The Metabolic Switch That Turns Your Brain Against Itself | David Perlmutter, MD

Hello everyone, I'm Dr. David Perlmutter. I am a board-certified neurologist and a fellow of the American College of Nutrition. Today we're going to talk about neurodegenerative conditions and focus on Alzheimer's disease. You know, over the past several decades, it's been pretty well considered common knowledge that the cause of Alzheimer's disease is the accumulation of a particular protein called beta amyloid. We now recognize for the past couple of years that there's actually a far more important mechanism involved in what makes a good brain go bad in Alzheimer's, Parkinson's, and really across the spectrum of neurodegenerative conditions. And that is a dysregulation of the brain's immune system, and particularly the The brain's immune cells that are called microglial cells. This will be the focus of my presentation. Microglial cells can be supportive. The brain's immune system can do a lot more than what we typically associate with immune function. And when they are supportive, they are nurturing brain synapses. They are allowing the blood-brain barrier to work efficiently and actually fostering the growth of new neurons. When the microglial cells, however, shift their metabolism, then they become threatening. They can lead to disruption of brain synapses, the loss of the ability to grow new neurons, again, neurogenesis, and even disruptions of the blood-brain barrier. And as it turns out, our lifestyle choices have a huge role to play in determining whether our microglial cells are supportive or they are destructive. And this understanding of the brain's immune system now transcends Alzheimer's disease, and is seen to underlie virtually all neurodegenerative conditions. We recognized, in addition, that when we are able to shift our microglial cells back to being supportive, this is a powerful new entrée to regaining and protecting brain health. We'll begin our discussion today with a look at Parkinson's disease and how this discovery was actually made that the immune cells of the brain are playing such an important role. We will then shift our discussion to neurodegenerative conditions in general and then focus specifically on Alzheimer's disease. Please enjoy. So we are going to explore the notion of defending your brain, brain defenders, how we can chart our brain's destiny, what you can do to chart your brain's destiny. We're going to begin our story with Dr. J. William Langston, a neurologist at Stanford. And many years ago in the early 1980s, he was suddenly alerted by his residents that there was an interesting patient in the emergency room and they didn't know what to make of it. This patient, George Carrillo, came in and was actually seen to be frozen in his position like a statue. No one had seen anything like this. And shortly thereafter, several other patients presented with similar symptoms. And what Dr. Langston was able to determine, the thing that united these individuals, was that they had all been intravenous drug users and that their medication or altered medication had come from a single source and that this drug was actually contaminated with something called MPTP. Dr. Langston wrote about this and described how this Parkinson was a consequence of the use of this meperidine analog synthesis. In other words, these people thought they were shooting IV heroin basically, and, or meperidine, Demerol, and that it was contaminated with something called MPTP. What he found was that this MPTP that this was contaminated with was metabolized into something called MPP+. I'm gonna relate this in just a moment through our brain's immune system to all manner of neurodegenerative conditions, including Alzheimer's, in just a moment. But what Dr. Langston discovered was that this MPTP actually remained active in the brain for many years. He determined that these individuals who had self-administered this synthetic heroin had survived anywhere between 3 and 16 years, and that this MPTP was actually toxic as it relates to their mitochondria. And in this case, specifically to the part— in the parts of the brain that are making the chemical neurotransmitter called dopamine. And this led to the clinical symptomatology that he observed. Many years later, patients began to die, and Dr. Langston had the opportunity to examine their brains. This is one of the patients who at age 29 years was injecting this designer drug every day for a week. He died at age 42. And this is what his brain looked like, specifically an area of the brain called the Substantia nigra, or black substance. It's called that because this is the normal control. You can see that it is dark. These are cells that are rich in something called neuromelanin, and they produce the chemical dopamine that is deficient in the Parkinson's brain. When we look at the patient's brain, patient number 1, we see a virtual absence of those cells that produce dopamine, and hence this patient develop the clinical symptomatology that we see in Parkinson's disease. When you look under the microscope at those cells, what we see are remnants of neurons and neuromelanin that have been basically digested away. And here is the fascinating part of this story. The yellow arrows point to what are called activated