Don't Wait for Alzheimer's — A Neurologist's 30-Year Plan to Protect Your Brain

When we recognize that 40 to 50% of adults in America who live to be age 85 will have a diagnosis of Alzheimer's disease, at 65 years and older, risk is 1 in 9, or 11% of people age 65 or older have dementia. It is almost a fully preventable situation that people shouldn't fear, that people should feel empowerment as it relates to making the right choices.

David, welcome back to the podcast. So good to see you again. And I know you're coming in from British Columbia, which is exciting. And I think you're taking well-deserved rest before the launch of your new book, Brain Defenders, which I'm very excited about, how to harness the power of your immune cells to protect your brain for life. We're going to get all into that and go deep on this because it's really an important topic. You know, David, I think, you know, we've known each other for, I don't know, 30 years now. And you were one of my mentors. You originally taught me so much about the brain that I was I was recollecting about the original book that you had written that helped me understand Parkinson's mitochondria. And you were the first one to talk about this idea of the brain on fire.

That's right.

And you had this really crappy slide.

All of our slides were crappy back in the day.

And it was at the conferences and it really stuck with me and that so much of what's wrong in the brain, whether it's neurodegenerative diseases or mood disorders. The whole spectrum of brain dysfunction is in some ways tied to dysregulation of immune function and immunity and inflammation in the brain. And your new book goes really deep on this. So maybe you can kind of start out by helping us understand a few things. Why are you focusing now on this whole framework of immunometabolism, the mitochondria and the immune system interacting in the brain? as a root cause of so much of what we're seeing that's wrong in today's brains.

Well, Mark, this represents, I think, for me, a significant convergence of everything that we've been talking about for such a long time. And it's incredible because it really unifies the mechanisms that we've talked about. You mentioned the brain on fire. This embraces the idea that neuroinflammation is a central player in what makes a good brain go bad. But beyond that, well then, where does the inflammation come from? And it comes from exactly what you described, those microglial cells, these brain immune cells, innate brain immune cells. Who knew that the brain had its own immune system? And we tend to think about, well, that's what makes a good brain go bad. And the reality is these cells are, I hate to say designed, but what they do on a good day is maintenance and good things. They maintain our synapses, they maintain the function of the neurons, they maintain the blood-brain barrier. So it really broadens the scope of what we would classically consider to be immune function. I mean, you ask somebody, what does the immune system do? And the response is going to be, well, that's what comes into play when there's a challenge by a bacterial infection, viral infection, surveillance for cancer cells, whatever it may be. But the reality is that You know, these firemen in the firehouse are doing a lot of work to maintain the fire engine when there's no fire. And I think that tends to broaden our understanding of this immune system. It has a good side and a downside. And to be very technical about it for our discussion today, these microglial cells can exist either in a very supportive— we call it the M2 role— where they're shoring up these barriers and keeping our synapses working. Or they can shift to being destructive, what I call in the book the evil twin, the M1 configuration, where they are going around and destroying the synapses, creating that neuroinflammatory environment where the neurons can't work well anymore and the blood-brain barrier becomes more permeable, letting bad things into the brain. And that said, the most empowering part of our discussion today is that the shift from being supportive to being destructive is under our control. And, you know, for me, uh, that really represents a whole heck of a lot because it explains everything we've been talking about for so long. It explains why, you know, in Grain Brain, why a higher carb diet— and we'll unpack this today— is associated with activation of these microglial cells. It explains why permeability of the gut for all, you know, of all things, from having changes in our gut bacteria leads to increased inflammation that will activate these microglial cells and shift them to becoming again the evil twin. We now see that we can, research-wise anyway, image the brain in living humans using what's called a TSPO scan. This scan images when the microglia are activated to their destructive So a positive TSPO scan shows activation of the microglial cells. And we see that the TSPO scan is positive, as you would expect, in Alzheimer's, in Parkinson's, in multiple— multisystem atrophy, progressive supranuclear palsy, major depressive disorder, post-traumatic stress, and even long COVID. So really, This whole notion of activation of the brain's immune cells called microglia throws an incredibly large net, and that is giving us all a level of empowerment now that we've never had access to in the past.

I think there's a whole new way of thinking about the brain. I think we've kind of lost this sort of central idea in medicine, which is that we can help the brain. We know we can prevent heart disease by lifestyle. We know we can prevent diabetes by lifestyle. I mean, we even know in some ways cancer can be prevented by reducing toxin exposure and helping with your metabolism and a lot of other things. But brain health is just something that we think of as this black box and that traditional medicine doesn't know what to do with. It's like, okay, well, I hear so much of this from my friends who have family members with Alzheimer's and they go, well, I don't want to know my test because there's nothing I could do. They're this fatalistic view that the brain is fixed or it progresses towards disease with this inexorable path that can't be altered. And this was so important about your work and the things that you highlighted decades ago and that you continue to work on is that the brain is changeable, that the brain can be influenced by what we're doing, by our microbiome, by our diet, by exercise, by sleep. by our nutritional status, by reducing exposure to environmental toxins, by helping our mitochondria work better. There's so many pathways to actually improving brain function and not only just slowing and preventing neurodegenerative diseases like Alzheimer's or Parkinson's, but actually intervening and reversing many of them. And that's kind of a heretical thing to say in medicine.

Think of what you just said. You're right, it's considered heretical. But as our colleague Dale Bredesen has mentioned many times, We all know of cancer survivors. Do we know of any Alzheimer's survivors? And now we're starting to see that happen. And it's really based upon what you just described, and that is these metabolic inroads. And that is what you originally teed up for our conversation today, this concept of immunometabolism. Immuno being what we're talking about, these microglial cells in the brain, the brain's immune cells, and their metabolism. So When these immune cells shift their metabolism, when their metabolism changes, then they shift in becoming the evil twin. They shift from being supportive to being destructive. It's all predicated on their metabolism that changes. Their mitochondrial function is declining suddenly and rapidly, and that induces this shift to becoming what we call M1. And destructive. And here's the take-home bullet point message, and that is that the metabolism of the microglial cell mirrors the metabolism of your body. Wow, that is incredibly empowering. So if I dedicate my lifestyle choices to improving my body's metabolism, to keeping my weight down, to keeping my blood sugar in check, to keeping insulin functionality where it needs to be, to keeping keeping my blood pressure where it should be, then I am actually working lovingly with my microglial cells to really become the architect of my brain's destiny. And, you know, in, in my case, having a family history of Alzheimer's, it's what I need to do. And I am certainly not alone in that. When we recognize that 40 to 50% of adults in America who live to be age 85 will have a diagnosis of Alzheimer's disease tells me a couple of things. Number one, that's a flip of a coin, and I want to make sure it lands on the right side for me and for everyone I'm interacting with.

