FULL TRANSCRIPT:

Brain Health: Insulin Resistance, Biomarkers & Alzheimer's Risk | Dr. David Perlmutter & Mike Haney

In a recent episode of A Whole New Level, Levels editorial director Mike Haney sits down with Dr. David Perlmutter, a board-certified neurologist and multiple New York Times bestselling author whose books — including Grain Brain and Brain Maker — have shaped how millions of people think about diet, the gut, and neurological health. After a decade in conventional neurology practice in Florida, Perlmutter pivoted to preventive neurology at a time when that field barely existed, building a practice around the metabolic and lifestyle roots of brain disease. He has written 15 books and remains one of the most prominent voices connecting insulin resistance, inflammation, and microglial function to Alzheimer's and other neurodegenerative conditions.

The conversation covers how our understanding of Alzheimer's has evolved over the past four decades, why the amyloid hypothesis has failed, how insulin resistance and microglial cell function sit at the center of neurodegeneration, what biomarkers actually tell us about brain health risk, which lifestyle interventions matter most, and where emerging therapies — from GLP-1 drugs to gamma oscillation technology — may be heading.

"A third of a trillion dollars is spent every year to deal with a disease which is significantly preventable." — Dr. David Perlmutter

From hurricane hunter to neurologist: an unconventional path

Mike Haney: Well, Dr. David Perlmutter, thanks for joining us. I'll set up a little bit of the context of what we're going to chat about today. We're doing this series of shows that's all about different biological systems of the body — whether that's specific organs like kidney or liver, or systems like cardiovascular or metabolic — and today we're diving into neurology and brain health. Obviously a key part that connects with all of those other systems. Before we get to it, I just want to start for folks who maybe don't know you as well. Multi-time New York Times bestselling author, good public communicator. I'd love to hear about your background. How did you come to study neurology?

David Perlmutter: It's a great question. I began studying neurology — I guess before I was a pre-teen. My father was a neurosurgeon and it really became clear that any relationship I was going to have with my dad would pretty much need to be on his turf. And so he began explaining to me about the brain and his work. I found that sometimes on weekends I would make rounds with him, and even at times when I was 12 and 13 years old in the operating room with him as he was taking out brain tumors. I was very taken by the way that he appreciated the history of neurology, the leaders who had discovered things for whom various disease states were credited. Those names have stuck with me over the years, though there's been a move to get away from naming diseases after people, more along the lines of functionally what's going on in the brain.

That was my earliest experience. When I went to college — prior to college, my goal in high school was actually to become a meteorologist. My plan was to be on the hurricane hunter airplane. I used to spend my free time on weekends at the National Hurricane Center, which was in Coral Gables, Florida, a few blocks from my home. I thought that'd be fun. And then I realized in high school that to be a meteorologist, you have to study science — things that are daunting, like physics and chemistry. So I said that's not for me. Look what happened.

My first year in college I was a business major, and then I realized that these basic science courses, even more advanced science courses, were nothing more than fun. And so I went to medical school. Prior to medical school, actually, I spent a year doing neurosurgery research and was an instructor in microneurosurgery of all crazy things, prior to medical school at Shands Hospital in Gainesville, Florida. We were teaching neurosurgeons how to use what was very novel at the time — an operating microscope. Bringing a binocular microscope into the operating room so that we could preserve tissue, not have to remove as much tissue, and be much more judicious about surgical procedures. In addition to teaching that course, it was important to give doctors a microscopic road map of the brain — never had that been done before — so we published a book about that.

Then I went to medical school, finished my neurology training, went into mainstream clinical neurology practice in Florida, and did that for about 10 years. It was towards the end of that decade that I had a bit of an epiphany, realizing this isn't how I wanted to spend the rest of my professional career — treating symptoms, treating the smoke, ignoring the fire — and I really began to explore what the heck is going on with these people in the first place. How did they end up in my office, or worse, in the emergency room with this or that neurological problem?

I realized that was a pretty lonesome endeavor on my part, because neurologists don't do that kind of work. Preventive neurology was not then and pretty much still isn't now a dedicated field. But as I began to explore it, I found it to be extremely empowering. I was told that I would not succeed and no one would refer patients to me. And my wife and I went to Sanibel Island one night — our office manager took the kids — and the final question we asked ourselves was, what's the worst that could happen? So I set up a practice and began to learn as much as I could about what was underlying Alzheimer's, Parkinson's, MS — what's going on here — and realized that lifestyle factors were playing a very important role, and that that wasn't ever taught in neurology school. So it became very exciting to be very proactive and not reactive as it related to my practice dealing with brain issues. And you know, the rest is history — that's what I've dedicated my life to.

Mike Haney: What kind of work were you doing in those early days? Who would come to you and what would the engagement look like?

David Perlmutter: A lot of general medicine, oddly enough, which I wasn't expecting. I had established myself as having a good track record related to brain issues — chronic headaches, movement disorders, cognitive issues, etc. — and people started to come who had other problems. And it was really quite early on that I recognized that there were fundamental mechanisms involved in what makes a good body go bad that are shared with the brain.

You talked about how we're going to explore the neurological part of lifestyle choices, metabolic issues, etc. — and also the liver, the kidneys. I began to realize that these fundamental mechanisms were kind of unified across the subdisciplines, and it made life easier because the recommendations could become to some degree standardized. Though as things developed, we began to develop an interest in much more personalized medicine — looking at unique laboratory nuances in individuals and then later on looking at genetic profiles to determine risk for the development of disease states. And even upstream of that, what were the risks for the fundamentals — the inflammation, the free radical-mediated stress, the mitochondrial dysfunction — that ultimately downstream would manifest as neurologic disease, for which mainstream remains focused.

