THINKWELL

AGEWELL

Microglia and Memory Loss: What Really Drives Neurodegeneration

Dr. Heather Sandison, ND (00:01.22)
Welcome back to this episode of Think Well, Age Well. I’m your host, Dr. Heather Sandison. And today’s guest is truly one of the legends in brain health. Dr. David Perlmutter is a board certified neurologist, a six time New York Times bestselling author, and one of the pioneering voices who has helped bring nutrition, metabolism, inflammation, and lifestyle medicine into the center of the brain health conversation.

His book Grain Brain changed the way millions of people think about food and the brain. His work has been published in 32 languages, reaching readers all over the world. He has lectured internationally, appeared across major media, and has served in leadership roles, including with the American College of Nutrition and the Journal of Alzheimer’s Disease.

On a personal note, Dr. Perlmutter has had a meaningful impact on my own career. He has helped me launch successful summits, supported my book when it mattered, and has been one of the leaders whose shoulders I stand on today. In many ways, he helped pave the way for the work that I do. His upcoming book, Brain Defenders, is available right now for pre-order and will be launching in August of 2026. Here he focuses on microglia.

the brain’s immune cells and how they can either protect or repair the brain or contribute to the neurodegeneration when they become metabolically hijacked. Dr. Perlmutter, welcome. It’s an honor to have you here.

David Perlmutter (01:31.33)
Well, thank you. What a nice introduction. I really appreciate it.

Dr. Heather Sandison, ND (01:36.08)
Yeah, I really appreciate you. And so many patients do as well. I can’t tell you how many patients come into my office and say, well, my first introduction to what might be going on was through one of your books. And so I’m really curious, what made you decide to focus in on microglial activation, immunometabolism, and at this moment in the conversation on brain health?

David Perlmutter (02:06.254)
can’t really say how it happened, but my goal was to try to connect dots. My goal was satisfying curiosity to allow me to be compassionate. And the curiosity really was to try to find what unifies everything we know are risk factors that relate to making a good brain go bad. What are those pillars of neurodegeneration?

you know, what is it that’s similar in terms of mechanistically between inflammation, elevated blood sugar, a head trauma, toxic exposure, PM 2.5, the list goes on. And ultimately I learned that everything converges on the brain’s immune system. That is the lens through which each of these seemingly disparate influences ultimately leads to a state of disrepair in the brain.

It is through this unique population of cells, we call them as you said, the microglial cells, that can be either friend or foe. We call the friends the M2, supportive, nurturing, loving microglia. And the evil twin is the M1 configuration that destroys our synapses, damages our neurons, and actually disrupts the blood-brain barrier. The empowering part, I think, about what you and I are going to talk about today is that this shift, or scientifically called the polarization, between that

cell being on our side or working against us is determined based upon our influences. In other words, we, through the choices that we make and the incorporation of certain lifestyle issues, either yay or nay, help determine whether that microglial cell or the population of microglial cells is going to be supportive or pave the way for a situation in the brain that actually leads to destruction. And the empowering part of the whole narrative is that we

can control that.

Dr. Heather Sandison, ND (03:59.888)
There’s so much we can do. You know, when I think about immunology and the immune system of the body, I feel like I could take an immunology course every year and learn more about it. I have a humility and a reverence for how complex that system is. And I’m curious in this context, how is the immune system of the brain different from the immune system of the rest of the body? And where’s the overlap? Where is it maybe disconnected or

Or not? Maybe it’s not? I don’t know.

David Perlmutter (04:31.214)
Well, there are lot of similarities. I think functionality shows the greatest similarities of these microglial cells to peripheral cells called macrophages that really are classic members of the immune system whose job by their very name, macro big fudge eat, go around and digest away things that shouldn’t be there, whether those are misfolded proteins in the brain or bacterial debris or debris left over from synaptic destruction or neuronal destruction. And that’s the similarity.

There are important differences, however, but I would say importantly that macrophages also exhibit both the M2 supportive and an M1 destructive, what we call phenotype as well.

But the differences are even from their very origin. The entire rest of the immune system in the body comes from the bone marrow originally. it comes from one area where the microglia cells actually arise from what is called the yolk sac. Though they ultimately…

go down a similar path in terms of functionality and what influences them, cetera, even at their very origin, they’re coming from different areas. They come from the yolk sac, they make their way into the brain, and then they populate the brain and reproduce there.

