Why Microglia Are the Key to Brain Health, with Dr. David Perlmutter

In this episode we discuss:

• What microglia are and why they’re essential for maintaining healthy brain function
• How chronic inflammation can transform protective microglia into drivers of neurodegeneration
• The emerging science of immunometabolism and mitochondrial function
• Why insulin resistance, obesity, and type 2 diabetes dramatically increase dementia risk
• The limitations of the traditional amyloid hypothesis and what newer research suggests
• How lifestyle interventions have demonstrated measurable improvements in cognitive outcomes
• The powerful connection between the gut microbiome, systemic inflammation, and brain health
• Why sleep, exercise, and nutrition remain the most impactful tools for protecting the brain
• The truth about the APOE4 gene—and why genetics are not destiny

Show notes:

There’s been a lot of discussion about brain health over the past several years, and particularly in the context of dementia and cognitive decline. I’ve had Dr. Dale Bredesen on the show a couple of times, maybe three times. He’s been a major figure in advancing the idea that cognitive decline, dementia, and Alzheimer’s are not merely our destiny or our fate based on our genes. We actually have a significant amount of control over our susceptibility to those conditions based on our diet and lifestyle choices. So, I’m really excited to welcome a legend in the field to the show today, Dr. David Perlmutter.

I’m sure many of you have heard of him, and he’s been a guest on the show a couple times in the past as well. Dr. Perlmutter is one of the foremost experts in the world on neurodegeneration and brain health, and particularly the role of diet and lifestyle, and the impact that those can have on brain health. And he has a new book out called Brain Defenders, which examines the role of the microglia, which are the immune cells of the brain, in our cognitive function and brain health. So this was a really fascinating discussion. We cover what the microglia are, how they impact our brain health, what influences the health of the microglia, the major diet and lifestyle levers that we can pull to affect the microglial health, the role that genetics play in developing these conditions, which is perhaps much smaller than you might think based on what the mainstream media have told us over many years, and many more topics.

This was one of my favorite conversations I’ve had with a podcast guest in quite some time, and I think you’re going to love it too. Let’s dive in.

Chris Kresser:    Dr. Perlmutter, pleasure to have you back on the show.

David Perlmutter:  Dr. Kresser, it’s been a while. I’m glad to be back.

Chris Kresser:  So, I was really excited to see your new book, Brain Defenders, and the focus on microglia. That’s something I’ve paid a lot of attention to over the years, and I’m just really excited by the research in this category. Let’s dive right in there, because I think a lot of people who listen to the podcast and follow this stuff know what microglia are, but I would wager that in the general public, not that many people know what they are and why they’re so important.

David Perlmutter:  Well, I am so glad that this term microglia is going to come into the general lexicon for all of us, because it’s really, really important. So, the microglia cells are the cells that comprise the brain’s immune system. So, in the brain, everybody knows we have neurons that have gotten all the attention for the past 100 years, but it turns out the brain has its own dedicated what we call innate immune system, and the cells of that system are called the microglial cells. Glial was originally a term used because it was thought when they looked at the images of these cells in just static images in the microscope, they looked like they were gluing together the neurons. So the term glia means glue, and they’re small, so microglial cells. But now we recognize that these are extremely active, and very, very mobile, I might add. They do go around the brain doing surveillance and picking up debris and fixing things that they see need fixing.

So they’re doing a heck of a job in really creating the perfect environment, or not, that’s what we’ll talk about today, for neurons either to thrive or for neurons to fall apart. And they’re especially influential in the formation and the function of our brain synapses, meaning how one neuron connects to the next neuron, and that’s really critically important as it relates to not only developmental issues like autism spectrum disorder, but also things like Alzheimer’s– that the synapses are really where the problem really begins, and where it manifests in terms of its clinical symptomatology. The reason we become demented is because we lose our connections, not only within the brain, but to ourselves and to people around us. That’s what characterizes Alzheimer’s. And it is these microglial cells, these brain immune cells, that are determining whether or not we’re going to preserve and have functional synapses, or they are going to be digested and lost.

Chris Kresser:  This fascinating thing about the immune system in general, and microglia specifically, is when it’s operating in its functional state, it’s protective, and yet when it overreacts, it gets stuck in a pattern of hyperreactivity, it has the opposite effect. We see this in the immune system with autoimmune disease, right? And in the case of microglia, the same thing can happen. You talk about this as a Jekyll and Hyde quality of the microglia.