Yeah.

And number two, we should absolutely consider this to be an epidemic. That segment of our population is the most rapidly expanding. And when you look at those statistics in terms of Alzheimer's risk, I mean, it's 65 years and older. Risk is 1 in 9, or 11% of people age 65 or older have dementia. I will say here on your podcast, it is almost a fully preventable situation that people shouldn't fear, that people should feel empowerment as it relates to making the right choices. It's an awful situation for certainly the patient and for the loved ones as well. Having been through that, Again, I want to dedicate everything I do to giving people this information that we can rewrite your brain's destiny.

I think that's important, David. This is such an important concept that we can do stuff to keep our brains healthy, functioning, and mentally sharp. And the question is, I'm 66, you're a little bit older than me, not too much, and you're a little ahead of me like my big brother.

71. I'm on the continuum. 71.

You're my big brother. How do we keep our brains healthy for the next 20 years? So we're thinking about it for ourselves, but it's really an important concept. What causes brain damage? What can I do differently now to make sure I stay mentally healthy and my brain stays healthy and I have no neurodegenerative diseases over the next 20 years? And what should I be measuring and looking at in my own biology to track what's happening? And this is important for us to sort of unpack, I think, because— We know that the changes happen in the brain decades before you ever forget your keys or somebody's name or get lost in a grocery store. These are things that happen in their 30s, 40s, 50s before you see any changes in people's 60s, 70s, and 80s. Can you help us understand what are those things we should really be thinking about in terms of what is causing brain damage and how do we stop that? How do we stop this fire in the brain that you've been so elegantly describing for decades?

Yeah.

And this kind of how do we optimize our metabolism metabolism, reduce inflammation, and all these core concepts? Because we know now so much more than we did even when we all started this 30 years ago that it's really doable.

Well, I think the most important step is that you embrace the idea that you are in charge. If you don't do that, then you're not going to pursue the other things that we will now talk about. So really, job one is I am the architect of my brain's destiny. Okay, Dr. Perlmutter, Dr. Hyman, what do I do? That's your question. And the reality is it's not difficult, it's not really that sophisticated. If what makes a good brain go bad across the entire spectrum of neurodegenerative conditions— yes, we're fearful of Alzheimer's, but there's a long list of other things that can make a good brain go bad, that's for sure. I mean, you know, people don't realize that Parkinson's is also influenced by metabolism. If you have type 2 diabetes, your risk of Parkinson's is increased by 85%. So this notion that metabolism is important is, you know, the answer to your question. We've got to do everything we can to remain metabolically intact in our 40s and 50s. We have a big buffer there cognitively such that we don't really see the cognitive changes in the brain until Maybe we're in our 60s, maybe we are in our 70s and are forgetful of our keys, Wi-Fi codes, grandchildren's names, etc. We're way down the continuum of brain decline when that stuff starts to happen. And you're exactly on point that the issues that sow the seeds for the brain's degeneration happen when we are a lot younger, in our 30s and in our 40s. That's who I'm hoping are listening to our conversation today, because that's when we really begin to establish our personal set points as it relates to metabolism. That said, to answer one other part of your question, then what are those markers? And they are very straightforward, simple markers that you've talked about for years. How important is your fasting blood sugar for your brain's destiny? It is fundamental. Know your fasting blood sugar. And, and that is something— as need I tell you, you don't need a doctor's prescription To understand your fasting insulin level, your A1C.

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Want to take it a little deeper? Let's look perhaps at your C-reactive protein. And as I describe in the book, there are a suite of very brain-specific blood tests that we can get. Like p-Tau 217, which we, we could talk about. But the main players are those blood tests that I mentioned that look at your blood metabolic markers. Know your blood pressure and, and buy a very, very sophisticated and expensive tool called a tape measure and put it around your belly and put it around your waist and then do the math and determine your waist-to-hip ratio. Ratio. And, you know, this is an extremely valuable way of understanding what is your risk. How does that relate? Well, when your belly is big, you have more visceral fat, and you're increasing inflammation. Those microglial cells in your brain that are in charge of whether your brain will be healthy or not— call it like it is— are very receptive to inflammation coming from anywhere in the body. When inflammation chemicals called cytokines are produced anywhere in the body, like from a leaky gut, for all, uh, who knew, right? Those chemicals can make their way to the brain through the blood-brain barrier that becomes less and less functional as we age. Those microglia see inflammation and they shift to becoming the evil twin. Now that they're shifted to becoming the evil twin, they go around the brain and destroy synapses. The, the main issue In the Alzheimer's brain that leads to decline in cognitive function is the loss of connection, one neuron to the next via the synapse. That's the connection. So at a microscopic level, it's a loss of connection. At a macroscopic level, Alzheimer's patients lose connections with themselves, with people around them, and with their entire environment. So this loss of connection is really, you know, kind of the central issue. that is involved in the Alzheimer's brain. But we lose connection in Parkinson's as well. We lose connection of these cells that make dopamine in the part of the brain called the substantia nigra projecting to other motor areas, and it's the same mechanism. That was demonstrated by Dr. Langston in the 1980s when he first saw these patients who used a designer IV drug that was contaminated, the microglia were activated in their brains immediately and destroyed those cells that made the dopamine. And immediately they got Parkinson's. And he, he studied their brains 13, 14 years later, and these microglia were still at it, still destroying tissue. So this is, you know, Science Technology Magazine called this the number one discovery of 2025. incredibly central— centralized role of microglia in brain degeneration. And gratefully, it's great to have another explanation finally that takes us away from this idea that, for example, Alzheimer's is caused by— ask anybody, they'll tell you what causes Alzheimer's— the accumulation of beta amyloid in the brain. I think my blood pressure just went up saying that because I'm really getting tired of hearing it and reading. I read it last night in some news report that what can we do to lower beta amyloid, that is absolutely not the cause of Alzheimer's disease. I say that in the book, provide the data, explain how the whole amyloid hypothesis was flawed. But when we look at that discussion through the lens of these new amyloid-targeting drugs, they are not working. If beta amyloid is the cause of Alzheimer's, then you would think getting rid of the beta amyloid might do some good. A Cochrane analysis was published about 2 months ago. This was an analysis of the 17 top studies that evaluated the effectiveness of the drugs that do indeed lower beta amyloid in the brain. The study that involved 20,342 individuals, each study lasting about 18 months, looked at 2 things: risk and benefit. That's what we always do, right? To determine, are we going to write a prescription for something, an intervention? What's the risk and what's the benefit? What they found was the benefit was zilch. That's not the word they used. The word they used was trivial. They don't work. And the risk was really high. 20% to 25% of these people on these drugs develop brain hemorrhages, brains and/or brain swelling, or even death. And for a drug that doesn't work. So that's a powerful argument against putting people on these $40,000 a year intravenous infusions every 2 weeks. And the response when I challenge doctors who are doing this therapy is, well, we've got to do something.