But I think that your point is very well taken that, you you say, I want to take an immunology course every year just to stay up to date. You know, our classic understanding of what the immune system does is, well, I’ve got to have a good immunity so that I can fight off the next cold or COVID or maybe identify cancer cells and eliminate them. All the things about kind of the hygiene of the body, getting rid of cancer cells, getting rid of infections that we kind of associate with the immune system. And I think that we’re moving to a place

David Perlmutter (06:16.368)
of really a broader understanding and getting away from this myopic understanding of the immune system and recognize that there’s a lot of upkeep that the immune system does that’s away from reading it of dangerous elements. And it’s really a broader view, especially as it relates to what’s going on in the brain. That these microglial cells, yeah, they’re doing the good things that the immune system does. They’re helping rid our brains of beta-amyloid and other misforms.

proteins and bacterial components and breakdown of nerves etc. But they’re also doing really good things. are…

providing what we call trophic factors so that neurons can be nurtured and grow and replicate. They’re providing support for the maintenance of our synapses where one neuron connects to the next synapse and even keeping the blood-brain barrier functional and intact as opposed to when these microglial cells…

adopt what I call the evil twin phenotype, in which case they immediately digest away our valuable nerve connections, the synapses. They destabilize the health and functionality of neurons and even work to destroy the function, the important function of the blood-brain barrier. This shift from being friend to being foe is characterized by a shift in their metabolism, in other words, how they make energy.

When they’re healthy, M2 supportive, their mitochondria are working really well, producing a lot of this ATP energy and keeping these microglial cells doing a great job to what we want. But when they shift to becoming the evil twin, as it were, and damaging our brains…

David Perlmutter (08:09.506)
their actual metabolism changes away from relying upon the mitochondria to what we call glycolysis, a different pathway by which this ATP energy currency can be produced. That’s good in the short term for a sudden release of energy, but in the long run, it’s less efficient. And it is associated with this morphology of this cell that wants to be helpful, but now is being destructive. It’s spitting out pro-inflammatory chemicals

it’s creating an environment within the brain that is not salubrious as it relates to brain health and functionality and really paves the way for brain destruction. We can actually image those M1 threatening microglial cells in living people now.

doing a special kind of scan called a TSPO image. And we see, for example, in Alzheimer’s that the TSPO images are absolutely lit up, meaning M1 damaging microglial cells in comparison to a normal brain. But what is so empowering?

And what has really represented for me a convergence of everything I’ve studied over so many years is that these images, these TSPO images showing activation of these microglial cells are seen to be positive in Parkinson’s, in frontotemporal dementia, in multi-system atrophy, progressive super nuclear palsy, long COVID, post-traumatic stress disorder, depression, major depression.

So it’s really across the spectrum of what makes a good brain go bad that we see this central role of the brain’s immune cells activation of these microglial cells.

Dr. Heather Sandison, ND (09:56.239)
I know you and I share the perspective that…

amyloid is not necessarily the cause of Alzheimer’s, right? This is part of that pathway, but not the primary causal level. When we talk about microglia, it kind of reminds me of the conversation around inflammation. And even in the functional medicine circles, I’ve heard people say, Alzheimer’s is caused by inflammation. Neurodegeneration is caused by inflammation. And it always makes me wonder what caused the inflammation to begin with. And so when we start the conversation about microglia, do we run the risk of kind of

going down the same path of focusing on microglia instead of what’s triggering the microglia into that M1 phenotype versus the M2 phenotype. Because even as you described the TSPO images, and I’m curious if those are widely available, and I’m wondering how do we use that in a really practical clinical setting to help people shift that phenotypic expression rather than just say,

what we need to do is go in there and genetically modify the expression and get every microglial cell to go M1, when really that M2 microglia, it has, or wait, I’m going, I got confused. The M1 is the evil twin, right? And so if we’re trying to get everybody to go M2, do we run the risk of not having…

David Perlmutter (11:09.174)
Right?

Dr. Heather Sandison, ND (11:15.194)
protection, enough protection from the toxins or infections or whatever that microglia activation is trying to protect us from.

David Perlmutter (11:25.55)
You’ve unpacked a lot and I absolutely love the curiosity here. And so it’s a wonderful question. So there is a role for the M1 microglial cell and it is our first responder, as it were. If there’s an injury, if there’s a stroke or head trauma.

or infection, then we want our MCELs to show up and do their job and then leave. We don’t need the firemen to remain in the neighborhood once the fire is out. But that’s the problem.

that we have these other triggers that keep those microglia activated. And when they’re activated, they are spewing out pro-inflammatory cytokines that further activates other supportive microglia cells to become destructive. So it spreads to the brain like a cancer. needs to be shut off. mean, you know, we’ve talked in the past about…

how important it is to resolve inflammation with resolving mediators, pro-resolving meters, how important it is to have an inflammatory event, but it’s got to be shut off. It’s good that our brains mounted an inflammatory expression when we had COVID, for example, but when it got out of line, it needed to be turned off.