microglia. What are those? Those are the components of the brain's immune system. that have become activated and are digesting away. Here we are many years later, but they're still actively destroying those cells in the brain that have had their mitochondria disturbed by the initial event of being exposed to a toxin. It creates a self-perpetuating inflammatory process that continues to act long after the exposure to the toxin has passed. A self-perpetuating inflammatory process is what is going on here. And what is happening in the brain's immune cells, the microglial cells, is there has been a shift from these supportive, loving, nurturing M2 microglial cells that we depend upon to nurture our synapses, to grow, help us grow new neurons, to keep the blood-brain barrier intact, they have shifted under the influence of this drug, a contaminant in the drug, to being threatening M1 microglial cells that are destroying brain cells, damaging synapses, and threatening the brain's blood-brain barrier. When the microglial cells shift from being supportive M2 to being destructive M1, they increase their production of chemicals involved with inflammation called inflammatory cytokines. And these inflammatory cytokines feedback upon the loving, supportive M2 microglia and further shift them to becoming threatening, creating a feed-forward process whereby there is continuing decline in the brain. We see it in CTE, chronic traumatic encephalopathy, that we see in football players, Alzheimer's, Parkinson's, any manner of neurodegenerative condition, even long COVID. and PTSD. The relationship that is seen in Parkinson's disease with exposure to toxins has been well described by Dr. Ray Dorsey, written several books about this. He's appeared on my podcast. This is Dr. Dorsey appearing on the Empowering Neurologist podcast, where he talks about this and where we recognize that exposure to various toxins in the environment, at least as it relates to Parkinson's, is well documented. documented. For example, in exposure to paraquat. Paraquat is an herbicide that is sprayed on the very food that we eat. This study demonstrates that people who are exposed to paraquat demonstrate a significant increased risk of nerve cell degeneration. We saw this with Dr. Langston's report, and we see it now in relationship to individuals who are exposed to paraquat. People exposed to paraquat by the nature of their work or living near agricultural concerns that use paraquat have a 60% increased risk in developing Parkinson's disease. Paraquat, like the MPT I showed you earlier with the IV drug exposures, paraquat itself is similarly a mitochondrial toxin. The good news is that countries around the world have banned or significantly restricted paraquat usage in agriculture. I'd like you to take a very close look at this chart. In the United States, paraquat usage has increased dramatically in recent years. Why? Because we have been using a lot of glyphosate and many of our crops are becoming glyphosate resistant or Roundup resistant such that we now have to employ other herbicides. To spray on the very food that we eat, an herbicide, in this case paraquat, which is a known mitochondrial toxin, which is known to be associated with increased risk of Parkinson's disease. When we look at Parkinson's prevalence in America and we look at the agricultural usage of paraquat, we see some strong correlations. We know that paraquat, which is sprayed on our food, is actually used in laboratories to create Parkinson's disease in laboratory animals. The notion that we're using more and more of this environmental toxin on our foods, and specifically Paraquat, which is known to produce Parkinson's in laboratory animals, is certainly concerning. Well, here is our loving, supporting M2 microglial cell that wants to do nothing less than nurture our neurons, Help us grow new neurons, nurture our synapses, and shore up the blood-brain barrier. But in the presence of things like inflammation, exposure to pesticides and herbicides like paraquat, rotenone, glyphosate, even air pollution, oxidative stress. Number 3 on those, hyperglycemia, elevated blood sugar and insulin resistance. This supportive, loving microglial cell, our brain defender, can shift away from being supportive to its other phenotype, if you will, what I call the evil twin, the M1 phenotype of the microglial cell that is threatening. It is threatening to our synapses. It is reducing our ability to grow new brain cells and is even threatening the integrity of the blood-brain barrier. And this is then associated with things like increased neuroinflammation, Mitochondrial dysfunction, neuronal dysfunction, the loss of our synapses, the digestion away of our synapses, and even threatens the blood-brain barrier. And what is really important is that this leads to further polarization of what would have been supportive microglia to turn them into threatening M1 microglia. And what I'm going to be presenting to you in just a moment is the The idea and the tools that you have to actually first reduce this from happening and next actually revert your microglia back to being supportive. Again, so many things threaten the brain's microglial cells, including systemic inflammation that can come from the gut. Leaky gut leads to increased inflammation in the