There's nothing else to do. Yeah, but there is.

We've got to do something. We've got to offer something. Well, you're offering something that is very threatening. And has no efficacy. So that raises the hair on the back of my neck. And so what do you do in a situation like that? You write a book.

Thank God. I mean, one of the things I think, you hinted at a little bit, which I think is important to double back on, is this really important idea that all the conditions that happen to the brain, Alzheimer's, Parkinson's, ALS, MS, long COVID, fibromyalgia, chronic fatigue, mood disorders, psychiatric disorders, they're all related. They may manifest differently in different people based on their particular unique genetics or predispositions, but the fundamental mechanisms underneath all these things are very similar. And they have to do with our inputs, right? The things that we have control over, our diet, our lifestyle, exercise, stress, sleep, all that, environmental toxins, and our microbiome. And then the downstream effect is very similar dysfunctions around inflammation, around mitochondrial dysfunction, metabolic dysfunction, oxidative stress. These are all things that we actually have been talking about for decades in functional medicine. And we're down into the kind of weeds of things looking at these diseases rather than kind of zooming out and saying, okay, what do they have in common? What can we do to optimize our overall health, but particularly our brain health? from this lens. And that's what we should be focusing on. And I think this is a very powerful modality. I remember I had a patient who had pretty significant dementia. We really helped her in so many ways. She had heavy metals, she had methylation issues, she had gut issues. We fixed a lot of things and she kind of did really well for quite a while. Then she had a decline because her husband died and it was a big loss for her.

Mm-hmm.

And I said, well, why don't we just try a ketogenic diet? And this might've been 20 years ago. Because, you know, I was reading about the literature and mitochondria and inflammation and insulin resistance to the brain and type 3 diabetes, which would be Alzheimer's. And I was like, let's try it. And it was amazing. You know, the family was wealthy enough to have a chef. They gave her the food and it was like she woke up. And, you know, it lasted for quite a while. And it just alerted me to the fact that even in people who are fairly down the road, There are things that can be done to really help this. And as you mentioned, you know, Dale Bredesen is talking about the Alzheimer's survivors. You know, somebody's— who's an Alzheimer's survivor? Nobody, right? But there are now people, and I've had them in my practice as you have, that when you aggressively treat these factors, the causes, and you optimize the immune system, you optimize mitochondria, metabolic function, that these people do better. And it's quite remarkable.

Yeah, you bring up a really good point. I don't want to miss this while it's still in our minds, and that is—

Yeah.

That you mentioned mitochondria multiple times, and that is the metabolism of these microglial cells. And ultimately, when the microglial cell shifts from being supportive to being destructive, it actually is characterized by a loss of mitochondrial function. The M1 destructive microglial cell does not use mitochondria to any significant degree. It's using glycolysis. So its energy production is much less efficient, much less ATP produced. So in a very real sense, all of those neurodegenerative conditions that you listed are mitochondropathies or based upon failure of their mitochondria. You can get there from mold exposure, from having insulin resistance, from head trauma, From exposure to environmental toxins, from PM2.5s in the air that we breathe, which is certainly very important right now vis-à-vis the incredible fires that we're seeing across North America. And you're right. And when we target the mitochondria, we get responses like you've described and I have seen, and certainly Dale Bredesen has described as well.

Well, there was something really new that you said in your book that I thought was so striking. that I hadn't really thought about before, which is that the microglia basically are the immune cells in your brain and they have mitochondria. And I never thought of how the mitochondria in the immune cells affect the function and health of the immune cells. And that was a kind of an aha for me. Like, wait a minute, the metabolism, AKA mitochondria, of the immune cells, when it goes awry, is what's causing so much of the brain inflammation and the brain on fire that you've talked about for so long. And that's contributing to all these neurodegenerative and neuropsychiatric disorders. Is that right?

Immunometabolism. What a term.

So talk about this because I think this is a new idea. I mean, Jeff Bland has talked about it, one of our friends and mentors, but like, tell us about what is this? And is this kind of a new idea? And how do we start to think about it? How do we start to act on it and even diagnose it?

It's important because it's certainly not just these microglial cells in the brain, but it's immune cells throughout the body that are Uh, dysregulated when their metabolism goes awry. And let me make one point that I think is really important. This is bidirectional, that when these immune cells are targeted by glycated proteins, elevated blood sugar, toxins, inflammatory cytokines, it will then shift their metabolism. It will reduce their mitochondrial function. At the same time, as mentioned a moment ago, when mitochondrial function is challenged for other reasons, then the immune cell will be targeted as well and shift to being less supportive. So it's a bidirectional support system. Immunometabolism support, you know, goes both directions. And the manifestations of dysregulated metabolism of our immune cell is seen throughout the body. But the central and pivotal role as it relates to the brain, I think, is so powerful because we can influence it deeply by targeting metabolism, targeting the things that I mentioned, you know, the markers of metabolism that we can easily measure. When we do that, we are absolutely targeting our brain's immune cells, these microglial cells, to be back on our side and back to being supportive. As we've talked about, this is the upstream mechanism well above the accumulation of alpha-synuclein or beta amyloid or other proteins that people tend to want to focus on, even phosphorylated tau. The phosphorylation of tau happens, which is, for your viewers, phosphorylated tau, p-Tau 217, which is the blood test you can get doing functional health, for example, you can go and get your p-Tau 217 measured. Uh, is a very valuable indicator of loss of synapses. If you really want to know what it's telling you, the higher the level of this p-Tau 217, a blood test, that is an indication of loss of synapses. It is therefore— and what is causing loss of the synapses? Activation of the microglial cells. So this is a very important— And now, arguably, A more specific blood test in distinction, contradiction to the simpler blood test that you and I talked about earlier. So, in a very real sense, you're evaluating what in the heck's going on in your brain's immune system when you look at that test. But, as I mentioned earlier, it can be as simple as measuring your waist-to-hip ratio.