Alzheimer’s as Dr. Bredesen has said many times, is not the cytokine storm, it’s the cytokine drizzle. It’s just this long-standing upregulation of inflammation that becomes destructive. Again, we want some inflammation in the acute sense to help us deal with…

David Perlmutter (12:55.532)
bacterial components, infections, misfolded proteins, and even cancer. But it’s this long standing prolongation of this inflammatory response that gets us into trouble. So the question becomes, why? Why is the shift to the M1 dangerous damaging phenotype so persistent and prolonged? Why is it not resolving? And that’s where our leverageable inputs come into play. Let me give you an example.

In one study that looked at type 2 diabetics experiencing head trauma, they took a large number of individuals who experienced head trauma of various degrees of severity. And what they found was that by and large diabetics did worse. Worse outcome, longer hospitalization. Why?

because their event within their brains did not resolve quickly and the microglial cells remained activated. Here’s another example. It’s called chronic traumatic encephalopathy and it’s something we see, for example, in individuals who have repeated head trauma like NFL football players. Why is it that after they quit playing football, they continue to decline?

they continue to decline for exactly what you just elucidated, and that is that these microglial cells became activated with the head trauma in a very appropriate way.

But once the trauma had resolved, they didn’t revert back to being supportive. They’re still destroying the brain. They’re still spewing out these pro-inflammatory cytokines and further, like zombies, influencing those around them to become the damaging phenotype as well. Hence that positive TSPO image that we talked about in chronic traumatic encephalopathy.

David Perlmutter (14:42.446)
to answer the second part of your question, that TSPO imaging is not yet available for you and me. It’s purely a research tool, but…

I can give you some very simple surrogates that will tell you whether or not your microglia are activated in terms of being destructive. Here’s one. It’s called a fasting blood sugar, fasting blood insulin, hemoglobin A1C, C-reactive protein, tape measure around your waist. All of these things are indicative of metabolic changes that…

present clear and present danger as it relates to shifting the microglia away from being supportive to being destructive. So the take home message here is that we in a very real sense can control our brain’s destiny by reining in our microglia gaining control. you know, oftentimes

In interviews, I’m asked, OK, Dr. Palmer, you’ve talked about sleep and exercise, nutrition, getting out of nature, social connection, all the things, right, all the pillars. What’s the one most important? And I always say, well, the one most important thing to do is you haven’t mentioned it yet. The one critical upstream issue that has to be resolved is for people to gain the knowledge and the understanding.

and embrace the idea that they are the architects of their health destiny and certainly their brains destiny. That has to happen first. Once you get your arms around that fact and embrace the idea that the ball’s on your side of the court and move away from this notion of live your life however you want to, whatever’s comfortable, and modern medicine’s gonna fix your problem.

David Perlmutter (16:31.906)
That’s a strange kind of paradigm, isn’t it? We know that we need to really shift the burden of opportunity, as it were, to the individual. And that’s what you do. That’s what I do. That’s what the outreach is all about, empowerment and letting people become their own architects.

Dr. Heather Sandison, ND (16:49.315)
And you…

You mentioned the type 2 diabetes on top of head trauma and how there’s different outcomes. I think some of what you’re sort of referring to there is the stacking of those risk factors, but we can also stack in the other direction, right? You can have that downward spiral or you can have that upward spiral. And so…

David Perlmutter (17:04.959)
Exactly.

Dr. Heather Sandison, ND (17:14.448)
Let’s dig into some of those practical matters. You talked about metabolism, waist circumference, hemoglobin A1c, these things we can measure. But how do you structure, because I know that there’s so much more to it than that, how do you structure an approach to systematically looking at both risk factors and ways that we can optimize so that people even know how to start, but also know how to be complete?

David Perlmutter (17:44.719)
Well, I think we’ll never define complete, right? I mean, because every couple of days, there’s a new variable that’s important. And I think I really kind of shoot for the broad stroke here. I look at the things that people are familiar with and may have already studied, because I think we’re going to get the bulk of the work done by looking at the big levers like blood sugar and blood pressure.

and things in lifestyle that lead to inflammation and relates to lifestyle, looking at the big players, looking at sleep and exercise and diet and social connectivity and stress. Those are huge. In the book, I, of course, do a deeper dive and we look at more sophisticated laboratory studies. But I think the big…

the big push is gonna to be the broad strokes. In the Lancet in 2024 was a fascinating report that looked at 14 variables and indicated that if we could approach these 14, in fact, all of them, that dementia risk could be reduced by about 50%. That, you know, I would take 10%. I would take, you know, one fifth of that.

Dr. Heather Sandison, ND (18:55.728)
And yet my clinical experience is that it’s probably closer to 80 % of worldwide dementias that could be prevented.

David Perlmutter (18:58.986)
I agree with you. And that’s right. And, and so, you know, these are just the big strokes. And frankly, some of the things they talked about were

You know, not necessarily considered metabolic, but things like wearing a helmet when you’re involved in an activity that puts your head at risk, not smoking, know, reducing the amount of alcohol you consume, getting your blood sugar under control, blood pressure under control, attention to hearing, getting hearing aid. They added this time around, because this has been done before, air pollution exposure, reducing that. But interestingly, as an aside, they didn’t mention nutrition.