David Perlmutter:  Yeah, it’s the same cell. It’s the same cell genetically. It’s like identical twins. One is the football coach and teaches kids in high school, and the other is in jail for a felony or something. But they’re genetically the same. They’re not epigenetically the same, that’s for sure. But the point is that the shift away from being supportive brain defenders, what we call the M2 microglial cell that we really want, to this M1 configuration, brain destroyers basically, is a shift over which we have control based upon our lifestyle choices. So things that you’ve been talking about for an awful long time now can be looked at through the lens of how these lifestyle choices affect the brain’s immune cells. And really, ultimately, the term immunometabolism is used here. That’s a term that means that the metabolism of these cells, how they use energy, produce energy from their mitochondria or not, really determines whether they’re going to be friend or foe, supportive or destructive. And we have a huge say into whether these brain cells are going to be supportive or leading to destruction based upon what we decide to do with our lifestyle choices, day in and day out.

Chris Kresser:  So yeah, I was going to ask you about immunometabolism. I love this term. Are you suggesting that metabolism is the primary driver of microglial function, whether they’re working harmoniously or whether they’re inappropriately attacking the tissues and structures of the brain?

David Perlmutter:  It’s a great question, and you asked, is metabolism or changes in metabolism the primary driver that shifts this cell away from being supportive to being destructive? And actually it’s an interesting response that I want to offer you, because it goes both ways. Things that threaten to change the microglial cell from being M2 supportive to being destructive will shift its metabolism. And at the same time things that target that cell’s metabolism will also shift it from being supportive to destructive. And it works the other way too. When we can target the cell’s metabolism, we can coax them back away from being the evil twin, back to being supportive. That’s where all the research is right now, and that’s basically getting to targeting their mitochondria. So metabolism, at least as it relates to energy, is something that the mitochondria do. When those cells shift away from being supportive, mitochondria come offline, and the other form of energy production that is common is called glycolysis. That’s not going to be on the quiz for your viewers, but the point is that a less efficient way of making energy is utilized by the destructive microglial cells. And one of the techniques to coax the microglia back to being supportive is indeed to target their metabolism, target their mitochondria.

Leading edge research is looking at mitochondrial transplantation as a way of coaxing the microglial cells back to being supportive, but in your work over the years, you’ve discussed how we can do other things right now to improve mitochondrial function. That’s why exercise matters. Supplements like CoQ10 and urolithin A, periodic fasting, time-restricted eating. All of these things nurture mitochondrial function and help us rejuvenate our microglial cells back to being supportive.

Chris Kresser:  So you mentioned in the book a direct line between conditions like obesity, insulin resistance, type II diabetes, and neurodegenerative disease, and we’ve heard the term type III diabetes, which is dementia and cognitive decline driven by metabolic issues. What is the state of the research now in terms of drawing the connection between those conditions? And I would assume, given that we have now something like 40 percent of the population obese, over 70 percent overweight, that we could see on a chart the incidence of dementia and Alzheimer’s rising in a pretty strong correlation with the incidence of those conditions.

David Perlmutter:  Chris, I’m going to tell you something I have never said in an interview or on my own podcast, and that is I just realized how much I really enjoy this stuff, because it’s just so cool. I mean, that was a great question right there. We know that there’s a strong correlation between all of the metabolic factors that you mentioned, like obesity, like insulin resistance, and full-on type II diabetes. But if you’re a type II diabetic, that’s associated with around a three fold increased risk of becoming an Alzheimer’s patient. But why? I mean, what is the connection? And it turns out that it’s through the effect of this metabolic issue of being diabetic on the brain’s immune cells, these microglial cells. So, these are all inroads to trigger the microglia into becoming destructive. There are a host of receptors on the surface of the microglial cell that is very much allowing it to be aware of what’s going on metabolically in the body.

So what I just said is really quite interesting, because the microglial cells, you think they’re the brain, they’re in another place. The rest of the body is in Chicago, but the brain, of course, is in Houston, or something. No. The brain is deeply involved in understanding and needing to understand what’s going on with the body metabolically, day in and day out. When we become insulin resistant, we increase our blood glucose, obviously, and one mechanism is we form changes in our proteins. We glycate, or we bind glucose to our proteins. When that happens, those proteins are looked upon by the brain’s immune system, the microglial cells, as being something foreign, and they react. How do they react? They change into being M1. So that’s just one way that metabolism is sensed by these immune cells in a way that the immune system thinks is appropriate, but ultimately is not appropriate. These changes that happen trigger what’s called a feed forward cascade.

Once those immune cells transpose into being threatening M1, it’s associated with their dramatic increase in production of chemicals called cytokines, which are the inflammatory mediators throughout the body, and of course in the brain. And here’s where the story gets really worrisome. Inflammatory cytokines are sensed by the loving M2 microglia as a danger signal and converts them also to being M1 or threatening. So as these M1 microglia are formed, they send out signals to recruit even more of the good M2 microglia to their side, like spreading through the brain like zombies. And that explains a lot, as far as we understand why various neurodegenerative conditions are in fact progressive over time. Let me give you an example. We know about this thing called chronic traumatic encephalopathy. That’s the almost universally fatal brain disease that sports participants get after repeated head trauma, like NFL players get this issue where they become demented, lose their mental faculties, and ultimately perish from the fact that they have now a progressive neurodegenerative trauma event, even though the trauma has ended. They’ve retired, but yet they’re still continuing downhill. We never really understood why until quite recently, when the evidence was made clear that what’s going on is there’s an activation of these cells that propagates throughout the brain through the process I just mentioned.