Yeah. I think this is important. Let's kind of double down on this because I think this is really new information for people, which is Up till now, we didn't really have a good way of checking your blood sugar of your brain. In other words, what is your— diabetes, oh, my blood sugar is high, I've got diabetes. Or my blood pressure is high, I've got high blood pressure. But we didn't have a biomarker or a set of biomarkers that we could look at that would be impacted by lifestyle. We could check your ApoE4 gene, which gives you a risk of Alzheimer's, but those are genes that can't be changed. You can change expression of them. But now we have biomarkers that are really revolutionary, I think. It gives us an opportunity to start to look at people's blood work very early and see what are the progressions and what are the changes and how do we modify those? Because it's not just finding this lab work and going, oh, shit, I got this problem. It's like, oh, wow, I have this problem. My blood sugar is a little high. Maybe I should stop eating bread and sugar. Maybe my p-Tau 217 is high. Maybe I should change my lifestyle. Maybe I should eat better. Maybe I should reduce my insulin resistance so I can improve my metabolic health. Maybe I should look at my microbiome and help that. Maybe I should look at my toxic load and things that might be triggering this. Maybe I should exercise more. Maybe I should focus on my sleep a little better. Maybe I should think about nutrients I could take that would help my mitochondria or help regulate my immune system or my microbiome. So it gives you an opportunity to think about creating a plan for yourself that's very proactive instead of reactive. I mean, by the time you are in end-stage Alzheimer's, there's not a whole lot you can do. But early on, you can see a lot of things changing. And then, I've been actually using these tests. And in Function Health, we now offer a full suite of tests that include as your basic panel a lot of things you were mentioning: insulin resistance markers, insulin A1C, particle size, hormone levels, toxin levels, nutritional levels, homocysteine, all the things you'd want to look at. as a foundation. But we also offer an advanced sort of brain panel, which allows us to look at p-Tau 217, amyloid AD4240, looking at neurofilament light chain, which is often damaged when the brain's damaged from traumatic brain injury and other injuries, and GFAP, which is another protein. So there's a lot of things you can look at. And so I think for me, it's a really empowering moment in neurology. And I mean, I'm going to make fun of you, you're a neurologist, but the joke we had about neurologists in medical school was diagnose and adios. Basically, You would just, you would be great at diagnosing things, but there was nothing you could do about it.

It is so true. And, and, you know, and that was how I diagnosed an audiosis, diagnosed an—

and hola, ¿cómo estás? Let's go.

Well, for me, it's, it's, uh, I want to be interventional long before we diagnose. And, you know, I think what you just described is really fundamentally important, that the, the standard of, uh, approach in medicine has been to treat illness once it has manifested. And what you're describing is the approach of keeping people healthy in the first place. Which is more valuable? I mean, I would submit it's absolutely the latter. And, you know, we describe our healthcare system in America as nothing to do with health. It's treating illness. And so this is very much preemptive, preventive approach that you were describing, and it's very, very empowering. And I remember back in the day, this thought came, uh, came to mind again early on in the PSA blood tests, prostate-specific antigen. Insurance wouldn't cover it unless you had a diagnosis of prostate cancer early on, the PSA, before your time, sonny boy. But anyway, and I thought, how ridiculous is that? Is this? And, and then there was a notion of breast cancer prevention. And you know, wear the pink ribbon, all this. And breast cancer prevention was really emphasizing the way to prevent breast cancer is to let women get mammograms all over the place. You know, every year have them, or whatever the interval was, have a mammogram. Mammograms don't prevent breast cancer. Excuse me, they early detect breast cancer. So I think that what you're describing, and in fact that suite of blood tests that you describe, you know, the gliofibroblastic, the GFAP, the neurofilament light, NFL, looking at phosphorylated tau, p-Tau 217. We describe them in the book because they're available to people and they do give you a sense as to where you begin the process. And, you know, people talk about, well, what about your genetics? And what if I do carry the APOE4 allele and I know therefore if I'm heterozygous, I have a 5-fold increased risk, if I have 2 of them, Homozygous, my risk for Alzheimer's may increase 12-fold. Should people even know that? And my answer is, you bet, 100%, because that will be much more encouragement for you to do what Mark Hyman and I are talking about today, and that is get busy and get your metabolism, get your metabolic house in order, and you can absolutely rewrite your destiny. And that's what this is all about. And, and it— does it fly in the face of modern, uh, medicine, how medicine's practiced here in America? Yes, indeed it does. I mean, you know, I— we see how the deck is stacked, and that's okay. I mean, uh, Robert Kennedy Sr. once said, some people see things as they are and ask why. That's what we're doing right now. Others see things as they could be and simply ask why not. And that's what we're doing as well. Why not? Why not give people the tools to set the stage for a healthy brain now and not have to suddenly awaken at age— at my age, 71, and notice some cognitive issues and then hope for a cure? Do I hope for a cure, a pharmaceutical cure for Alzheimer's? 100%. If that existed, if GLP-1s turn out to be effective, I'm going to sign up for that. You bet I will. I will be Recommending that, and I talk about that in the book. My mission is not to really think outside of the box, it's really to make the box more inclusive. And I am open to a drug intervention, you bet I am. And having mentioned GLP-1s, I think there is some promise there, but for now, let's do the metabolic work.

Yeah, I think it's so important. And the name of your book is so important, Brain Defenders, because it talks about how do we defend our brain? Like, what are the things we can do to defend our brain? And right now, I think people don't really know. Like, they know if I shouldn't smoke and I should manage my blood pressure and I should, you know, not eat too much saturated fat and I should exercise to prevent myself from getting a heart attack. But if you ask people, what should I do to prevent getting Alzheimer's? It would be pretty much a black box for people. So I'd love to sort of spend a bunch of time on that.