So I, along with a couple other misrecreants like Dr. Richard Johnson and Dr. Robert Lustig, actually called them out and wrote them a letter to the Lancet and said, hey, great study on and on. Must have been an oversight, but you left out nutrition and here are the citations that indicate why nutrition is critically important. And we got a pat on the back and said, thank you for this information, but we’re not going to publish your letter.

Anyway, but please don’t don’t distance yourself from the Lancet, which was a bizarre thing anyway, but that said, the point is that.

You know, how deep can we go? Can we look at microtoxins? Can we look at heavy metals, lead, cadmium, mercury, arsenic, et cetera? Yeah, that’s important. Can we look at other contaminants in the blood, Lyme infection, et cetera? There are a lot of things. The list is clearly endless. Which mouth-borne bacterium, aside from porphyromonas gingivalis, is important? Who knows? So it could be a very, very long list.

David Perlmutter (20:51.568)
That gets to the notion of knowing the patient. What might she or he really need to focus on as it relates to what’s leading to their risk or already existing cognitive decline? That’s where your work really is so valuable.

But I wrote a book that everyone can read and not necessarily have to go to a clinic. Laboratory studies are now freely available, though people can ask their doctors to get this relatively simple baseline of metabolic blood tests along with things like homocysteine. If you want to push it a little deeper, let’s get a neurofilament-light GFAP and perhaps PTAW-217. But I tried to keep it as simple as I could.

But I think these are again broad stroke approaches. Just looking at homocysteine. I mean, if we if we recognize that about 28 percent of people have this MTHFR polymorphism and will therefore likely be at significant risk for having an elevated homocysteine, elevated homocysteine is a significant risk factor for Alzheimer’s and cardiovascular disease as well. And it’s a simple fix. I carry the MTHFR

polymorphism, my homocysteine when I started checking it was elevated, 11 and change, are now under wonderful control by taking methylated B vitamins and little extra methylated folate along with the folates that’s in my multi and actually little methylated B12 in addition to what’s in the B complex. That’s what worked for me. So, you know, that gets to notion of personalized approach to brain health. I happen to know my pTAL-217, which is less than one, and that’s good to know.

So you can get granular, you really can get granular, but I think that’s the book that is written, not actually to be published, it’s the book that you would write one-on-one with a patient based on how you evaluate that person, looking certainly at the big stroke, easier things to deal with. Certainly a person is showing evidence of mycotoxin.

David Perlmutter (23:01.518)
exposure, etc. You would agree that’s a much more challenging thing to deal with, but it’s nonetheless important than it is to help a person who want to die to keep their blood sugar under control.

So there’s an argument to be made for I think both sides of this equation that on the one hand, giving the general population these really important broad strokes and at the same time, valuing, know, Heather, what you do in terms of the personalized approach, that is incredibly important.

Dr. Heather Sandison, ND (23:37.349)
Yeah, it’s interesting in how we apply that at a societal level. And the Lancet Commission report obviously informs so much of what I do. I think part of what it does is it helps justify our existence, right? It’s like, okay, there’s this very credible institution out of the UK that’s saying…

David Perlmutter (23:51.427)
Right?

Dr. Heather Sandison, ND (23:53.029)
There’s a bunch of things that we can do for dementia. It’s not all beta amyloid, right? And that’s helpful. And yet, yeah, their list is incomplete. They have a whole section about, it was from the 2020 update about sleep, but then they don’t list sleep as one of the modifiable risk factors. Yeah, it’s interesting.

David Perlmutter (24:11.094)
Yeah, you gotta wonder.

Dr. Heather Sandison, ND (24:15.268)
But however, it’s helpful, right? It’s helpful. And I think, you you mentioned mycotoxins and heavy metals. That’s not in there, but cigarette smoke and toxic pollution exposure are. so it’d be nice if it was sort of organized and that helps me to systematically get through these things.

David Perlmutter (24:30.412)
Hey, we wrote to them. I think, you know, clearly in the intent was can we help, you know?

Dr. Heather Sandison, ND (24:35.362)
Yeah!

David Perlmutter (24:36.264)
And anyway, but you know, you you I think it’s sort of serendipitous that we’re having this conversation about, you say it’s it’s more than beta amyloid. We’re about, I guess, 10 days out from the this public cock crane analysis of the efficacy or clearly the lack thereof of beta amyloid targeting medications that are the go to treatment for Alzheimer’s disease. FDA approved in the United States in the United States today, the FDA

The Cochrane analysis reviewed 17 studies, 20,375 individuals involved in these studies, 18-month evaluations in these studies, and the benefit of these drugs was to use their quote, trivial, end quote.