I won't denigrate the utilization of a drug to help a Parkinsonian patient with his or her tremor or rigidity. But this is a metabolic problem. Clearly a metabolic problem. We're going to talk about that. And the fact that it is gives us great leverage on the front end to help keep people healthy. And that was, and remains, a profound motivator in my life.

Mike Haney: How did you make the shift into public communication? You've written several books, you've done a lot of appearances. How did that start out of your small practice down in Florida?

David Perlmutter: I started first with a radio program in Naples, Florida — southwest Florida. It was interesting to do. Had sponsorship — I think a personal injury attorney and a car dealership in those days. And then I actually had my own local television program and would highlight the local doctors and talk to them about their practices, but always ask them about the prevention side or the lifestyle issues. And sometimes we'd be rewarded by realizing that some doctors had an interest in this, others did not — and that was a very important lesson.

My wife asked me to visit — to go to a lecture of a fellow by the name of Bernie Siegel — Love Medicine and Miracles, a surgeon from Yale-New Haven. Because she was involved in organizing this, we got to go to dinner afterwards, and he became a very close friend in the years to follow. He said, "You really have to explore a group called the American Holistic Medical Association — AHMA. Their next meeting is in Seattle, Washington. Why don't you go?" I didn't know anything about it, and I went, and I was really blown away by the quality of the lectures, the degree of scientific scrutiny that backed up what these researchers and clinicians were saying. And that was game-changing.

I met an individual there by the name of Dr. Jeffrey Bland, who had started an organization called the Institute for Functional Medicine, and he invited me to be a speaker at the next IFM meeting — and that was also a very important game-changer, because these are organizations that had focused on exactly what was interesting to me. And an outgrowth of all of that was then writing books. I've written 15 books. I'm working on another one now. And each one has been nuanced by different perspectives that seem to change with time in a very good way — some have to some degree refuted earlier contentions, which I think is a very good thing, to remain nimble in your thinking such that you can recognize changes in science that help to either refute or validate your contentions.

How the story of Alzheimer's has changed — and why the amyloid theory failed

Mike Haney: I think that's a good transition into Alzheimer's and dementia, cognitive decline. Within this space, we could talk about depression, anxiety, other mental health disorders, Parkinson's, MS, and other specific conditions, and we can get to those. But Alzheimer's and dementia seems to me to be one of the most interesting spaces over the last five years that I've been paying close attention to the research. And it feels like to me the headline around Alzheimer's is: it's multifactorial, it's not just the amyloid plaque and tau story that maybe 10 years ago we were sort of told it was — and it's so preventable. Not entirely, but we're ever more learning that lifestyle choices can prevent a lot of the cases. As somebody deeply embedded in the space, how do you feel like the story of Alzheimer's and dementia has changed over the past decade or so?

David Perlmutter: I want to take it back a little bit further than that. Back to the early 1980s. In the early 1980s, we were told that Alzheimer's represented a lack of acetylcholine in the brain. End of story. The research had in fact demonstrated that there was a decrease in acetylcholine in the brains of Alzheimer's patients. We learned subsequently that was an effect, not the cause. It was a downstream effect — much as is the accumulation of beta amyloid and phosphorylation of tau that is so front and center now in terms of looking at therapeutics.

Once that was established — the so-called cholinergic theory — pharmaceutical companies went to work to develop ways of increasing this missing chemical in the brain. They targeted acetylcholine by targeting the enzyme that degrades it: if you can inhibit cholinesterase, there will be more acetylcholine in the brain — problem solved. And that's what we were led to believe through advertisements, through in-services, left, right, and center. Drugs were developed and FDA-approved. Donepezil, trade name Aricept, became the go-to drug for neurologists treating dementia broadly. And that remains a go-to therapeutic approach for Alzheimer's — despite one simple fact. It doesn't work. It doesn't work at all.

As a matter of fact, one researcher — last name Kennedy, University of Alabama — did a meta-analysis of all the studies of this cholinesterase approach and found that not only does it not work, but in Alzheimer's patients taking that type of drug, their cognitive decline is more rapid in comparison to those who don't take it. And yet it's still pretty much the go-to approach for treating Alzheimer's. I have family members and friends who have husbands and wives who have been prescribed this medication, and it's a little bit breathtaking. And I guess it gets back to the question you posed to me earlier — why do I do it? That's why I do it.

Because if the gold standard is peer-reviewed science, and in my world it should be and is, then what does the peer-reviewed science say about this approach to treating Alzheimer's? It says that this is not a meaningful approach, and it also violates primum non nocere — above all do no harm. Thereafter there was a push to identify that beta amyloid accumulation within the brain was somehow going to be the answer to dealing with Alzheimer's. In the Alzheimer's brain postmortem — after someone had died — there did tend to be an accumulation of beta amyloid in comparison to non-affected individuals who died for other reasons like trauma or other events. It began to be recognized — or at least messaged — that this was causal, though it was only correlative.

With time, there were attempts to get rid of beta amyloid — initially by giving antibodies through immunization, and subsequently most recently by the development of monoclonal antibody type therapies like donanemab or lecanemab. These drugs have been approved by the FDA. Interestingly, they don't cure Alzheimer's disease in any way, shape, or fashion. Do they slow the progression of cognitive decline? Minimally. In 18 months they slow the progression by about a month and a half. And they are associated with dramatic risk of hemorrhages in the brain in as many as 28 to 30% of individuals given these drugs — which, by the way, costs around $30,000 a year per individual. But nonetheless, that's the pervasive underlying ideology with reference to what Alzheimer's is — that's what people are taught at medical school. And we still see the advertisers saying get rid of the beta amyloid — home run, that's the treatment of choice. It doesn't work.