More M1 microglia produce these damaging inflammatory chemicals that further recruit even more of the M2 supported microglia to their side. We see it across the spectrum of neurodegenerative conditions. And amazingly, we now have technology to image these M1 dangerous microglial cells in living humans. It’s called a TSPO scan. And we see that it lights up incredibly in Alzheimer’s, Parkinson’s, schizophrenia, PTSD, long COVID, major depression, things that we normally would not associate with immune activation. And yet there it is. So the good news is, as we develop more advanced techniques to revert those microglia back to being supportive, it really allows us to throw a very large net in terms of a variety of neurodegenerative conditions, and even neurodevelopmental conditions as well.

Chris Kresser:  Yeah, I mean, I would say this is largely good news in light of the fact that the dominant narrative about Alzheimer’s for decades has been that it’s purely genetic. There’s nothing we can do about it. It’s just a slow progression decline that we have very little control over. And that’s been dominated by the amyloid hypothesis that has really driven the focus of research and treatment for many, many years. I chatted with our colleague Dale Bredesen about this a few times. I know that you know his take has always been that we’ve been looking for a silver bullet when what we really need is buckshot, meaning a multi-pronged approach. I know you mentioned when we were chatting before the show that a recent Cochrane review that looked at all the FDA-approved anti-amyloid drugs found that they’re really quite useless, actually. And this is not for lack of trying, right? We’ve been at this for a couple of decades, at least.

Could Alzheimer’s begin decades before symptoms appear—and be influenced by everyday lifestyle choices? In this episode, Dr. David Perlmutter explains how the brain’s immune cells, called microglia, shape cognitive health and why inflammation, metabolic health, sleep, exercise, and nutrition may play a far greater role than genetics alone. #ChrisKresser #brainhealth #microglia

David Perlmutter:  Yeah, and again, exactly as you said it. And to paraphrase Dale Bredesen, the idea of targeting beta-amyloid is looking for a silver bullet, a single monotherapy that will be a blockbuster billion dollar drug. And need I say more, but I will say more. But you’re right. So this Cochrane analysis came out quite recently and evaluated 17 studies comprising 20,345 individuals who were participants in that study. And these studies typically take 18 months, looking at the ability of the drugs to do two things: number one, did they remove the beta-amyloid, and number two, much more importantly, how did they affect cognitive decline? Well, what the study found was really quite interesting. Yeah, the drugs removed beta-amyloid quite handily, but their effect on the cognitive decline was nil. And that’s what the study, the analysis, made clear– that the effectiveness of the drugs were trivial, and yet the risk was significant in that 25 to 28 percent of people taking these drugs have what’s called AREA or amyloid-related imaging abnormalities, which basically means hemorrhages into their brain and/or swelling called edema in the brain. And the statement has been made by many of the researchers in support of the drugs as well. We don’t really know if there’s any long term consequences of those events.

I kind of think that bleeding into your brain and swelling in your brain might not necessarily be a good thing, but the point is that here this Cochrane analysis came out with no agenda and confirmed a word that you used, which I think is brilliant, and that is the amyloid hypothesis. A hypothesis means something that needs to be validated. That’s really where we are now, and in fact, it’s been refuted, because these drugs removed the beta-amyloid and had no effect on the continued decline of these individuals. So, I think the idea that beta-amyloid is the cause, or as Dr. Bredesen would say, the one event for which we’re trying to develop a silver bullet, is let me say myopic to be kind, silly to be maybe a little bit less kind. And we now recognize that things like metabolism and inflammation are really upstream, and the polarization of our immune cells very much upstream of this accumulation of beta-amyloid. And I will look at a study from 2024 by our friends Dr. Rudolph Tanzi at Harvard and Dr. Dean Ornish, who did a lifestyle intervention on patients with existing early Alzheimer’s disease. A 51-individual cohort studied for 20 weeks with an intervention that changed their diet, changed their physical activity, managed their stress. And what did they find in existing Alzheimer’s patients? That this intervention did not slow their decline. No, it arrested their decline. It stopped their decline, And in fact, in 70 percent of the individuals in their study, they demonstrated either complete arrest of their decline or actual cognitive improvement. That’s the big enchilada here. Can you imagine a study of Alzheimer’s patient intervention leading to cognitive improvement? And yet we don’t hear about that, And the side effects of their intervention were weight loss, improvement of metabolic status, better blood sugar, all the things, right? Lower C-reactive protein and mark of inflammation. And yet nobody pays attention to that. People are still focused on what’s the drug I should be writing on the prescription pad for my patient, or I should be recommending for mom or dad, or my husband or wife, if they have been diagnosed with Alzheimer’s disease?