They didn’t find really any benefit of these drugs. Yeah, the drugs clearly worked to reduce the beta amyloid in the brain dramatically, a matter of fact. But the clinical value of changing that biomarker was really nothing. At the…

Dr. Heather Sandison, ND (25:36.113)
Yeah, I have this in front of me and I want to read for our listeners the author’s conclusions here. So I’m going to quote, removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research on disease modifying treatments for Alzheimer’s should focus on other mechanisms of action. That was the conclusion from that publication.

David Perlmutter (26:02.134)
Yeah. And, you know, I we’ve been saying this for an awful long time. And, you know, it’s interesting that in 2020. Twenty twenty, I think was the when these drugs were first developed, they were petitioned.

Dr. Heather Sandison, ND (26:07.748)
you

David Perlmutter (26:25.29)
in front of the FDA as Alzheimer’s treatments and they failed. know, the vote, there were 12 people that voted, one voted zero, abstained, one voted in favor of approval and 10 said no, the drugs aren’t altering the course of cognitive decline. So clever pharmaceutical people went back and said, yeah, we still got to get these drugs approved, after all, we’ve expended such funds to create them. They said, okay, here’s what we’ll do.

We’re gonna say, petition the FDA to approve them to get rid of the beta amyloid in the brain, because as we all know, that’s the cause of Alzheimer’s and they got approval because the drugs do reduce beta amyloid in the brain. But as you well describe here in this Cochrane analysis, they don’t change the downhill slide of these patients to any meaningful degree. And that’s in the face of…

of really good research. You know, I’m thinking of Dean Ornish and Rudolph Tanzi’s report in 2024 that looked at lifestyle intervention, exercise, eating more plant-forward diet and stress reduction in 51 individuals over the course of 20 weeks, I think it was, showing that in 70% of these people with established Alzheimer’s disease. So these are the people who you’d give the drugs to. Instead, they

Dr. Heather Sandison, ND (27:38.351)
Yeah.

David Perlmutter (27:49.551)
Clean up their acts, they put them on a good diet, exercise and manage stress. 70% either stabilized or improved. No person on the IV beta amyloid therapy improved. And the side effect of their treatment was some people lost a little bit of weight, their blood sugars came down, their C-reactive proteins improved, and there were some epigenetic issues I think they looked at as well that also were more favorable.

You know…

Dr. Heather Sandison, ND (28:18.736)
Very similar to the outcomes that Dr. Brettison has published that we published out of my clinic. And then also there was the pointer trial that came out in the summer of 2025, over 2000 patients with these lifestyle interventions improving cognitive function. So I think it’s very well established. The controversy is real here, right? And frustrating, think for both of us, there’s sort of this exasperation in both of our voices as we talk about this. I wanna continue on the controversy.

line of thinking here, statins, cholesterol and brain health. So in that 2024 Lancet Commission update on dementia, they added LDL levels. And I think that there is this concern that like, we, you know, are we saving our brain, but going to have a cardiovascular event instead, particularly when we start talking about ketones or adding fats. And so I’m curious how you thread that needle around.

how you help people approach cholesterol management in a healthy way.

David Perlmutter (29:26.85)
I would say that it’s important. And maybe that’s surprising to people who’ve been following me for many years, but I think it’s important. I think that when LDL is elevated, increases obviously the presence of oxidized LDL that becomes a significant source of inflammation in the lining of the arteries called the endothelium. And here’s the point that really matters.

Inflammation anywhere in the body is not a good thing because it makes its way to the brain and can shift the microglia away from being supportive. That’s why…

Endothelial inflammation is not a good thing. It’s why a leaky gut is not a good thing as it relates to the brain. Now, what I’ve just said is it finally allows us to understand mechanistically how can gut dysbiosis and changes in the diversity and functionality of the microbiome in the gut relate to increased risk of Parkinson’s and Alzheimer’s and other brain degenerative conditions. Why? Well, here’s an explanation. Those inflammatory cytokines that make their way to the brain

through the blood-brain barrier, which happens to become more permeable as we age, change those microglial cells away from being supportive to being destructive. Activate this NLRP3 inflammasome, then we get up regulation of the production of interleukin-1-beta. This IL-1b, a pro-inflammatory chemical, makes its way through the brain and further targets receptors on microglial cells to shift them away from being supportive to being destructive.

whereby they now go around and destroy our synapses. And as Dr. Bredesen has well described over many years, that Alzheimer’s is a synaptopathy. In other words, it’s the clinical manifestations are not as much from the fact that we lose our neurons, it’s that we lose our connectivity. We lose our connections between neurons, our connections with ourselves, our connections with other people, and our connections with the world around us. So that goes from microscopic to macroscopic, and it’s