It doesn't work to the extent that when the first studies came out on this monoclonal antibody type approach to treating the beta amyloid, it was realized early on that the FDA did not give approval because they didn't affect cognitive decline. So the goalposts were moved — to say: well, we get that, but as we all know beta amyloid is the problem — is it at least getting rid of beta amyloid? And they do. But what's the point.

Mike Haney: Why do you think this space has chased these dead ends and stuck to them so vigorously even in the face of evidence? What's unique about the dementia space that has led to that? It just seems odd to me that over the course of 20, 30 years — I get that we haven't solved it, it's hard to solve, but why are we chasing things that don't work?

David Perlmutter: We're chasing individual approaches. What pharmaceutical companies are trying to develop is a monotherapy — a single-handed approach directed at one issue that will solve the problem, and that can then be the brass ring. And the Alzheimer's-beta amyloid relationship could have been that: if indeed beta amyloid were the problem, then getting rid of beta amyloid — problem solved, home run, everybody's happy. But that's not the case.

We know that Alzheimer's is multifactorial. There are vascular issues, inflammatory issues, free radical-mediated stress, metabolic issues — which are really front and center — mitochondrial dysfunction, genetic issues, and the relationships with other metabolic problems in the body, like elevated blood sugar and insulin resistance. These things all contribute to what makes a good brain go bad, and they can be individually targeted to bring about an improvement in Alzheimer's patients.

One of my close colleagues, Dr. Dale Bredesen, took the approach — and continues to take the approach — of treating Alzheimer's disease recognizing that it's not one factor, it's multiple factors. If we address what those are in a personalized medicine approach — that is, what is that individual's issue that has led to his or her cognitive decline — then there might be some improvement. And in fact, he's demonstrated that, though the article that appeared in the New York Times a couple of days ago would lead you to believe otherwise. He describes, metaphorically, a roof with 36 holes in it — they're all leaking. If you plug 35 of the holes, you're still going to get water in the room. You have to find out what they are in each individual and then target them. Whether it's hormone-related or mold-related or infection-related or related to insulin resistance, whatever it may be, these are all factors.

This approach runs counter to the whole monetizable monotherapy approach, and that has been an incredible disservice — not just to the 6.5 million Alzheimer's patients in America, but to their loved ones, their families, and their caretakers. And the economics of it as well. This is a $380 billion experience for America every year. A third of a trillion dollars is spent to create protocols and deal with patients who are failing of a disease which is significantly preventable.

Mike Haney: I was just thinking as you were talking about that — the fact that it is multifactorial, that lifestyle plays such a role — but the current treatment system is set up to find the pill. That's the whole answer. You could stop right there. The treatment system is set up to find a treatment, and yet it's preventable. We're done. That is — you know, that could shine as a poster or the title of a book. That's the challenging part, and it's hard to deal with that every day when we see the latest development, a drug that's just been released and they're on the news because there's another drug targeting amyloid or whatever it is. And time to give it up in my opinion. Well, you know what I was going to say — and I feel like others have used this phrase — there's no lifestyle pill. But as I said that I thought, well, GLP-1s are sort of being marketed that way. I'm curious what you think about GLP-1s in relationship to neurological health. Do you think there's any promise there?

GLP-1 drugs and what their success tells us about metabolic disease in the brain

David Perlmutter: How much time do we have today? The answer is yes. But I want to couch my response — to nuance it to the extent that what have we learned from the preliminary data as it relates to the use of GLP-1 agonist drugs in terms of neurodegenerative conditions? We've learned that they are indeed effective. And what does it tell us? These are drugs that target metabolism, that improve metabolism. They are showing promise — but there's a big lesson here, and the lesson is that these are metabolic issues, whether we're talking about Alzheimer's or Parkinson's. It takes us back to the notion that these are primarily metabolic issues.

The results of an interventional trial published in the New England Journal of Medicine in May of 2024, looking at 156 patients with Parkinson's, randomized to either receive lixisenatide daily — a GLP-1 agonist — or placebo, were pretty stunning. These individuals not treated got worse in the one-year period of time, as one would expect, as rated on what is called the Unified Parkinson's Disease Rating Scale — declined by about 3.2 points, which is huge, but that's the typical time course of Parkinson's. It looks at activities of daily living, motility, assistance requirements, etc. The group receiving the GLP-1 agonist drug not only stabilized but actually improved a little bit. That is breathtaking — that's targeting the fire, not just the smoke. I'm all in favor of targeting the smoke, i.e. the symptoms — you've got to give a Parkinson's patient L-dopa so they can be mobile, anticholinergics so they can reduce their tremor and be functional. Totally reasonable. But at the same time, let's put the fire out, and that's what this drug seems to have done.

The drug was chosen interestingly because we do know that if you are, for example, a type 2 diabetic, you've increased your risk for developing Parkinson's by about 45%. So there's a tie-in there that Parkinson's is related to our body's metabolism in some way. Similarly, we know that when we look at drugs that diabetics are taking and their risk for subsequent development of Alzheimer's disease — in comparison to one drug used for type 2 diabetes, which is insulin — those receiving a GLP-1 agonist called semaglutide had a 69% reduced risk in comparison to the insulin-receiving group of developing Alzheimer's disease. That's pretty amazing.

What are these drugs doing? Primarily they are affecting metabolism in an incredibly positive way. Again, I'm not suggesting GLP-1 agonist drugs for one and all. I am suggesting that it again tells us that metabolism is the key player here that we need to pay attention to. They are improving insulin functionality, insulin sensitivity, improving mitochondrial function, reducing inflammation, reducing glycation of proteins — a very important issue.