I get the calls or emails several times a day. We’ve been diagnosed, gone to the doctor, I’m enrolling in an IV drug therapy that may or may not work. Well, what you brought up, this Cochrane analysis, has told us it’s not going to work. Why should we do that again? Primum non nocere. Above all, do no harm. Look at the risk-benefit ratio. So it’s about the lifestyle changes we can make, and how those lifestyles affect the polarization or the activity of the brain’s immune system, that really is center stage these days.

Chris Kresser:  Yeah, those lifestyle changes can’t be turned into a billion dollar blockbuster drug, though.

David Perlmutter:  No, but they’re gonna save a lot of money.

Chris Kresser:  Agree, 100 percent. And this is unfortunately what we’re up against. Our entire medical industrial complex is geared toward the silver bullet solution, because frankly, that’s what generates profits for the drug companies. And fortunately, we have people like you who are educating folks who have, like the veil has been pulled, and they’re interested in finding these solutions, because it’s a far more empowering reality in which we can take action, not only once we start to experience cognitive decline, but actually far before that.

David Perlmutter:  I fully agree, and when you look at the economics of it, it makes sense. We’re spending about $360 billion today caring for Alzheimer’s patients. But beyond that, we should consider the emotional impact of this diagnosis on the patient and on the families. It is horrendous. And I watched my father die of this illness, and so I get it. Believe me, I understand. So that’s what motivates you. I had a conversation the other day with Bruce Willis’s wife. He’s been diagnosed, as you well know, with frontal temporal dementia. And upon that diagnosis, she set about to create an awareness of this issue, awareness of brain degenerative conditions in general, created a foundation, and is being proactive in terms of giving people this information on the front end that might keep people from having to deal with what she had to deal with. Been there, and it’s a devastating experience. But again, I think your point is well taken, that this information needs to get out to people before they’re demented.

There was a very important study called the POINTER study. It appeared in JAMA last year. What the POINTER study did was followed 20,111 individuals over a two-year period of time. And what they did was they had two groups, and the main intervention group was a group that got instruction on diet, lifestyle, exercise, stress management, etc, and management of cardiovascular issues as well. These were people entered in the study in their late 60s who were metabolically not in the best of shape, but were cognitively intact and had not had a history of stroke. So, group one gets this vigorous interaction with 36 interactions with coaches during a two year period. Working on your diet, working on your exercise, working on lifestyle modifications, stress management, on and on. The other group, we can’t really call it a control group because there was some sort of intervention, only had six one-on-one meetings with people to coach them. And what they found was really quite fascinating. And these are people in their late 60s, early 70s. In a two year period, almost everybody has some degree of cognitive decline during that period of time. What they found was really fascinating. The people who got the heavy coaching, the 36 interventional coaching, they not only stabilized but they actually demonstrated cognitive improvement, whereas they would have otherwise declined. And everybody talks about that. Wow, look at this. You coach these people, they improve cognitively. And the part of that story that I think doesn’t get enough air time is the fact that the other group improved as well. They only had six interventions, or six contacts with a coach, only three times a year where they got a check in. But they were given the information, and hopefully most of them pursued what they were told, and they improved as well, as opposed to stabilization or declining.

So, again, to the point that you just raised, it’s critically important that we emphasize that we are each the architect of our brain’s destiny, based upon what we choose to do right now, and I’m speaking to you, 30- and 40-year olds, right now, because you’re setting yourself up right now for metabolic health or metabolic mayhem as you get older. The seeds are sown for Alzheimer’s disease, not when you’re 60 or 70, but when you’re 30 and 40. That’s when the problem begins. You don’t really realize it. You got a lot of brain reserve, but that’s when things actually begin. Two or three decades prior to what we call the clinical manifestations of memory loss of problems with executive function.

Chris Kresser:  That’s such a crucial point, and it’s a good segue into the next few questions I want to ask, which is, so we’ve established our lifestyle as a primary driver and also the primary interventional lever that we can use to prevent and slow or even reverse this condition, depending on where you are on that spectrum. So, let’s talk first about the gut-brain axis. This is a favorite topic of both of ours, and I’m really curious to hear the latest on the connection between the microbiome and gut health, and then the microglia specifically.

David Perlmutter:  Well, how fascinating it is that our gut organisms, bacteria, viruses, a variety of organisms that we have, 10-fold more viruses than bacteria, as a matter of fact, many of them are there actually controlling the genetic expression of our bacteria. Who knew the microbiome we should be talking about? But that said, those bacteria, or the entire ecosystem rather, beyond the bacteria, are powerfully influencing the function of the brain’s immune system. Wow. I mean, so we’ve known for a long time that things go on in the gut that do affect the brain, the organisms create various chemicals, like the short chain fatty acids and B vitamins and neurotransmitters, etc. that act at a distance and can bring about changes within the brain. But I think the big issue here seems to be that when we experience inappropriate changes in the diversity and functionality of our gut organisms, it often leads to their loss of ability to maintain the integrity of the gut lining, such that we develop leakiness or permeability issues of the gut lining, which is not a good thing. Because things in the gut need to stay in the gut, by and large, except for, of course, nutrients, and things that make their way across this very delicate one-cell thick lining can increase inflammation. That’s a powerful mechanism.