It's pretty much what you just said. Go ahead.

Well, it's those things too. Yes. It's like, the good news is what treats anything treats everything. You know, it's kind of like a, kind of a joke. But if you look at the fundamental reasons we get sick, there's only a few. It's what we eat. It's our lack of activity. It's stress. It's lack of sleep or poor sleep. It's environmental toxins. It's changing our microbiome. It's our genes combined with all those things to determine who we are. And those things are highly modifiable. I mean, we can't change our genes, but we can change the expression of those genes. And so let's talk about Like the fundamental things that people can do other than looking at these causes, right? And looking at the blood tests, which help you see where you are. What are the things that people should be doing to help their immunometabolism, to help their brain immune system, to help their metabolic health, both with their body and their brain? Because I mean, the brain and the body are the same. Like, it's not like we have— we talk about the body-mind, mind-body. That's just one thing. It's not like 2 things. So I think that we kind of get all confused about that. But I think we really need to think about, you know, what are those things that people can do very practically that have the most impact on the brain? And maybe kind of walk us through what you discovered around how to optimize immunometabolism related to the brain.

You bet. And again, you know, so many things came to mind when you— in that setup. And first, you know, back in the day, there was a Heart-Smart Diet. Remember the Heart-Smart Diet? As if, well, I don't have heart disease, I have another situation, so I shouldn't go on that diet. No, it's a body systemic good diet to be on because it's involved with keeping blood sugar where it needs to be and lowering inflammation. And those are the keys. Those are the keys for brain health too when we talk about diet. But the big number one most important thing is to embrace the idea again that you are in charge, that your decisions matter in terms of your brain's destiny. All right, now where are those— what are the decisions? And I'm not going to rank them, but I'll just go through them. Let's first talk about exercise. You know, when we look at the data that looks at levels of— let me preface this by a study appearing in The Lancet in 2024 that looked at 14 modifiable factors and indicated that Attention to these 14 modifiable factors is associated with about a 50% reduced risk for developing dementia. And by and large, these modifiable factors are the things we've already talked about that affect metabolism. Interestingly, as a kind of a sidelight, they did not mention diet. They did not mention nutrition. So I, along with Dr. Robert Lustig, Wrote a letter to the Lancet, letter to the editor, saying, hey, you know, it must have been an oversight. Here are the references that describe diet, you know, the MIND diet, various diets, intervention, Mediterranean, and their effects on Alzheimer's risk. And we got a letter back from Lancet saying, well, thank you very much, but we're not going to publish your letter to the editor. So I don't know what's going on with that. We'll leave that. But let's first talk about exercise. So The data that relates regular exercise with reduced risk of cognitive decline is vast. And that really came to us in actually the late 1980s from a Dr. Kirk Erickson, who randomized a group of just over 100 individuals. One group stretched, one group aerobically exercised. After 1 year, he did 2 things. He did a cognitive assessment. And he actually did 3 things. He measured their BDNF, we'll talk about that in a minute, and he actually measured the size using an MRI of their memory center in the brain. And he was first to demonstrate that this intervention, this program that you put people on, was associated with an increase in size of the brain's memory center, a preservation, in fact, an improvement of cognitive function just because these people exercise. You know, the epidemiological studies looking at people based on their self-reported exercise has shown strong relationship to reduction with more exercise of risk of cognitive decline. And as we look at interventional trials, your friend Rudolph Tanzi at Harvard, along with Dean Ornish, published a study last year demonstrating an interventional trial on 51 individuals, not a huge trial over a 20-week period of time demonstrating that when they changed people's diets, allowed them to exercise regularly, or invited them to exercise regularly, reduce their stress— these are individuals with Alzheimer's disease diagnosed— that their cognitive function didn't slow in its decline. By and large, it stopped declining completely. That's amazing.

Crazy.

And in fact, this is in 70% of their interventional people. In many of them, it actually improved. I'm going to let that one hang for just a minute. So, you know, getting back to exercise, the question I think that you and I are often asked is, okay, I get that being sedentary is bad for my brain, you know, sitting around not doing things, and it's important to exercise. One question is, Well, what's better then for my brain? Is it aerobic or is it resistance? Is it the weightlifting or the bands or whatever machine you might use at the gym or aerobics? And that was actually looked at in a journal called Clinical and Health Psychology in 2025. A study that looked at— was a review of 36 interventional trials where they put people on these programs, and it was close to 6,000 individuals. And their conclusion was, Is it aerobics? Is it resistance training? Their conclusion was it is both. It's the combination that seems to work best. And, you know, as you and I know, these types of interventions work a little bit differently. That when we do resistance training, we're building muscles, which is really important because muscle tissue is an endocrine gland secreting various chemicals that ultimately positively influence brain health. So the muscles make chemicals that go elsewhere in the body, therefore it's an endocrine gland, more involved in, you know, regulating metabolism. The aerobic part of the story improves blood supply, improves insulin functionality. So it's the combination. And what Zhang and the other researchers in that report noticed was that the best bang for the buck, in other words, the best response was in individuals who were age 65 or older, you and me, and also those individuals who already had some cognitive impairment.

Yeah.

For brain preservation, cognitive preservation, and even as a therapeutic intervention, exercise is really, you know, one of the fundamental legs of the stool. Great.