I'll take this a little bit further. We are concerned that — well, if we're going to target Alzheimer's or Parkinson's or other neurological problems, we've got to make sure to select a GLP-1 agonist drug that has good blood-brain barrier penetration. The reality is: no, you don't. And here's why — what does get into the brain that we have to keep in mind are inflammatory cytokines. So if we're able to quell inflammatory cytokines peripherally, that has a big effect in the brain in terms of influencing the brain's immune system. Anything to reduce inflammation in the body is going to be good for the brain — like the use of a GLP-1 agonist drug, like paying attention to the gut barrier, like PM2.5 particles, all the things — not getting enough sleep, all the things that we know increase inflammation throughout the body. Insulin resistance — another one.

Mike Haney: I'm really glad you framed it that way, in relation to what the success — the seeming success — of GLP-1s, the early indications, is telling us. Because you've put voice to something that I've been trying to figure out in my head, which is when we see these connections — from Alzheimer's to gambling addiction, obviously a lot of the weight loss and those kinds of issues with these drugs — the idea is not that this is a miracle drug. What this is is a signal that the issue was metabolic all along. And so when we apply a metabolic drug to the situation, we could solve it. Which speaks back to the point that well, if we didn't have the metabolic issues to begin with — to the extent that those were preventable with lifestyle — that's the key to a lot of this kind of stuff. So I think that's a perfect place to go into — I would love for you to just explain more about the relationship of glucose and insulin resistance to neurological health, because I think that's a thing you've been really articulate about for so long.

Insulin resistance and the brain: microglial cells, the blood-brain barrier, and why metabolism drives neurodegeneration

David Perlmutter: I'll diverge a bit from the role of insulin and glucose in the brain, but let me start just by framing it in broad strokes. We recognize that these metabolic shifts in the brain take place 20 or 30 years prior to the clinical manifestations of Alzheimer's, which generally involve issues related to understanding where you are in space, short-term memory, behavioral issues that characterize the clinical manifestation of that disease. So the good news is there's this incredible buffer of time — and more importantly, functionality — that we could take advantage of. That is, identify those individuals in their 40s and 50s who are manifesting these metabolic issues that we know are threatening the brain, and say: you're likely destined to be cognitively impaired if we don't change these issues. And by the way, chronic renal disease, fatty liver disease, metabolic-related cardiovascular disease, some forms of cancer are coming your way if you don't make some changes soon. That's preventive medicine in my world. Very, very valuable as it relates to what the destiny will be of your brain.

There are parts of the brain that are dependent to some degree on insulin functionality from a glucose — and therefore metabolic — mechanism. But I think it's really valuable to consider that insulin is a trophic hormone in the brain. If you want to grow neurons in a petri dish, you need to add insulin and they're going to grow. So there are some really fundamental things that the brain can do when insulin is present — like grow new neurons, like form new synapses, like shore up the blood-brain barrier. And now we're recognizing that insulin functionality is important for keeping the brain's immune system on the side of being our friend as opposed to being foe.

This is now looked upon as a powerful upstream pivotal mechanism involved in virtually every neurodegenerative condition — that the brain's immune system shifts from being supportive, the M2 phenotype of these cells called microglia, to being the damaging twin, the threatening twin. Same type of cell — the microglial cell shifts when it is metabolically challenged. That's breathtaking, because not only does it tend to unify all of the neurodegenerative conditions — because it's present in all of them — but it gives us opportunities to leverage this notion of immunometabolism: the fact that the immune system is so highly regulated, systemically and in the brain, by its metabolic status.

It explains to us why risk for Alzheimer's, for example, is so dramatically increased in the type 2 diabetic — perhaps in some studies as much as fourfold. I mentioned the statistic of in the upper 40 percentage with reference to diabetes. Why any metabolic issue can manifest ultimately as increased risk for brain degeneration. It happens throughout the body as well — that the immune system is shifted to being in an unfriendly phenotype, increasing the production of these damaging inflammatory cytokines that then circulate throughout the body back to the brain. As I mentioned earlier, they make their way into the brain and then shift those microglial cells from friend to foe.

So that allows us to understand, for example, how changes in the gut bacteria are related to Alzheimer's risk. How shifts in our microbiome — called dysbiosis — that ultimately lead to downregulation of certain neurochemicals and increased gut permeability — how they increase the risk of things like Parkinson's disease. The Yellow Emperor in the 4th century BC tagged Parkinson's disease as a gut and liver issue. I don't know where that knowledge comes from, but we should pay attention to it.

But that said, while this is breathtakingly interesting, I think the message of the day is this opens the door for us from a therapeutic perspective. If we're able to measure gut permeability, or simply measure the level of inflammatory cytokines in the body, we know what's going on in the brain. We measure fasting insulin levels or A1C. We use a continuous glucose monitor — get a real good understanding of how that individual is handling blood sugar. It lets us know what's going on in the brain. What will the brain's destiny be? There are more sophisticated tools available for us, but these are simple — and the fix is relatively simple as well.

"We measure fasting insulin levels or A1C. We use a continuous glucose monitor to get a real good understanding of how that individual is handling blood sugar. It lets us know what's going on in the brain. What will the brain's destiny be?" — Dr. David Perlmutter

Key biomarkers for brain health: what to measure and why

Mike Haney: How can somebody — especially folks who are maybe younger or middle-aged who think of themselves as healthy but want to get ahead of anything that might develop later in life — how do we take stock of the systems in our body? You mentioned some of the key blood tests there — insulin, fasting glucose, A1C. What are some other ways that you would recommend somebody measure and assess either their brain health directly or those things that we know can affect it down the road?

David Perlmutter: Well, one of the most sophisticated tools that an individual can avail himself or herself of is called a tape measure. Very highly sophisticated. Waist circumference is an indicator of risk for inflammation, and inflammation damages the brain. So that's a very low-tech approach.

