeah, you don't wanna get anxious about it. You wanna 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, w- could one argue, David, that the recommendations that we would make to you for your brain health are the same irrespective? So for example, if someone was listening and they said, "David, listen, I'm gonna get Brain Defenders, and I'm gonna do everything in that book. Why should I go to the trouble and expense of getting an ApoE4 test?" You know, does getting that allele back practically make any difference in terms of what I do?

    23. DPDr. David Perlmutter1:40:24

        I, I think the answer is that I cannot imagine, uh, anyone doing everything I talk about in the book.

    24. RCDr. Rangan Chatterjee1:40:31

        Yeah. [laughs]

    25. DPDr. David Perlmutter1:40:31

        So there's a hierarchy, and I think that, uh, 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. And beyond that, I think being much more aggressive in terms of following your cognitive function. You know, we have the ability, uh, 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.

    26. RCDr. Rangan Chatterjee1:41:07

        Yeah. There's so much you've covered, um, 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 wanna say I read a lot of health books, and this, I think, is beautifully written. It'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?

    27. DPDr. David Perlmutter1:42:09

        I- if anybody i- 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, and ready to take full advantage and, and redirect their brain's destiny. So absolutely have at it.

    28. RCDr. Rangan Chatterjee1:42:27

        Yeah, great advice. Very empowering, David. The book's called Brain Defenders. Thank you so much for coming back on the show.

    29. DPDr. David Perlmutter1:42:32

        My absolute pleasure. Thank you.

    30. RCDr. Rangan Chatterjee1:42:34

        If you enjoyed that conversation, then I think you are really going to enjoy this one that I picked out especially.

Episode duration: 1:42:50