Well, I worked out in the gym this morning at 7, and I went for a hike up the mountain. So like I got my, I got my exercise in, my brain feels good. I know, I know, another doctor talking about protein, but stay with me for a second because what matters isn't just how much protein you eat, it's actually whether your body can actually use it. As we age, we naturally lose muscle and become less efficient in absorbing and utilizing protein. There's actually a term for this, anabolic resistance. And that's why I add Perfect Amino to my smoothie every morning. It gives you all 9 essential amino acids in a highly absorbable form that supports muscle protein synthesis and helps maintain muscle and bone health As you get older. And unlike many whey proteins that can spike insulin levels similar to sugar, Perfect Aminos doesn't. Plus, it can help you hit your protein goals without adding a lot of unnecessary calories. So if you wanna learn more, head to bodyhealth.com and use the code HYMAN20 for 20% off your first order. That's bodyhealth.com and use the code HYMAN20. Most of us are walking around in a state of chronic stimulation. Your cortisol is elevated, your nervous system is stuck in go mode, And we wonder why we can't sleep or focus. Now, one thing I've been using that I genuinely look forward to at the end of the day is the infrared PEMF wrap from BoneCharge. PEMF, otherwise known as pulsed electromagnetic field therapy, delivers gentle electromagnetic frequencies into the body that mimic what you naturally absorb spending time on the earth. Combined with red and near-infrared light, it's one of the few recovery tools that works while you're absolutely doing nothing. I throw it on for 30 minutes while I'm reading or winding down. And I notice I sleep better on the nights I use it. It's lightweight, it's low EMF, it's free shipping, HSA and FSA eligible. And honestly, one of the simplest things I've added to my evening routine. So head to boncharge.com/hyman and use the code HYMAN for 15% off. That's boncharge.com/hyman and you'll get 15% off. So David, let's talk about a few other things around diet, And what is so crucial to understand for people as they bring a healthy diet? And I think we've talked about this a lot, but I think it'd be good to just crystallize your thinking about this in 2026.

What I endeavor to do in Brain Defenders is simplify because, as you well know, there are so many diets out there, whether it's Mediterranean, Mediterranean Plus, added greens, the MIND diet, diets named after people, Paleo, Primal, whatever it may be. And I wanted to look upon diet not so much in terms of what you should be eating day in and day out by being prescriptive about that, but rather what is the effect of the diet that you choose, but with some stipulations. And I think most importantly, it's a diet that's going to control your blood sugar. And I will say that we've got to get some metrics here, and I'm all in favor of wearing a continuous glucose monitor. Not all the time, but from time to time, to get a sense as to what is this diet I have chosen for myself doing in terms of controlling my blood sugar, because my blood sugar is fundamental in terms of controlling my microglial cells and therefore charting my brain's destiny. So get a sense as to the foods you're eating. Make choices that are reflecting a better control of your blood sugar. That said, I like a more plant-based diet. It doesn't have to be fully plant-based, but a diet that is colorful, meaning a lot of different colors of fruits and vegetables on the plate, giving you the polyphenols, giving you, importantly, the dietary fiber. That fat we described should be healthful fat, not fat that is threatening to your body, to your brain, as if the brain were not part of your body. So I really did my best to simplify. We talk about why it's good not to eat later in the evening to increase that window of fasting and all of the things that people are very familiar with. But it's the outcome that is measurable of your dietary choices that I think doesn't— the outcome doesn't get, uh, as much attention as it needs. And that's what I focused on in this book.

Yeah. And, and also, I think, you know, one of the things that people Our understanding now about neurodegenerative disease in general, whether it's Alzheimer's or Parkinson's or even things like MS, they're often related to changes in the microbiome and gut dysfunction. And maybe you could kind of talk about that because you wrote a whole book about that. But I think it's worth sort of double-clicking on that again for people to understand how important keeping your microbiome healthy is because that's what's determining a lot of inflammation in your system. It can control and affect insulin resistance. If there's bugs in there that are not friendly bugs, it can affect you by producing toxic metabolites that affect the brain. So can you kind of talk about a little bit about the microbiome and the brain in that context?

You bet. And you're right, I wrote a book years ago called Brain Maker. And to be fair, some of my colleagues were not— the eyebrows went up. What do you mean, you know, the microbiome affecting the brain? That's the gut. That's, you know, the brain's in Chicago and the gut is somewhere south of Los Angeles. And so, yeah, it was an interesting time. But now I think the mechanisms have been, you know, much more fully fleshed out, delineated, that we can understand, you know, the fundamental relationship between what's going on in the gut, even beyond the microbiome. But let's just talk about that for a moment. So I think one of the fundamental tasks of the microbiome, aside from the metabolites that these bacteria and other organisms produce, is maintenance of the lining of the gut. And as my friend Mark Hyman used to say, probably still says, you know, it's the garbage dump in the gut. That's the term you use. Make— and things should stay in the gut that remain in the garbage, and they shouldn't make their way into systemic circulation. Remember, you used to say that.

I probably did at some point.

No, I think I remember when you did say that. But the point is that there's a lot of stuff in the gut that needs to remain there, and it stays there because we have really good protection. We have a strong barrier that keeps that stuff from making its way into the systemic circulation. The maintenance of that barrier is predicated on diversity and good functionality of our microbes in the gut called the microbiome. When that is challenged by any number of issues that we can discuss, Then they are less able to do that job, less able to maintain that barrier function. Things get out from the gut into the systemic circulation and even into the gut lining, the outside of the gut, and challenge immune cells. What do these immune cells do now that they are challenged with various chemicals like LPS? People may have heard of that lipopolysaccharide. They increase their production of these inflammatory cytokines. If we go back to our original conversation early in this interview, we remember that cytokines, these inflammatory chemicals, make their way to the brain and stimulate our microglial cells to shift from being supportive brain defenders to being destructive. That connects an awful lot of dots between the microbiome being changed and ultimately paving the way for Alzheimer's, Parkinson's, other neurodegenerative conditions, to the extent that there is now a publication— publications allowing us to recognize that we can almost fingerprint the gut microbiome and relate it to risk for neurodegenerative conditions of very specific types. That's how far we've come in studying the makeup of the organisms, and more importantly, what they are producing. In other words, the technical term is the metabolomics of what is going on in the gut. But let me just extend this a little bit further. The most powerful influence on the makeup and functionality of the microbiome are the foods that we choose to eat. So now we've added one more dot, one more step, fundamentally relating our food choices to our brain's destiny. Now, it's through now the lens of the microbiome that you teed up so eloquently. And having said that, it then allows us to understand why it is one nuance of the clear and present threat posed by our consumption, widespread consumption of these ultra-processed foods. And we live in a country where in adults, 60% of calories are coming from these Frankenfoods, as the term you've used in the past. These ultra-processed foods that represent a clear and present danger to your brain's destiny. Consumption of these foods— one study that was published in the Journal of Prevention of Alzheimer's— can you imagine a Journal of Prevention of Alzheimer's? Be still, my beating heart. And this study that came out last year followed a group of 1,111 individuals over a period of 12.7 years. And basically asked these folks during this 12.7-year— during the period of time that we're going to study you, what do you eat? So they kept a food frequency diary. What did they find? They found that those individuals who consumed as an average 1 serving per day of ultra-processed foods experienced a 13% increased risk of Alzheimer's disease, a disease—

Just 1 serving. That's not much.