David Perlmutter (31:36.413)
Clearly Alzheimer’s is this loss of connection, which is induced by inflammation that can come from elevated LDL to get back to your original postulate here. that’s why I think that we should be looking at ways of lowering LDL. Lifestyle choices, of course, are gonna be front and center. But…

know, some people have elevated LDL and are doing the best that they can, full on vegetarian and have genetic issues that predispose them to elevated cholesterol and LDL and may benefit from pharmaceutical interventions. That’s what I just said. Maybe not a Satin on the first pass, maybe a Rapatha-like drug.

uh… is is reasonable or is that you know inhibit the uh… torsion reabsorption of of cholesterol but there are uh… pharmaceutical issues that can be implemented to bring ldl and and and cholesterol down

That’s not exactly the messaging I would have given 20 years ago, but I think it’s becoming clear now that this is important. Inflammation across, you know, not to mention, I don’t know why people say not to mention, because now I’m gonna mention it, right? But anyway, to mention that we’ve gotta care for the endothelium and the glycocalyx within the brain as well. The glycocalyx is actually, makes up part of the blood brain barrier.

And that is threatened by elevated oxidized LDL.

Dr. Heather Sandison, ND (33:10.86)
And so I think that this is exciting time in medicine, right? Because we don’t just have statins in our tool belts. We have supplements, we have lifestyle interventions, and then we have different mechanisms of action to keep that LDL under control. And, you know, it’s surprising. Sometimes people will get on a ketogenic diet. They actually are consuming more good, high quality fats, and we see their cholesterol levels actually improve. Their risks go down even cardiovascularly. And the data is also, it’s confusing, right? There was a recent trial

that was published that said people who are APOE4 positive actually benefit from eating meat, whereas in the past, yeah, do you wanna, we’ve seen others that like process meat increases risk. How do you parse that?

David Perlmutter (33:45.9)
Yeah, yeah.

David Perlmutter (33:52.847)
What you just said I think is very important because that’s what the study showed. It showed that red meat consumption in APOE for positive individuals was associated with a decreased risk of dementia. But making a very good point, processed meats, higher risk of elevating your uric acid, for example, was associated with increased risk.

You know, it’s often like the discussion of should we drink wine or not? Well, let’s talk about alcohol. Not something I said. I said wine. What about coffee? Well, let’s talk about caffeine. No, I didn’t say caffeine. I said coffee. What I’m saying is context, I think, matters a lot. So when people…

talk about coffee, they immediately default to, well, is caffeine a good thing or a bad thing? You know, not considering the other 90 bioactive components of coffee, and not to mention, though I’ll mention it, the polyphenol content, coffee representing the number one source of polyphenols globally in our diets. pardon me?

Dr. Heather Sandison, ND (34:54.992)
in absence of the anin, in the absence of the anin that is in Kti.

David Perlmutter (35:00.598)
Yeah, that’s true. But getting back to the recent study, looking at APOE4, I think, was that Sweden it was published in? Nonetheless, I think that the big default, I think, goes to the protein conversation.

And it shouldn’t, because there’s a lot going on with meat, including the fat that it contains. We could have a discussion about TMAO in the gut and its cardiovascular issue that would be negative as it relates to…

you know, threatening the brain, a negative issue. But I think the default in the conversation I’ve had with reference to that specific, it’s funny because I was at a conference a couple weeks back called PLMI, we went to dinner, and on way home from dinner, was sitting in the back seat with, on my right was Dale Bredesen, he asked me that exact question. And yeah, and again, so I think a lot of people fall back as well, how much protein do we need, meat gives you a lot of protein, and on and but I think context is really important, that there are other things

that we’re gonna get from meat, like iron, like fats, be they good or bad, depending on really how that animal was raised. So I think it’s really important not to generalize from a study saying red meat good, red meat bad. I’m grateful that they at least looked at processed meat and studied that, they needed to. So…

Yeah, I think that that rewrote a lot of what the messaging was for the APOE4 positive, you know, 20 to 25 percent of people in America were the messaging that they were getting from, you know, a couple of the websites and certainly from from the previous studies that had been published with reference to their dietary fat intake. There’s even some discussion these days. A publication came out quite recently indicating that perhaps APOE4 positive individuals should not be using an omega three supplement.

David Perlmutter (36:56.878)
And that needs to be looked at. There was actually a study that came out a week ago that indicated that across the board that there may be an increased risk of dementia associated with taking fish oil as a supplement. And it was interesting. I thought about it, read the study and thought about it and realized that that’s not really a fair study for a number of reasons. Number one, we can’t just say fish oil.

You and I know that grocery store, pharmacy store shelves have fish oil that you would never go near. I mean, you know, just the clear bottle, the way they’re marketed, you know, and the way they’re cared for, you wouldn’t go near it. So it’s not fair to.