It happens every time we eat food to a small degree, but when we have inappropriate changes, it’s called dysbiosis, or changes in our gut diversity and functionality. We can increase that leakiness and increase inflammation throughout the body. These inflammatory chemicals, called cytokines, can make their way to the brain and easily make their way to the brain through the blood-brain barrier and are immediately sensed by the microglial cells. And what does that do? It changes those microglial cells from being friend to being foe. So inflammation anywhere in the body, not just from the gut, but anywhere in the body makes its way to the brain and can help revert our microglial cells away from being supportive. And infection, of course, does the same thing, but infection is generally accompanied anywhere in the body by bumping up the level of these inflammatory cytokines. It explains now why we oftentimes see significant cognitive issues with bowel-related disorders. Why an Alzheimer’s patient maybe getting by will suddenly have a precipitous decline from a urinary tract infection. So, anything that shifts these microglial cells is going to have clinical manifestation that can be fairly acute. People can be going along, maybe declining a little bit here and there, and then suddenly seemingly fall off a cliff. It’s actually very common.

So again, this relationship with the gut explains why there’s a strong relationship between risk for Alzheimer’s and the utilization of non-steroid anti-inflammatory drugs. Why would that be? Well, one explanation has been changes to the microbiome. What about proton pump inhibiting acid blocking drugs? There’s a significant association with Alzheimer’s risk in people who are habitually taking these medications. Some people need to take them who have unique problems, like a gastrinoma, a tumor that secretes gastrin, or something called Zollinger-Ellison syndrome, or perhaps esophageal ulceration, or gastric ulceration. But to offer these drugs over the counter for people who don’t do well when they eat smoked sausage, and think that’s what the TV commercial tells them they need to do, to reach for these acid blocking drugs, what do they do? They decrease stomach acid, so they change the pH in the stomach. They raise the pH in the stomach. But it doesn’t end there. You’re going to change the environment in the entire digestive system, and even minute changes in the pH in the gut will have a significant effect upon the microbiome in terms of the organisms that can thrive in that environment versus those that cannot. So you’ve now sent a powerful environmental signal to the gut, and that, to me, explains why we see these really significant relationships between issues in the gut and issues in the brain.

Let me take it even further. We’ve known for a long time that the earliest symptoms often in autism spectrum disorder are gastrointestinal issues. These children have dramatic gastrointestinal issues, and then secondarily we begin to observe their change in terms of their development, in terms of their neurocognitive function. And those issues related to the gut can influence the microglial cells. One of the important functions of the microglial cells in our very earliest times of life is to actually, believe it or not, digest away synapses where brain cells are connected to each other. We call this synaptic pruning, and that’s a good thing. Synaptic pruning is a way that the brain actually refines and streamlines itself for better cognitive function. This is a job of the microglial cells. When we look at the brain of a one year old human, that brain is forming synapses, connections between neurons at a rate of around 1 million per second. That’s a lot. But about 20 percent of synapses are actually destroyed during development as well, and that’s a good thing. What we see in autism spectrum disorder is that the rate of synapse removal is reduced, so that brain becomes hyper-connected. And I think that when you think of a hyper-connected brain while you’re evaluating a patient with ASD, it kind of makes sense, because that’s a brain that tends to perseverate on certain things, while it cannot divert attention to other things. And so that’s a situation where synapses should be removed and might be a consequence of what’s going on in the gut.

In Alzheimer’s, we say an overreduction of synapses. The removal of brain synapses is a central feature of Alzheimer’s, as, again, Dr. Bredesen has made clear. He calls Alzheimer’s a synaptopathy, a disease in which synapses are abnormally removed. And guess what? The exact same process of microglia digesting away synapses is what’s going on in the Alzheimer’s brain, and it’s now thought that what’s going on in Alzheimer’s is a reactivation of the normal developmental process of synaptic pruning that generally shuts off in our mid teens. Now it’s been reactivated, and we’re digesting away our synapses. That’s a person who is going to suffer cognitively, when those synapses are removed.