body. It does make its way to the brain. It's why we see such incredible correlations now between changes in the gut microbiome Dysbiosis, if you will, and increased risk of cognitive dysfunction. But look at this list. And if that list wasn't enough, we'll just add a few more items that you should be considering, many of which, most of which we can evaluate and we can improve. So this shift away from supportive microglia to threatening microglia, M2 to M1, is something over which we have control. I.e., we can control our brain's destiny. When we shift to the M1 microglial cell, it creates these inflammatory cytokines that then can revert back and further worsen our situation by converting these M2 microglia to being threatening M1. This is why neurodegenerative issues can worsen over time. This is why Football players who develop chronic traumatic encephalopathy worsen over time long after they have retired from playing football because this is a, what we call a feedforward process. Here are our microglial cells, M1 and M2. The take-home message here is that this arrow is bidirectional. So many things I listed will shift the M2 away from being salubrious to an M1 phenotype that threatens our brain. But I'm going to show you we can revert our M1 microglia back to being supportive. Now, let's look at that M1 microglial cell and understand that when we accumulate these cells in the brain, it sets the stage for brain decline across virtually all neurodegenerative conditions. We can actually image these cells in the living human by doing something called TSPO imaging. We can image when the cells, microglial cells, have become activated and are in this M1-threatening evil twin, non-brain-defending phenotype. We do what's called TSPO imaging. This is the healthy control. What might it look like in the Alzheimer's disease brain? I will show you. I think it's quite clear that what's going on here is a dramatic demonstration of activation of the brain's immune system, the brain's microglial cells shifting away from being our brain defenders to a threatening, destructive phenotype. And let's be clear, this happens across a large nexus of issues related to brain decline, including Alzheimer's and Parkinson's and long COVID, for example, fibromyalgia, major depression. Dementia with Lewy bodies, even in ALS and traumatic brain injury. When the brain shifts, the brain does not improve. But again, this explains why these chronic brain degenerative conditions worsen with time. Fundamentally, what's going on in these microglial cells that characterizes their shift in function is a shift in their metabolism. On the left side of your screen, these cells have wonderful healthy metabolism when they are M2 supportive microglial cells. The mitochondria are producing wonderful amounts of energy via very high levels of production of ATP, the currency of energy production. Whereas on the right side of your screen, the M1 microglial cells are not really Demonstrating good mitochondrial function. They are using an alternative pathway called glycolysis. So what we are seeing here is a demonstration of a powerful relationship between metabolism and immune function, metabolism of the cells and immune function, because after all, the microglial cells are the representatives of the innate immune system. in the brain. And this now goes by the term of immunometabolism, one of my favorite terms at this stage in my research. Immunometabolism, the powerful relationship between our immune systems and body metabolism and cellular metabolism as well. That these systems, the immune system and our metabolic system, as demonstrated by our utilization of energy, by our production of proteins, etc. These are not disparate, but they are united in the term immunometabolism. And fundamental to this presentation is the idea that the metabolism of our microglia, which determines friend or foe, mirrors our systemic metabolism. Meaning that if our systemic body metabolism is in good shape, We are favoring supportive M2 microglia. We are charting a wonderful destiny for our brain. When we are suffering from metabolic dysfunction, we favor the M1 microglial cell and we are setting the stage for brain decline. In the journal The Lancet back in 2024, they demonstrated that modifying 14 risk factors might delay Or prevent even half of dementia cases. And by and large, these were issues related to metabolism. You know, wearing a bike helmet, of course, is not necessarily a metabolic issue, but certainly helps reduce the risk of serious brain injury that becomes a pro-inflammatory metabolic— metabolically threatening issue. But we're now recognizing that, you know, the notion of just focusing on beta amyloid as being the cause of Alzheimer's disease is certainly myopic. Upstream of the accumulation of beta amyloid, we see this change in the microglia. As SciTechDaily has said, the hidden culprit behind Alzheimer's is now revealed in December of 2024. Microglial cells, looking at them under the microscope, that Alzheimer's shock, the new suspect rewriting everything we thought we knew. May 20, 2025. Breakthrough discovery, Alzheimer's disease, that the brain defenders— that'd be a great name for a book, wouldn't it?