That's a handful of chips. That's a 13% increased risk of Alzheimer's, a disease for which there is no pharmaceutical treatment available as you and I have this conversation. Further, they found that in those individuals who consumed 10 or more servings of ultra-processed foods a day— now that's in the, in the context of a country where 60% of our calories is coming from. Yeah, so that's not out of— that's 10 servings of chips.

That's probably on the low end. Yeah.

Their risk is increased 270%. That's of a disease for which we have no meaningful pharmaceutical treatment. So—

270%?

Yeah. Basically a threefold increased risk of getting Alzheimer's, which, you know, if you live to be age 85, as mentioned, is already a flip of a coin. Now you've really tipped the scales out of your favor. And that's just based on food choices. And so what do the ultra-processed foods do? They threaten blood sugar regulation, they threaten insulin functionality, they are pro-inflammatory, and they mess up your microbiome.

Mm-hmm.

Vis-à-vis the discussion we just had, we know that's bad. When, you know, the microbiome is threatened, back to that, it's not only the gut permeability issue, but it's the lack of production of certain metabolites, products of these bacteria that make their way to the brain. These short-chain fatty acids that are important for gene expression regulation. What did I just say? That our gut bacteria are regulating our gene expression, our life code. I better take good care of my gut bacteria because they have a big— they have a very important job. They are determining gene expression throughout my body, and yes, even in my brain. For crying out loud. So yeah, food matters.

I think what you're saying is so important and people don't realize how just dramatic diet can be in prevention and also treatment. And, you know, you've written a lot about it. I've written a lot about it. I think one of the things that I think would be really worth sort of diving into a little bit is something that people don't really think about that much, which is how do we think about the Immunometabolic effect of toxins. And they're ubiquitous and they're everywhere. We're exposed to so many of them. And yet, many of us don't really have a way of sort of understanding how to diagnose them or treat them. And we feel a little bit confused because it's like, well, what do we do? And I think you and I have both been involved in this field. And I think that having an understanding of how to assess environmental toxic load, how it affects the brain, how it affects metabolism, how it affects immune function is really important. And I think that was one of the biggest ahas I had early on was that toxins can be directly poisonous, but they can also be immunotoxic. In other words, they can trigger immune dysfunction. And there's a whole phenomenon of autogens, which are autoimmune-inducing toxins. The same can be true for the brain, I think. So maybe you can sort of help us understand that a little bit.

Well, you know, we don't put this microglial activation in the category of classic autoimmunity, but in a very real sense, it is. These microglia are activated and then go about destroying our own tissue. So in a very real sense, I think it's fair to indicate that this is, you know, it's not a classic description, but it is an autoimmune situation. I think back to your question though, how does toxic exposure relate to this? And I think, in a word, fundamentally. So, I don't know how deep you want to go, but whichever toxin comes to mind. I think let's look at toxins that are directly affecting the mitochondria. I recently had the opportunity, I think you did too, to interview Dr. Ray Dorsey. I think you had him on your podcast.

Yeah, yeah, yeah.

And he made it very clear that he considers Parkinson's, for example, to be a man-made disease as a consequence of first the Industrial Revolution and our exposure even back in the 1800s when James Parkinson wrote his treatise on the shaking palsy is what his book was about. And he didn't describe what was— it was a toxic event, but this was when people began to be exposed to these higher levels of toxins. And even to this day. And, you know, by and large, the toxins that are at play here are toxins that threaten mitochondrial function. When we threaten mitochondria, we threaten the microglia and cause them to shift to becoming the evil twin. It's really that straightforward.

Yeah.

We're threatening metabolism. And this is again the term immunometabolism, the relationship between mitochondrial dysfunction and this dramatic life-threatening change of our microglial cells, our brain's immune cells. So what Dr. Dorsey made very clear is that we are exposed to a variety of toxins these days in our environment that directly target mitochondria and therefore can manifest as things like Parkinson's. As you discussed in your interview of Dr. Dorsey, he's really very much fixated on this trichloroethylene, which had been used as industrial cleaner, dry cleaning fluid, makes its way into water. And there are places where groundwater is still contaminated by TCE. And in my lecturing, I've opened up this discussion a little bit further, looking at first something I alluded to earlier, this MPTP contaminant of this IV drug that people were using in the '80s and getting Parkinson's. Because MPTP targets the mitochondria. Well, are there any mitochondrial toxins that we may be exposed to these days? And the answer is, you bet there are. Let's talk about something called paraquat. What is paraquat? Paraquat is an herbicide. It's used to kill weeds around our crops. The good news is that 70 countries around the globe, because it is such a devastating toxic experience, exposure to paraquat, have banned or significantly reduced the use of paraquat in agriculture. The country that is not on that list is the United States. In the United States, our usage of paraquat, a mitochondrial toxin, is skyrocketing. The reason being that our weeds are less responsive now to glyphosate, So they're developing what's called Roundup resistance. So we've had to turn to the use of paraquat, a mitochondrial toxin exposure to which is associated with increased risk of Parkinson's, to treat the weeds in our modern agriculture. And let me be really clear about this paraquat thing. Paraquat is used experimentally to create Parkinson's in primates in research laboratories, and we are spraying it on our food. Something, uh, something's wrong here. Something's very, very wrong that we are— you know, it's been said that man is the only animal who will befoul his own nest. So, you know, we're spraying a mitochondrial toxin on the food we eat. Something's wrong with that. Taking it even further, glyphosate itself, the active ingredient in Roundup, Buy it at the hardware store and spray it around your vegetables. I'm telling you not to do that. It's similarly a mitochondrial toxin. And, we're seeing the politic around glyphosate currently, and we'll see how that ends up playing out.