Dr. Heather Sandison, ND (37:35.502)
Mercury.

David Perlmutter (37:44.183)
look at that product as being equivalent to an Alaska cod where the liver is taken out of the cod on the boat and the oil is harvested right then and quickly nitrogen packed or whatever is done. That delivery of EPA-DHA is quite a bit different than, it’s again like making a global statement about coffee and just focusing on the caffeine. The other thing is,

One other criticism that I think should be raised, raised in thinking of writing a letter to the editor of the Journal of Prevention of Alzheimer’s where this article appeared.

is to say, who is now taking fish oil supplements? And I would think that people starting to show some cognitive issues are the ones who are gonna get a little bit more dialed in. You they’re listening to people like you and think, I should be taking fish oil supplements because that’s what these smart people are telling me I should be doing. Therefore, you’re selecting for a population of people who already at risk, who already have at least subjective cognitive impairment, if not mild cognitive impairment.

There’s a lot to be criticized about that. And I think, you know, the lion’s share balance of…

Studies, you know going back to Martha Claire Morris I mean make it very clear that you know the risk of dementia increases in people whose blood levels of omega-3s are lower and that as an intervention taking a good omega-3 supplement or making sure your diet is rich in omega-3s even if it’s not from supplements is reasonable and supported

Dr. Heather Sandison, ND (39:19.504)
But the dietary information out there is confusing at best, right? And so is there a single message? I think for me, I try to share with patients, reduce processed foods. If it looks like it came from the tree, came from the ground, came straight from the animal, and it hasn’t been heavily processed, it’s not in plastic, then that’s going to be better than anything that is more processed. Do you think there’s a… Yeah, okay, so you agree. Is there anything else that you would add?

David Perlmutter (39:42.786)
Right. I’m go with that.

David Perlmutter (39:50.071)
Well, when I wrote my new book, I didn’t want it to be the brain defenders diet or the Dr. Perlmutter diet because

Lord knows there are countless diets out there, whether it’s mind or paleo or mind your paleo or primal or carnivore or vegetarian or med or med green plus med, whatever it may be. And it’s just overwhelming for people because A, there are so many of them out there to choose from and B, once you go on that diet, it’s real specific. So my endeavor this time was to create some very wide guardrails, but high guardrails.

In other words, I recommend be on whatever diet you want that fulfills just a few criteria, and they are, keeps your blood pressure, blood sugar under control. Monitor your blood sugar.

Either wear a glucose monitor or get it checked frequently or do a finger stick, whatever it may be, but get on top of that and whatever diet you choose that keeps your blood sugar where it needs to be and I define what that means. So 100 is not good enough and A1C of 5.8 is not good enough. We define it in the book. That’s job one in my opinion because right off the bat you’ll take out the ultra processed foods because if you’re eating like

Most Americans do. 60 % of our calories in America come from ultra processed foods as adults. If you’re eating a lot of ultra processed foods, you have dramatically bumped up your risk for Alzheimer’s disease. Higher blood sugar through this mechanism. So that’s job one. Job two is I need to see in deference to our friend, Deanna Minnich, the lots of color on your plate, i.e. fiber and polyphenols. So I want the

David Perlmutter (41:38.605)
Whatever you choose to keep your blood sugar under control, I want there to be a lot of color on your plate. Meaning, you know, a plant-forward diet. Eat meat if you like, have fish, chicken, whatever, eggs, but a lot of plant, therefore a lot of fiber. Get those polyphenols and nurture your microbiome. P, be judicious with reference to your fat.

eat only good fats, unprocessed fats, and pretty much with those guidelines, that’s the broad strokes. Can I get more granular? Of course I can. So can you. But if people could just do that, that’s a home run.

Dr. Heather Sandison, ND (42:16.548)
we would reduce the burden of disease.

David Perlmutter (42:19.15)
That’s it. Again, you know, I could have created the Dr. Perlmutter diet and you know, you’re to eat X number of times a day. You’re going to time restricted eat. You’re going to fast one day, you know, a week or whatever it may be. I didn’t I don’t want to complicate it. I want these broad strokes to cover a lot of territory and make it easier for people. Because the biggest issue we have is acquiescence, you know, is adherence to what we’re recommending. the moment it becomes too complicated, the book gets closed and

I’m done and I’m going back. I’m opening a bag of chips. I’m going to watch TV this afternoon and that’s what I’m comfortable doing.

Dr. Heather Sandison, ND (42:57.168)
And that doesn’t serve you, so we gotta keep you motivated. So for people who are depressed, depression is on that list of modifiable risk factors in the Lancet Commission Report. But anxiety, depression, dementia, they’re connected through immune dysfunction of the brain. Can you help us connect those dots?