Understanding metabolism vis-à-vis glucose and insulin is key. Why people don't have their fasting insulin measured frequently in doctors' offices — I don't get that. It's really a predictor of being pre-diabetic or full-on diabetic way in advance. Your fasting insulin level is up, yet your blood sugar is normal? Hey, your pancreas is working overtime to try to deal with that blood sugar. Get busy. Subsequently, your A1C is going to go up, and then your fasting blood sugar goes up — the thing you might check once a year. We can do better than that.

Are there some sophisticated tests? Of course there are. There are cognitive tests that people can do — apps available, you can do them online. I think those are reasonable for people in their 40s and 50s. There are more dedicated laboratory studies that people can get. Phosphorylated tau-217 is a pretty good predictor of Alzheimer's — that's available now. People don't even need a prescription. They can get these lab studies done. GFAP — glial fibrillary acidic protein — is another one that indicates neuronal damage. Neurofilament light is also available and shows damage.

But beyond those, I think other predictors are more simple things — like homocysteine. About 28% of the American population is genetically predisposed to having an elevation of homocysteine by virtue of what's called an MTHFR polymorphism. I have it. What does it mean? Simple fix: take methylated B vitamins. My A1C is 7.1, which is great, and that's because I'm really aggressive in taking methylated B vitamins. That's one hole plugged in the roof for me. There are others — including my age. Don't forget that the greatest risk factor for Alzheimer's is your chronological age. I'm not saying biological — if you did the Horvath clock or whatever it may be. It's the number of times you've circled the sun, and that relates to your risk for Alzheimer's more than anything else. What can we do about that? Well, that one you've got to tuck away. That one's a given.

We do look at genetics — did mom or pop have Alzheimer's? My father died of the disease. We look at the APOE alleles — do you carry the APOE4 allele? Gratefully, I don't. And there are others that get us back to this whole notion of immunometabolism. One of them is called TREM2 — a receptor expressed on microglia that controls these microglial cells. When TREM2 receptors are activated, it keeps those brain immune cells supporting your brain. When TREM2 is not active — by virtue, for example, of your genetics — you are at much greater risk of Alzheimer's. But here's the powerful message for today: levels of TREM2 are greatly increased in people who are not obese and not diabetic in comparison to those who are. Those individuals have much higher levels of TREM2, which tends to shift our immune cells in the brain into turning their backs on us, increasing inflammation, damaging their metabolism, downregulating their mitochondrial function. The problem with that is as these brain immune cells shift to become our enemies and destroy our brains, those chemicals that they produce influence the neighboring good cells and shift them. It's like zombies. But we can put an end to that.

We can target that TREM2 receptor right now by working on your waistline and by getting your blood sugar back where it needs to be.

Mike Haney: You mentioned APOE4 and I just want to come back to that quickly because I think this is one people might encounter if they're going to do a blood test. I know we had a lot of debate internally for our expanded blood test of whether or not to include it. The argument for was that it can help people learn something about their potential risk. The argument against is that without the right coaching around it, it can freak people out unnecessarily. How do you think about APOE?

David Perlmutter: I think it is a very important bit of information that can seem threatening, but I would couch it in the perspective of being motivating. You have more work to do because you have this strike against you. I have a strike against me because I have a family history. And I'm 70 years old. So maybe that's two strikes — but I think you get more than three strikes.

I think it's valuable to know because we now understand that one of the mechanisms by which APOE4 is an issue is because it does tend to shift those microglial cells from being friend to being foe, by virtue of increasing the intracellular levels of certain fatty acids contained in those microglial cells. A lot is discussed in terms of the brain's metabolism and the brain's microglial function being left out of that conversation. Many have said, oh, at rest your brain is 2 to 3% of your body weight yet using 20% of your energy — true. But there's a lot more happening in the brain than just the fact that neurons are firing and using a lot of energy. The brain's immune cells have huge metabolic activity, as does the immune system throughout the body. And I think that's very important — these immune cells are metabolically sensitive as well.

When we compromise brain metabolism, sure, we're not doing anything good for our neurons — they're not going to work as well as they should. But the story is a little bit deeper than that. What we are really doing is working on a system that is upstream of the accumulation of beta amyloid. Think about that. When those microglia shift from being M2 favorable to being M1 threatening, their ability to digest away beta amyloid is dramatically reduced. Number one. Number two, the blood-brain barrier becomes more permeable, letting all kinds of things into the brain that further this shift. The beauty of this understanding of immunometabolism as it relates to the brain is that it unifies all of these ideas that relate to brain decline risk — like gut permeability, like head trauma, like exposure to toxins, diabetes, hypertension. All these issues that we know are strongly related to risk filter through this very upstream event: the shift in the microglial cells.

Early warning signs, behavioral changes, and what age really means for Alzheimer's risk

Mike Haney: One of the other things I learned sort of reading about this that I thought was an interesting shift was that we're recognizing more that we can start to see signs — behavioral, mental signs — early. You mentioned some of these things can develop decades before somebody gets a full-on diagnosis. What kinds of things should people be paying attention to? For instance, I read that if you develop depression after the age of 50, your risk of Alzheimer's goes up pretty considerably. What kinds of behavioral things should you be looking for that might tell you that you are at an increased risk down the road?

David Perlmutter: I think there are a lot of co-factors that enter into the conversation at this point. Certainly having depression is a powerful risk factor. Why? Because depression is associated with inflammation in the brain — that makes sense. Lack of sleep, sleep disorders — really very important. People start to notice that they're not sleeping well, maybe they've had a full-on sleep study, or their Oura ring might tell them they didn't get enough deep sleep, or their total time of sleep was not where it needed to be, or they didn't have enough restorative sleep in general. These are important factors that again play through the mechanisms I just described. And therefore, in the context of inflammation and metabolic issues affecting the brain's immune cells, we can now understand why these things are all players.