— turn dangerous. It now appears that the immune system may be a powerful force in the brain's decline and, while we're together, may hold the key to slowing it or stopping it. So as we see, Futura recently published Alzheimer's Twist: This Unexpected Culprit Is Shaking Up What We Knew. Again, looking at the brain's immune cells, those microglial cells. And as the scientists told us, one of of the biggest, if not the biggest breakthrough in cell biology in 2025 is microglial reprogramming. What does that mean? How do we reprogram our microglia back from being threatening to being supportive, from the M1 phenotype back to the loving and nurturing M2 phenotype? Can you imagine being able to reprogram those microglia back to being supportive, How do we do it? We target their metabolism in order to change their immunological phenotype. How do we do that? Well, remember that the metabolism of the microglia, which determines friend or foe, is dictated by our systemic metabolism. So how we take care of ourselves in terms of our metabolism is reflected in whether our microglia are supportive or destructive. The Alzheimer's Association back in 2024 called attention to the fact that rates of Alzheimer's are certainly increasing, especially in the elderly population. And they really describe what we should be doing, that our problems begin on the left side of your screen when you're beginning to have cognitive concerns. You can't remember people's names, our grandchildren's names, the Wi-Fi code, you name it. Walk into a room, don't know why. And as we continue across their continuum, that you go to the doctor, you have a bunch of tests, you're diagnosed as having some cognitive issues, mild cognitive impairment, then you're tested for beta amyloid, and you end up on the right side of the screen where if treatment is started, the person has regular visits to a specialty doctor. And gets these infusions at infusion centers until the beta amyloid is gotten, is removed from the brain. I want to challenge that. We can do better. We don't want to wait until a person experiences memory and thinking problems or problems are noticed during cognitive assessments on the left side of your screen. I would modify this to be as follows. I'm cognitively intact, the first thing we should be thinking about, and plan to keep it that way. Thank you very much. I want to pay strict attention to this divergence between supportive M2 microglia and M1 microglia, which are damaging, and embrace the notion that this is a bidirectional relationship between these phenotypes and ask the question, can we intervene here? And again, remember that targeting the metabolism of these microglial cells is what determines whether they're going to be M1 or M2. And to be fair, there are almost an infinite number of types of microglia between M1 and M2. But this is a really simple way of understanding this phenotypic shift. Remember that microglial metabolism mirrors systemic metabolism, that reprogramming our microglial cells is front and center what we should do and what we can do. And, you know, anything that has an effect on our body's metabolism will play out in our microglia. There's some techniques that in fact focus on the brain, but, you know, by and large, the things that target our metabolism include the ketogenic diet, certainly exercising. What a powerful tool. Hyperbaric oxygen, increasing the function and availability of something called nitric oxide in our bodies by eating nitrate-rich foods like beets and being careful that we're not using antibacterial mouthwash. Various nutritional supplements like urolithin A. Fasting evoked gamma oscillation. We're going to talk about that specifically in a moment. Improved sleep. Dietary fiber to keep our gut microbiome happy so that we don't have leaky bowel, which increases inflammation. There are a lot of things here to pay attention to and some things that are being explored. So the complete list you will find in my new book, Brain Defenders, as Dr. Sinclair kindly indicated, a science-based actionable blueprint to shift the brain from decline to repair. To shift the brain that is characterized by one that is rich in these M1 microglia and shifting their metabolism by attention to your body's metabolism back to being supportive microglia. Indeed, as the scientists told us, the journal, microglial reprogramming being really one of the biggest breakthroughs in cell biology in 2025. Well, we know lifestyle factors are important. I'm going to conclude this presentation by giving you just a sense as to where the science is currently. Where we are going because it's very exciting. In the book, we talk about a lot of different new technologies currently available and those that are being evaluated and being developed. But I want to just spend some time talking about something called gamma frequency, gamma frequency attenuation, and how that actually targets our microglia. This is some pioneering work done by Dr. Li-Huei Tsai at the Picower Institute for Learning and Memory at MIT. And let's take a step back and talk about what is this gamma entrainment all about. We want to develop a really synchronized background wave activity in the brain called gamma entrainment. When we see disruptions of this beautiful sinusoidal gamma background symphony that is played in the normal brain, it correlates with a lot of different brain