Chris Kresser: That’s so fascinating, and I love the framework and context you introduce for understanding the relationship between gut issues and microglial brain issues, which is, well, it sounds like inflammation is the primary driver, and the movement of cytokines from the gut into the brain by the blood-brain barrier. And you also mentioned the role of cytokines earlier in the show. Is that also the way you think about the impact of other lifestyle factors like poor diet, environmental toxins, alcohol, inflammation being the primary mediating mechanism in those cases as well? David Perlmutter: Yeah, I mean, I think absolutely. I think when we see these profound relationships, for example, between consumption of ultra-processed foods, that was a 12.7 year evaluation of 1375 people demonstrating that having one serving of ultra-processed foods per day as an average was associated with a 13 percent increased risk of Alzheimer’s. That 10 or more servings a day, and that’s not uncommon, I mean that’s 10 handfuls of chips, for example, is associated with a 2.7-fold increased risk of developing what mainstream will tell you is an incurable disease. And face it, it’s a fatal situation, right? We know of cancer survivors, ask people if they ever met an Alzheimer’s survivor. Except for some of the people that Dale Bredesen has worked with, that’s for sure. So, I think that the new recommendations that have been put forth, which basically turned the food pyramid upside down and are really calling out what these ultra-processed foods are doing, I think that’s great news. There’s some minor comments I would make with these recommendations, but by and large, I think that the idea that these are threatening our health in a very big way, it’s really important messaging. It gives people an understanding that this crap that I may be eating because I like it, and we do like those foods, face it. I mean, they’re designed just to really knock down your will control to make it won’t control. The salt, sugar, and fat content is just bumped up to such a degree that who can resist? Well, you’ve got to resist. You’ve got to understand that it’s a really important decision that you make every single day. It’s right up there with how much exercise am I going to get today? And what will my diet be like? And that’s up to you. That’s what Chris Kresser asks himself every morning. How much exercise am I getting, and what in the heck am I going to eat? Those are fundamentals for brain health.

Chris Kresser: Absolutely. And I’m curious, when you think about the landscape of diet and lifestyle factors as we already mentioned, like processed food intake, alcohol, environmental toxins, chronic stress, sleep. Obviously, in an ideal world, people are thinking about all of those things. But if you had to, let’s say, force rank the top three. If someone’s listening to this podcast and they’re feeling overwhelmed, they just want to focus somewhere first. What would you choose?

David Perlmutter: Well, I’ll tell you what number one is, and there is by far a very important leader of what are the levers to pull, and that is the first thing is to embrace the idea that you are the arbiter of your brain’s destiny. You’re the architect. And unless you do that, then the others don’t really matter, because you’re not going to bring them on board. You’re going to say, why? I would rather eat the donut, I really would. There’s not a person walking the planet who doesn’t have a sweet tooth, because that’s hardwired in. Sweet is what allowed us to survive, right? Sweet means ripened fruit. It allows us to consume fructose. We like it. We raise our uric acid, we increase our body fat, and we can survive. Our ancestors survived during times of caloric scarcity or food scarcity. So it’s a powerful survival mechanism. So once you embrace that idea, and that’s my hope for our time together today, that people get the notion that what they’re seeing in the evening news about, I’ve lowered my A1C to seven by taking this drug, or I’m going to take this monoclonal antibody for my psoriatic arthritis, or other immune-related read metabolic-related issue. Once you realize that we don’t want to be reactive, we want to be proactive. We don’t want to wait until there’s no light at the end of the tunnel, and then think we’re going to do something. John Kennedy once said in his inaugural address, I think we say the union address, actually, that the time to fix the roof is when the sun is shining. And that’s why you and I are together today. So, once people embrace it, then we can look at the next three, and they are sleep, exercise, and diet. And there’s so much more that I wrote about in the book. But if I can just, if I could pull those three levers, I’m going to say mission accomplished. Absolutely. I mean, there’s fine tuning that we talk about, there’s cool technology that people can get, there are wonderful wearables that are more than just biometricsizing us, more than measuring, but that are actually interventional, doing things for us. I get it. There’s research being done with 40Hz light that can reprogram our microglia available now. It’s true. I mean, there are a whole array of supplements to target our mitochondria to help revert our microglia back to being supportive. True. But if we can rein in diet, make sure people get a satisfying good night’s rest, both in terms of quality and quantity, and make sure that we get people through this idea of being sedentary– that’s the new smoking, is sitting. That we’ve got to be active because that activates your body’s internal pharmacy that sends important chemicals to your brain, like an endocrine gland. I would say we’ve painted with the broad stroke here, and are going to, I can’t say what the percentage would be, how much success that will be, but it’s got to be, I’d say around 80 percent. The fine tuning, the other things to bring on board, are very, very important as well for people who are doing the big three. But that’s the first step, and if the other things don’t happen for 10 years, I’m going to be okay with that.

Chris Kresser: Yeah, it’s not surprising, and it makes a lot of sense to me. But let’s double click on diet, because people are pretty confused and overwhelmed by that.

David Perlmutter: I hear you loud and clear.

Chris Kresser: So we have Mediterranean, keto, MIND, fasting mimicking diet from Valter Longo, carnivore, more recently. What’s your take on these various approaches, specifically in the context that we’re talking about here?