In individuals in their 40s and 50s, there are things that sometimes are written off — like, well, maybe I'm too young for a senior moment. But we should remember the Wi-Fi code and the names of our children's friends, for example. And we can't write those things off. When we begin to rely excessively on our digital devices for phone numbers and addresses and birthdays and things like that, it doesn't do us any good. Number one, it's indicative that we can't keep up with those things on our own. And number two, we're not training our minds — the other side of this coin — to remember these issues.

So there's a lot of lifestyle things to talk about here in terms of keeping the brain engaged beyond your occupation. It's the avocation. I think those types of things are really important. You don't have to learn new songs on your musical instrument. You don't have to learn a foreign language. You don't have to learn a new skill or a new sport, for example. But they are good for you — to challenge yourself.

Mike Haney: One of the things that — that idea of keeping your brain active, right? This is one of the things I think we've been told — you can go download 100 games on the app store that market themselves as a kind of, you know, keeping your brain healthy, prevent Alzheimer's, etc. It makes sense that that does play a role, but I mean, I guess my question is how big a role does that play and how does that change over time? How should I think about some of these lifestyle things, these preventative things, differently if I'm 30 versus 50 versus 70?

David Perlmutter: Well, let me comment on the brain games. I think some of them have been very validated as being — I mean, Dr. Michael Merzenich, the father of neuroplasticity, he's involved in creating this interactive type of software that has really proven its merit. I think that if I had to vote on the list what's number one, it's going to be physical exercise. Not mental exercise — I'm not saying it's not important. Of course it is. We know it is. But physical exercise from the metabolic perspective, and then the relationship of body metabolism to brain metabolism — therefore the polarization of your brain's immune system, microglial cells — is on the top of the list by far. It affects everything we've talked about thus far.

Is there a particular kind of exercise that you think matters more? What the research has demonstrated as it relates to Alzheimer's risk really looks at the amount — many of the studies, how many steps do you take a day — and it seems like something around 9,200 was the sweet spot. So anything around 8,000 to 10,000 seems to be strongly associated with a modest reduction of Alzheimer's risk as well as all-cause mortality for that matter.

But I think these days mechanistically we're understanding that various types of exercise do different things metabolically. So we want to make sure that we are nurturing our mitochondria by virtue of doing resistance training and high-intensity interval training as well.

But I'm going to do a shout-out here for one other type of exercise that doesn't get mentioned very much, and that is flexibility. And the reason I mention it is because if you get injured, your exercise program comes to a screeching halt, and no one can afford that. So I like having a flexibility program incorporated into a broad program. And yes, in my generation and age people — even balance exercises as well — because one of the big things that happens to elderly — I guess that's me — people is they fall. And you fall and break a hip, your exercise program comes to a sudden shift, and in a significant number of people it ultimately leads to death. So I would add to the resistance training, the high-intensity interval training, the cardiovascular training — we need to be thinking about flexibility and also about balance.

Mike Haney: Yeah, I love that you mentioned that because I think it does back up even further. I'm almost 50 and I find my susceptibility to injury is so much greater. And same kind of thing, right? If I pull a muscle, if I break something, I'm out for 6 months. And I've seen it happen in other folks my age where they get on that and then they don't ever quite get back. And then you just watch that — being out for 6 months. Yeah, that just can't happen.

David Perlmutter: I remember many years ago I injured my shoulder snowboarding and had surgery on a Friday. I was back to work on Monday and I was back in the gym with my arm in a sling doing a stationary bike, just so I wouldn't lose ground. Because you know, that was a long time ago. If I lose ground at this stage of the game, it's going to be really hard to make it up.

Diet, the ketogenic approach, and how to think about nutrition for the brain

Mike Haney: Beyond exercise, let's get into diet. How do you think about — I'm not going to ask you to give us the Alzheimer's prevention diet, but relating back to all these lifestyle things we talked — let's talk about the Alzheimer's prevention diet. Okay? And let's look at this through the lens of what we can metricize. So we've talked about what needs to go into that diet.

David Perlmutter: It's a diet that keeps blood sugar under control and keeps us insulin sensitive. Beyond that, we'd like to have enough dietary fiber so that we can nurture the gut bacteria such that we can reduce gut permeability. We'd like to have enough polyphenols to help reduce oxidative stress. And we'd like to have enough natural sources of B vitamins to keep our homocysteine in check.

But you see what I've done? The pivot here was to looking at how diet affects certain things that we can then metricize, rather than saying it's XYZ diet, it's the MIND diet, it's the Atkins diet, whatever it may be, full-on ketogenic. These are approaches that have their merits, but I think that if we are looking at those metrics that we know are good for the brain, that's how we should approach nutrition.

Mike Haney: You've talked about this a lot and I've looked at a lot of the research. How do you think about the relationship between the ketogenic diet and neurological health?

David Perlmutter: I think the ketogenic diet is challenging for a lot of people. But I think that for people who have established neurodegenerative situations — be it Parkinson's or Alzheimer's — this has demonstrated to be really quite effective. And if people can stay in ketosis for whatever length of time they're able to do so, and add precursors like medium-chain triglyceride oil to help increase the presence of ketone bodies — I think ultimately we're looking at what can we do to improve metabolism. And Dr. Terry Wahls has talked about this extensively in the treatment of multiple sclerosis. A big study just came out two weeks ago using a ketogenic diet in — I think it was relapsing-remitting MS — and demonstrated efficacy. It's not an easy diet to stay on all the time, but you don't have to. When you engage this diet you are able to increase insulin sensitivity and blood glucose control through other mechanisms as well, and also increase the function and viability of mitochondria. So it really targets a lot of issues that need to be remediated.

Mike Haney: How do you think about supplements, micronutrients, the role of those things? We've talked about how some of those affect these other processes, but is there anything that you think is — do you think folks should just test and sort of make up for via supplementation whatever they can't get, or are there specific things?