disorders. We know that changes or abnormalities in this gamma background frequency— I'm going to show you that in just a moment— is seen in association with things like Alzheimer's and autism spectrum disorder and even schizophrenia, bipolar, epilepsy, Parkinson's, and even major depression. That we can go from, on the left side of your screen, a disrupted background activity that is seen in correlation with Alzheimer's disease to a— what we see in the healthy brain is this smooth sinusoidal curve that typifies a very, very healthy brain, a beautiful symphony playing in the background. What was determined in the original rodent research is that we see gamma oscillations before beta amyloid plaque appears. This is again seen in the rodent model of Alzheimer's disease, these PPP-positive rodents that in fact emulate what goes on in the human Alzheimer's brain as well. What the researchers demonstrated was they could reestablish gamma frequency in the background of the brain oscillation by exposing these laboratory animals to a light flashing at 40 times per second called 40 Hz flicker. And here's what it looks like. Not really, but it's what I made it for the purposes of this presentation. Now, when we look at the random mouse versus that Alzheimer's mouse that is exposed to the 40 Hz light, a dramatic reduction in the level of beta amyloid in the memory center of that mouse. We look specifically at one -40 beta amyloid in the visual cortex, the back of the brain, when they are seeing this flashing light, a dramatic reduction at 40 Hz in comparison to other types of light. Room light, specifically flashing at 20 times per second, 80 Hz. But look at the improvement at 40 Hz. Looking at beta amyloid 142, a very similar reduction in the beta rather in the Alzheimer's rodent model. And when we look at the microglial count, we want to get more M2 supportive microglia. First of all, the microglial count increases. We know that the good M2 supportive microglia are actually larger than the destructive M1 microglia. So we want to see, does the microglia diameter increase with 40 Hz flicker? You bet it does. Well, all well and good, right, for the Alzheimer's rodent, but what happens in humans? And in fact, interventional trial published in March of 2024 looked at the effects of this type of intervention and also exposing individuals to sound at 40 Hz in humans with mild to moderate Alzheimer's disease, What did the study look like? Randomized 6-month trial, 76 participants who did in fact have existing disease, and they verified what happened to their background gamma oscillation by doing EEG during the course of treatment to be sure that with this type of intervention, sound and light, that they were inducing gamma oscillation in these individuals. What did they find? First, in looking at the Mini Mental Status Test, a kind of standardized test that we neurologists use in the office, we look at what happened to the individuals who received the sham treatment or didn't receive 40 Hz light in their Mini Mental Status decline over 6 months, frankly, as expected, versus those who simply received 40 Hz light and sound treatment, a significant change in the 6-month period of time in terms of a very minimal reduction in their Mini Mental Status Test. What about their ability to perform what are called activities of daily living, like bathing themselves, toiletry, eating and feeding themselves, transferring, etc.? This is called the ADLS-8 Activities of Daily Living scale. When we look at that scale, and this is actually very important in terms of this individual's functionality, what do we see? In 6 months' time, individuals not treated declined quite precipitously in terms of this evaluation. But in those treated with simply a light flashing into their eyes for an hour a day over 6 months and a sound, virtually, ultimately at the 3-month point, leveling off of their rate of decline. This is incredibly dramatic. There is no pharmaceutical agent on the planet that can achieve this. What about the actual volume of their brains as determined by Looking at their MRI scans. When we look at MRI whole brain volume, we see that those individuals without or who received the sham treatment, not the 40 Hz light, they had a shrinkage of their brain, if you will, as opposed to those receiving treatment. When we look specifically at the back of the brain, the occipital lobe, where these individuals would have seen the light, if you will, that in the control group, There was a significant decline in brain volume, and in those treated, a virtual stabilization in terms of their rate of decline. Well, I hope you enjoyed this presentation. It is certainly interesting and certainly empowering that we actually are taking a role in dictating our brain's destiny. We are the architects of our brain's destiny. Need now through the lens of what we are able to do to influence whether our microglial cells are supportive or destructive. Our microglial cells function based upon their metabolism. And as I mentioned a couple of times in the presentation, the metabolism of the microglial cells that determines whether they are friend or foe is very much dictated by our body's metabolism. And that is incredibly empowering. Hope you enjoyed the presentation. I'm Dr. David Perlmutter. Bye for now.