David Perlmutter:  Well, I love the question. I love the way you framed the question, because people are absolutely overwhelmed. I mean, I think the first diet du jour was the Atkins diet, which was obviously crazy. I mean, here’s a guy saying that we got to cut back on carbs and eat more fat. I mean, where could that have possibly come from? A hundred thousand years of human evolution as one argument. So that became paleo, primal, MIND, Mediterranean, green plus Mediterranean, all of these, fasting mimicking diet, fasting. All the things that have their moment in the sunshine. Let’s be fair to Valter Longo, he’s done some beautiful work in, certainly cancer, and neurodegenerative conditions now as well. But I wanted to, again, paint a broader stroke, because, as you say, people just are overwhelmed with one diet after the next. Next week, it’s going to be something new.

So I’ve said in the book, I want a diet that does the following: controls your blood sugar, so whether you’re wearing a continuous glucose monitor, or checking your fasting insulin from time to time. I didn’t say glucose. Yes, check that as well. But fasting insulin. Looking at your A1C, that’s one of the metrics. So see where I’m going with this. A lot of times diets are diets that say you should eat this, eat that, but we just metricized the diet. How does it play out in terms of your blood sugar control and insulin sensitivity? That’s important, because we don’t look upon diets through their effects upon our bodies, and yet we have the ability now to measure these effects acutely. I’d like a diet that supplies plenty and plenty of fiber. I would love to say fiber should be considered the fourth macronutrient, but by and large, fiber is carbohydrate by definition. So that’s the missing link: fat, protein, carbs, and fiber. I can’t really do that, but I’m trying awful hard, because it’s so devoid in modern diets, especially here in the Western world. I’d like a lot of color. Why do we want color? Again, because it’s going to give you fiber. Because color comes from plants, and plants contain fiber. Animal products do not contain fiber. But the color means it’s going to be rich in polyphenols. And the other parts of the diet mean an adequate amount of protein and healthy amounts of good fats. And in the book, I, of course, unpack what does it mean, good fats, and how much protein should we be consuming?

And look, if you want to be vegan, you want to be full-on vegetarian, great. You want to eat animal products, fine, have at it. But these are very broad stroke, and I think ultimately going to be much simpler ways of assessing your diet to determine, did you check those very few boxes? So it’s not a micromanagement kind of thing that can make people bonkers. Oh gosh, is this on the diet, or it’s not on the diet, whatever. I really wanted to be very generous with people and let them understand what are we trying to accomplish here with this diet? And then we can move on to exercise, we can move on to sleep. But those are the important points that I think people need to take home.

Chris Kresser:  Yeah, I couldn’t agree more. It’s the end justified by the means in this case, meaning the end is better blood sugar control. It’s insulin control and metabolic function. And for one person that could be achieved through a Mediterranean diet, for another it could be paleo, for another it could be keto. And there’s so many factors, outside of this context of brain health, that go into what might be an ideal diet within that range of diets for a particular person.

David Perlmutter:  Yeah, I get that question all the time, which diet are you on, Dr. Perlmutter? Right? And I say none of the above. And oh, people are so surprised. Well, how could that be? This is how I eat. And beyond that, here’s something else I think is important. I interviewed Jason Wacob last year, mindbodygreen, after he and his wife wrote a really very good hands-on book for direction and navigating life. And he said don’t call them cheats, call them treats. And what does that mean? It means that about two weeks ago, my wife and I went to a really nice restaurant, and I ordered the pasta dish. Yes, indeed, I did. And I will tell you right now, I enjoyed every minute of that meal. It was delightful. So, you know what? Did that spike my blood sugar? I don’t know, I wasn’t wearing a CGM at the time, but probably a little bit. But I’m still here, and the amount of enjoyment I got out of that meal was absolutely worth it. So I don’t want to go with the 80/20 rule, because people justify anything with the 80/20 rule. I don’t sniff glue 80 percent of the time, whatever. You can take that to extremes. But you could tell I’ve had coffee, but nonetheless, enjoy life. But again, you’ve got to keep your blood sugar under control, and having a pasta dish from time to time isn’t going to take the train off the rails.

Chris Kresser:  Yeah, absolutely, I couldn’t agree more. So, let’s talk a little bit about a question I know people will be asking as they listen to this, because there’s been a lot of discussion about it in the mainstream, which is their APOE4 gene variant, and this very deterministic view that if you have this particular gene variant, then sorry, there’s very little you can do and this is almost just your fate. What do we know now about the role these genotypes play in driving dementia and Alzheimer’s? And if someone does have a higher risk genotype, what would you tell them?