David Perlmutter: I think there's a lot more to the idea of supplementation than simply looking at your blood level of a certain micronutrient, because everybody has different requirements. I suspect my B12 level was probably normal before I started supplementing, but yet I keep my B12 level in a higher range because I have that MTHFR genetic polymorphism putting me at risk for elevated homocysteine. So what you're seeing here is the use of a nutritional supplement to fix a problem. Now, we can't apply that logic to, for example, vitamin D. We would look at the research that indicates higher risk of cognitive decline with very low levels of vitamin D. Therefore — and this is not an interventional trial, which might be considered the gold standard, but there has just been one, I might add — it makes sense to me, understanding the multiple roles of vitamin D, and magnesium, and vitamin K2, and certainly DHA — a fish oil or derived from krill oil. We have plenty of data indicating that these are valuable players as it relates to the brain. The epidemiologic study in terms of looking at DHA consumption and now correlative studies actually with DHA blood levels and cognitive function I think are very compelling. So am I supportive? Yes, I am.

Enhancing mitochondrial function — we've seen some really good research on urolithin A published in respectable journals indicating that this supplement has a significant effect on mitochondrial function. Who wouldn't want that? But again, your best bet for upregulating mitochondria is exercise.

Mike Haney: How individual do you think neurological health is? How much is genetic, how much can we determine?

David Perlmutter: Let's talk about individualized approaches through two lenses. The first lens being genetics — and I think genetics has very little to do with, for example, Alzheimer's. Extremely little to do with it. I think that about 4% of Alzheimer's patients are getting Alzheimer's because they carry presenilin-1 coupled with APOE4 or TREM2 gene modifications or gene polymorphisms. That said, I think that looking at an individual through laboratory analysis to determine his or her risk is much more valuable.

So there is some individuality in terms of who gets it. Even when should we begin thinking about this — the high school football players? You bet. Contact sports during middle school, absolutely. Kids becoming pre-diabetic or diabetic — 40% of adolescents in America are either pre-diabetic or diabetic. Now, that's setting the stage for Alzheimer's disease when they get older. Call it what you will. There is evidence that your method of birth, how you were born, affects your risk for not only Alzheimer's but celiac disease, type 1 diabetes, other autoimmune conditions, and autism as well. So when does the anti-Alzheimer's program begin? In utero. It does.

Mike Haney: Well, I think that ties together a lot of what we've been talking about — that ultimately there's a big component that is preventable, or that can be prevented through the sort of lifestyle changes. The sooner you implement and the more consistency with which you implement these lifestyle changes, the more protective it's ultimately going to be. I guess I'll go back to the sort of idea of age. If I'm 60 and I've just started really taking my health seriously and thinking about this, how much can I still move the needle?

David Perlmutter: A lot. That's a very common question. Is it too late? Should I just cash in the chips and just, you know, go to Crispy Cream and spend the day there on the iPhone eating donuts? No. There's a lot you can do. The brain is significantly forgiving, and there can be significant recovery. We can grow new brain cells. We can form new synapses. We can become reconnected. We can reestablish patency of the blood-brain barrier. We can shift our microglial cells back to being supportive. I would indicate that if you were 90 years old and asked me that question, you'd get the same answer.

Mike Haney: That's great. I mean, I think that's really helpful. Yeah — I mean, of course we would tell anybody who's a senior, yes, doing all of these health things can always be good. But that a lot of these mechanisms we're talking about in the brain are reversible, are still changeable — it's not sort of once they're gone they're gone. You can continue to inform that. I think that's pretty helpful.

David Perlmutter: Yeah, and a thought comes to mind — and that is I'm not anti-drug at all. I think that we do recognize that beta amyloid, for example, is contributing to inflammation in the brain, and therefore in conjunction with other approaches is something to consider — i.e. a drug to reduce beta amyloid, if it weren't so risky. But I think that's coming. And there might be some patients who do respond to cholinesterase inhibitors or memantine or other medications that are out there. So I'm not anti-drug. I think that's the beauty of integrative medicine — integrating all that's available, but following the doctrine of above all do no harm. Sometimes you have to do a little harm — it's not no harm. It's looking at the risk-benefit.

Emerging therapies: drugs, gamma oscillations, TMS, and what's on the horizon

Mike Haney: Are there classes of drugs that you are excited about that you think show some promise here?

David Perlmutter: I think across the panorama of anti-diabetic drugs, I think there's something to look at there — whether it's metformin, which as you know is undergoing a very large evaluation right now in terms of longevity and other risks for degenerative conditions. I like how it works, where it targets: the role of AMP kinase, how that affects nitric oxide production, how that ultimately affects blood sugar, fat utilization versus fat storage — many things that AMP kinase activates. That said, we can activate AMP kinase via exercise and taxing our muscles. And I'll get back to the drugs in just a moment — but when we do that, muscles are an endocrine gland. Muscles create chemicals that have distant effects. In particular, interleukin-6, which we had thought was an inflammatory and terrible cytokine — no, that actually stimulates AMP kinase, that's one of the ways — one of the pathways — by which muscle activity is good for us. Cathepsin D, irisin, and brain-derived neurotrophic factor — all made in muscle and having distant effects in the brain, for example.

So there are other classes of drugs. You mentioned the GLP-1 agonists — I think there may be a role for those. I personally have had discussions with families about the use of these as being the drug of choice for treating diabetes now that so-and-so has been diagnosed with Alzheimer's. I had the discussion with a family two weeks ago — I say to them, I'm not your doctor, but here's what the literature shows. If you're going to use a drug for diabetes, then perhaps this is the way you want to go. And other diabetes drugs as well have shown promise.

Mike Haney: What do you think about ketamine, psychedelic therapy, and its role either in prevention of some of these things or in treatment?