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But, you know, we live in a toxic world. It's, it's true. And let me just pivot a little bit here to something I think that's really fairly germane as you and I are having this discussion in the summer months where wildfires are rampant in North America. Recognize that, you know, these are by and large forests that are on fire, but it's not like this smoke is benign when it's coming to our cities and we are breathing this. These particles, these PM2.5s, are powerfully pro-inflammatory, meaning they increase the cytokines in our bodies that make their way to the brain and will shift our brain defenders, microglial cells, to becoming brain destroyers. And also, the PM2.5s themselves can be inhaled and make their way through the nose into the brain directly and can induce inflammation. Takes me to one other topic I want to cover real quickly, and then we Unpack whatever else you want. And that is what we call a feed-forward cycle, that inflammation experienced from any source, be it the permeability of the gut, be it the PM2.5 particles that we might inhale, inflammation from any source will shift the microglia to becoming their M1 destructive phenotype, we call it. That is a pro-inflammatory phenotype, meaning— That once those microglia shift to being the evil twin, and let's be clear, they can shift back, that's what our work is all about. But once they're in that M1 damaging configuration, they are spitting out more and more of these damaging cytokines in the brain that further target other good microglial cells and shift them to being on the dark side, if you will, like zombies. So it becomes a feed-forward process. So you can induce that shift from head trauma, for example. That's why these football players with chronic traumatic encephalopathy continue to worsen once they've stopped after playing football. Look at Muhammad Ali, quit boxing, stopped the head trauma, but continues to worsen. Once this process has taken hold, it's a feed-forward process.

It's hard to stop.

It's hard to stop. But not impossible to stop. Can very well be stopped as you've demonstrated in your patients in whom you've improved their cognitive function, as Dr. Bredesen has demonstrated, as I'm describing, as Dr. Tanzi described in his recent publication. You bet.

And people are doing this. I mean, at our center, UltraWellness Center in Lenox, Massachusetts, we do a lot of this and we see these patients and we understand how to assess their Nutritional status, insulin resistance, metabolic health, immune health, to look at mold, to look at toxins, to look at the microbiome. I mean, that's one of the big advances of functional medicine is really understanding how to optimize the microbiome through what we call the 5R program as a reset for the gut. And these are just a different set of lenses and a different set of tools we use to address these kinds of chronic, often very quite scary illnesses, but we can really make a difference. And I think your work has just been so inspiring for me. This book is incredible. I Encourage everybody to get a copy of it, Brain Defenders. And, the subtitle of this amazing book, Brain Defenders, is Harness the Power of Your Immune Cells to Protect Your Brain for Life, which is what you have to do. Before we close, David, I'd love to just do a rapid-fire set of questions. You up for that?

Are these double value, 2 points each? Yes. Go ahead.

Okay. What's the single worst daily habit for your brain health?

I would say lack of connection. A lack of connection to others. Yes.

I like that. And just as a side note, there's a— in my new book that I'm sort of working on, I talk about this guy, Steve Cole, who's come up with this whole science of how disconnection and loneliness actually activates a whole gene expression pattern that drives inflammation. So you're right on target. What's the single best daily habit for brain health?

Connection.

Okay, there we go. How about alcohol? Is it ever good for the brain?

It's never good for the brain. Uh, you know, our messaging has changed over the years.

Never.

It's a, it's a toxic event and it's never good for the brain.

How about sleep? How many, how many hours should people sleep every night?

Ideally 7 to 8. Not just quantity, but I think it's important to study your sleep, wear the Apple Watch or the Oura Ring, and get a sense as to the You kind of addressed this a little bit, but what's more important for the brain, aerobic exercise or strength training, if you had to pick one? If I had to pick one, I would probably say aerobic.

And then walking, is walking enough or do you need to do more?

It really depends on the individual. What does walking do for you? Can you brisk walk and get your heart rate up to where it needs to be? That's the question. And I think walking on an incline is, you know, going to help build muscle mass, which is important as well.

Yeah, if you're a marathon runner, walking probably won't do it. But if you're a couch potato, it probably would start. How about blood tests? What's the most important blood test that people are not getting, but they should?

Fasting insulin.

Agreed. Agreed.

Wow.

We're on the same page, David.

If Mark Hyman agrees with me, I'm doing well.

What's another symptom that makes it bad in the long run for your cognitive health?

Increasing waist size.

Ah, so your belly fat. Yeah, that's a big one. Okay. Is it ever too late to improve your brain health? And can you really reverse loss? We've talked about it, but is it too late? Is there a point at which it's too late?

Well, there's certainly a point in which it's too late. I think end-stage Alzheimer's is too late. But as we now see, interventional trials using lifestyle modification have proven effective even in individuals with established Alzheimer's disease.

What's one food that you eat regularly for your brain?

Salmon.

Salmon. Okay. You're catching it up there in British Columbia right now.

I caught one last night when the sun was going down. Yeah, it was great with an orca in the background.

Oh, love that. How about what's one food you avoid?

Fruit juice.

Fruit juice. Yeah. No fruit juice. Orange juice is not a health food. And, what is one supplement with the strongest evidence that you would take for your brain health? Vitamin D. How about GLP-1 drugs? Are they going to be brain health drugs?

My sense is quite likely. I think there is some refinement that's obviously needed. We've seen an incredible interventional trial published in the New England Journal of Medicine where Parkinson's was stabilized. I think GLP-1s have a future in brain health, the brain health arena.

Interesting. So it's an evolving story. We'll pay attention. Okay. What's more important for your brain, doing brain games or staying socially connected? and intellectually engaged?

I would say socially connected for sure.

And if you're a 40-year-old right now, what are 3 numbers you want to know that reflect what's happening in your brain?

You need to know your fasting insulin level, your flat— your fasting blood sugar. And I would say your waist-to-hip ratio.

Those are good. It's all metabolic health. Okay. Now lastly, finish this sentence.

The best way to stay mentally sharp for the next 20 years is to change your thinking Today, to the extent that you realize that you are in control of your brain's destiny.

You are in control of your brain's destiny. That is a big one. I think people all understand this about their heart or their weight, but they don't understand that their brain health is in their control. And I think that's what so much of your work has been highlighting for the last 40 years. This last book, Brain Defenders: Harness the Power of Your Immune Cells to Protect Your Brain for Life, is amazing. It's out now. You can check out David's website, drpromonter.com. He's got a podcast, and you'll learn all about his amazing work. Uh, he's definitely one of my mentors and one of my close friends. I'm happy to be in this world with him because without him, I would be much less smart. So thank you, David, for—

I love you, brother.

I love you too.

Love all that you do.

Good to see you. All right, buddy, thanks so much. Enjoy salmon fishing in British Columbia. If you love that last video, you're gonna love the next one. Check it out here.