David Perlmutter:  I would say, forget everything you’ve been told, because it’s not going to serve you, and it’s wrong. So you described it, you set it up perfectly, that people are told this is your destiny. And nothing could be further from the truth. I will agree that carrying one or both alleles as APOE4 is a risk marker. It is not a determinant, it is a predisposition that can absolutely be overridden. In the POINTER study that I referred to earlier from JAMA, and it’s public access on JAMA, POINTER study 2025, people should look at it. It’s fascinating. And these are the group of individuals who adopted either their very intensive lifestyle change, supervision-wise, or less supervision, same lifestyle change, and improved their cognitive function. Stopped their decline and improved their cognitive function. 28 percent of those individuals were APOE4-positive individuals. Think about that. These are people who are told you’re going down the skids. You better put your wagons in a circle. But yet these are APOE4 people, and 28, 25 to 20 percent of people listening to you and me right now are carriers of the APOE4 allele, they need to know that that is not a determinant at all. Hear me well.

So, we can offset and even override this predisposition for Alzheimer’s disease by making the changes that you and I are discussing today. Mainstream has come up with a kind of a novel idea that I was reading about yesterday evening, and that is looking at gene therapy to actually transplant APOE2, which is, there’s APOE2, APOE3, and APOE4. APOE4 is associated with increased risk of Alzheimer’s. APOE3 is sort of neutral, and APOE2 is a lower risk of Alzheimer’s. So, the idea of transplanting APOE2 gene using a viral vector into people who are APOE4 carriers. Research is always going to be looking for something interventional, patentable, obviously, for reasons we talked about related to a beta-amyloid. But that said, again, these lifestyle issue implementations will override this predisposition. And frankly, I think knowing that you carry the APOE4 allele is a great thing. Why? Because it’s going to encourage you to be even more stringent about adopting this program. So, for years it was said, oh, we should never even tell a patient when he or she carries this APOE4 allele, because we’re stigmatizing them, we’re going to make them depressed, and yeah, with the narrative that this is a one-way street and a determinant, you will. You absolutely will. And that’s the wrong messaging, and it’s unfair to do that to people.

I think people should know their APOE status, and once they do, that’ll even give them greater resolve to implement these changes that you and I are talking about today.

Chris Kresser:  Yeah, that makes a lot of sense. Well, Dr. Perlmutter, this has been a fascinating conversation. I’m really excited about the book. Can you tell people where they can learn more?

David Perlmutter:  Sure. Well, here’s the cover: Brain Defenders: Harness the Power of Your Immune Cells to Protect Your Brain for Life. Brain Defenders. And you can get it wherever books are sold. That’s what I’m supposed to say, right? Wherever books are sold. The website, oddly enough, is BrainDefenders.com. So if people go to BrainDefenders.com, they will see how they can buy the book, and in addition get all kinds of other perks and discounts and various things, arrangements that we’ve made with various companies. So I’m very excited about this book, because I think you can see that it really represents the convergence of everything that I’ve been studying for close to 40 years now. Everything converges on how it affects, and you touched upon it all today. It was beautiful to go through the relationship of the gut to the brain, the relationship of the high carbohydrate diet. I talked about that in Grain Brain, and all the things, the inroads that we’ve talked about for so long, through the lens of these immune cells in the brain. But much more importantly, I think through the lens of being able to do something about it for once, and that’s what I find so exciting about this work.

Chris Kresser:  Yeah, absolutely. I’m really grateful to you for empowering people with the knowledge and the tools to take action, because as we talked about throughout the show, one of the most harmful parts of the amyloid hypothesis, and the idea that dementia and cognitive decline is driven entirely by genes, is the helplessness that that engenders and has engendered for so many years. And when people know that this is in their hands, they can do something about it, and they can do something early in their life, like 30 or 40, that’s incredibly empowering, and such a different message.

David Perlmutter:  Well, you’re right, the term doctor doesn’t mean healer, it means teacher, and it’s so empowering. That’s what this is all about, because I think it’s so valuable for people to hear the other side of the story. One side of the story is, live your life however you choose, in terms of your food and your activity, or lack thereof, and staying up late, not getting restorative sleep, and hope for the cure, right? And the other side is to be proactive and just stay healthy as it relates to your entire health, and certainly your brain health as well. And I think, to be fair, the brain has never really been in that conversation. We started talking 40, 50 years ago about the heart smart diet. That’s been around an awful long time. And similarly, there’s a brain smart diet, and they happen to be the same diet, I might add. Low inflammatory, controls your blood sugar, good for your metabolism, problem solved. Good for your bones, good for your heart, good for your body, good for your brain, as if that’s distant from the body. So it’s taken a while for the brain to enter this conversation, but it is now. It’s front and center, and I’m very excited to be involved in helping move this change along a little bit.

Chris Kresser:  Well, thank you again. Everybody, check out the book at BrainDefenders.com in the bookstore or online. And Dr. Perlmutter, thanks again. It was great to see you.

David Perlmutter:  Dr. Kresser, great and nice to see you. Thank you for having me today.