David Perlmutter: I think ketamine versus other forms — psilocybin, for example — ketamine is less likely to ultimately prove really efficacious in the degenerating brain than psilocybin. Mechanistically, we know that psilocybin is more apt to enhance neurogenesis and even neuroplasticity. So we're just at the very beginning of looking at the efficacy of these therapies — less so as it relates to neurodegenerative conditions, more so as it relates to things like PTSD and certainly depression. But we now understand that the effectiveness of psilocybin, for example, may actually get back to the role that it plays in shifting those immune cells from being friend to being foe — that is upstream, that is targeted, for example, in PTSD using hyperbaric oxygen therapy. That shift is targeted in the anti-inflammatory approaches to treat depression. So I think there's a lot to be said about that.

And there's a lot of developing technology. Dr. Li-Huei Tsai at MIT is a researcher looking at reestablishing gamma oscillation in the brain. The brain has various — when we look at a brain wave test, you have beta waves and alpha waves and gamma waves and theta waves. These gamma waves are really representing harmony within the brain. As we age, and certainly in the presence of neurodegenerative conditions, our gamma oscillations become fragmented, become less sinusoidal, and just don't look good. You can see them on an EEG, and that corresponds to risk for cognitive decline — perfect correlation.

Dr. Tsai developed a technique to reestablish gamma oscillation in the brain by shining a light into humans' eyes that is flickering at 40 hertz — pretty fast — as well as delivering an auditory signal at that 40 hertz. For whatever reason, that reestablishes this gamma oscillation. They're seeing slower declines in the mass of the brain's memory center, the hippocampus, when they follow people on MRI scans, and actual dramatic slowing of their cognitive decline. There are other companies developing this technology as well — one here in California making it available non-prescription.

Mike Haney: I did interact with one of these companies a while ago and got the measurement and got a sort of "here's what we could do for you," and I really couldn't unpack it — to a level of satisfaction — how seriously to take it. They seemed like very serious people, but I couldn't unpack it for myself.

David Perlmutter: It's tough. I had the opportunity last week to interview the CEO and founder of a company called Optosudix — my, is her name — just dedicated. She had a family issue and is making lemonade out of the lemons here. And her data — she sent me PDFs of about six wonderful studies that they have conducted — and it's hard to imagine flashing light and this happening. But I'm data-driven, and this is data that speaks for itself.

Mike Haney: Is there any other research or anything else on the treatment or preventive side that you've seen out there that you're excited about?

David Perlmutter: There's stuff in the research that I think we're going to see transcranial magnetic stimulation show promise as it relates to reducing inflammation, increasing neuroplasticity, and augmenting the M2 microglial cells — helping shift the M1s back to being friendly. I think that holds promise. It's certainly proven quite valuable in treating depression. There is some preliminary data that it may be helpful with respect to cognitive decline as well.

There are a couple of startups looking at targeting those microglial cells. One company has developed a way of using a small molecule technology to stimulate that TREM2 receptor that we're trying to keep active on that microglial cell to keep it supportive of a good brain. That stock was acquired last week and the stock value went up 250%. Some people are obviously thinking that this has a lot of potential. That said, TREM2 declines as we become obese and diabetic. So yeah, that drug may be developed in five or 10 years and then studied for who knows how long — but we can do it right now. We can target that TREM2 receptor right now by working on your waistline and by getting your blood sugar back where it needs to be.

"TREM2 declines as we become obese and diabetic. That drug may be developed in five or 10 years — but we can target that TREM2 receptor right now by working on your waistline and by getting your blood sugar back where it needs to be." — Dr. David Perlmutter

Mike Haney: Do you think that we're going to see a next generation of drug development here that is less obsessed with the single pill that's going to solve this all, and more of these kind of supportive — like a GLP-1 may end up being that — and that mainstream medicine will adopt this more holistic approach to the idea of neurodegenerative disorders?

David Perlmutter: As to the latter, I don't see it happening. I wish it would, but I don't see it. You can't monetize a holistic approach, and therefore — if you have to answer to your shareholders — that doesn't make good business sense. But having said that, getting back to the idea of GLP-1s — there is a study ongoing right now called the EVOKE and EVOKE Plus study that have enrolled 3,500 individuals taking an oral dosage of semaglutide. Those results are going to become available — I think in September-October of this year, of 2025. I know this is evergreen, but by the time who knows. But we're looking for that. They have to obviously work with the data, but I think it's going to be positive. And this is in the treatment of existing mild Alzheimer's disease. I think it's going to be positive. Would I be supportive of it if it's positive? 100%.

Mike Haney: Good. Anything else you want folks to take away from this? I feel like we've given people a lot of good advice in terms of prevention, what to focus on.

David Perlmutter: Yeah, we haven't talked about our toxic environment. Maybe we'll do that the next time. I think we're reading — we're seeing a lot of information about these PM2.5 particles that are happening more and more. We're exposed to more and more by virtue of fires and indoor air pollution. And I think that's turning out to be a much bigger player than people have recognized in terms of overall inflammation and certainly threats to the brain. So I'm very big on indoor air purification and considering where you live in terms of outdoor air exposure. I think it's very, very important.

I think the microplastic story is just beginning to be told. Is there inflammation induced by the presence of these particulates in the brain? Likely. But it's more, I think, the hitchhikers — the phthalates, the bisphenol A that are included in these particles — that make their way into the brain, that I think could have some — could be threatening.

So there's a lot to be said about what's going on environmentally. And I will make a plea to parents: protect your children's heads by having them wear a helmet when they're riding their bikes, their scooters, snow skiing. And think twice about do you really want your kids to play high school contact sports? It's great at the time, but that clock keeps ticking. You'll be 50, you'll be 60. And you want to offload as many risk factors as you can.