David Perlmutter (43:00.749)
Right.

David Perlmutter (43:05.6)
Yes.

David Perlmutter (43:14.87)
Absolutely. So we discussed this earlier in the context of this TSPO imaging that lights up those activated immune cells, those microglial cells that are activated because our blood sugar is elevated, because there’s inflammation in the body coming from, for example, a leaky gut or elevated LDL for that matter. I’m going to keep harping on that one because I know you mentioned that. So.

We see on those studies that these studies light up in major depression. What does it tell us? Well, it sort of solidifies this emerging understanding of the role of inflammation in depression, which is really getting a lot of attention these days. Dr. Uma Naidu at Harvard has done a lot of work getting this information out.

Austin Perlmutter, Dr. Austin Perlmutter, my son, has made it a point, he published in Psychology Today about this. The book Brain Energy, I think, really made it clear that there is a lot going on in terms of metabolism that relates to risk for things like depression and anxiety. And what Brain Energy really focused on is mitochondrial function.

And recall that we talked about at the beginning of our time together today that the function of our brain cell energy producers, these mitochondria…

in the brain’s microglial cells, the brain’s immune cells, is what is involved in whether they’re supportive or they are destructive. So that’s what Dr. Christopher Palmer talked to us about in brain energy, how that relates to this shift and the increase in inflammation in the brain that underlies these mood disorders. So isn’t it amazing that you and I are having this discussion that he so wonderfully unpacked these

David Perlmutter (45:17.516)
psychiatric issues and now we’re talking about Alzheimer’s. I had a chat with Dr. Ray Dorsey the other day about Parkinson’s but it’s all the same.

It’s all through the lens of the brain’s immune system and how they are involved in metabolism. And here’s the take home message. The metabolism of these brain’s immune cells, these microglial cells, that determines whether they are friend or foe, their metabolism mimics your body metabolism. I would say that’s all I wanna say, but I have a other things I wanna say. But.

We control our body’s metabolism based on those levers of exercise and diet and sleep and social interaction and being in nature. Those things affect our blood sugar. They affect levels of inflammation. Therefore, they’re going to have an impact on the microglial cells. Why would being socially connected be associated with a reduced risk of Alzheimer’s? Well,

Maybe it’s the cortisol thing, maybe, what could it be? That’s the kind of question I ponder in those 90 seconds before I fall asleep at night. Okay, I see the literature, the Blue Zone literature, that people who are socially involved, have volunteering and meeting people all day long, doing things, have a lower risk of Alzheimer’s. It’s very significant.

But why? Mechanistically, what’s going on? Well, what happens when you’re doing things with other people? Yeah, you’re reducing your cortisol. That’s good, because that affects the microbiome and cortisol at higher levels and prolonged is damaging to the hippocampus. We know that Robert Sapolsky’s work from, what, 25 years ago. But that said.

David Perlmutter (47:07.306)
Our microglial cells have on their surfaces that determines whether they’re going to be supportive or destructive. They have a receptor for something called oxytocin. Who knew? Think about it.

When you feel love, when you are with other people and you’re just feeling, you’re just glad to be with these people, you’re playing music, you’re playing bocce ball, whatever it is that you’re doing, you’re feeling joy and happiness, you’re creating more oxytocin, and that directly stimulates your M2 microglia to stay in their loving, supportive role.

So that’s what’s so exciting about all this science is the play out and the dot connection that we need. So many dots are being connected through this lens and gosh, that really is fulfilling to finally get an explanation, not that it happens, not that there’s this connection between socialization and lower risk of Alzheimer’s, but now we know how it happens.

Dr. Heather Sandison, ND (48:09.464)
Patients are coming to us asking and confused because there is literature that suggests that taking SSRIs and some of the antidepressants increases our risk for neurodegenerative disease later in life. So how do we navigate that in terms, and I think there’s these really hopeful lifestyle interventions, and for someone really struggling who’s maybe APOE4 positive and also struggles with depression,

how do they navigate whether or not an SSRI or another psychiatric medication is a good idea for them? And benzos too, right? It drastically increases risk.

David Perlmutter (48:47.15)
Well, think, yeah, I think the data on the SSRIs is not compelling as it relates to dementia risk. As a matter of fact, there’s data indicating that SSRI use might actually be associated with reduced risk. And mechanistically, we know that SSRIs fairly significantly do two things. They are anti-inflammatory and they actually enhance BDNF production within the brain. So BDNF being this

trophic hormone being a…

like a nutrient supportive for brain cells and the growth of new brain cells and synapse formation, all of which is very good. We call that a trophic effect of brain derived neurotrophic factor, which we can increase by involving another medicine called exercise. That’s what that does, right? So I would not necessarily put a lot of credibility into the idea that these drugs are going to

to be associated with a significant increased risk of dementia. In fact, again, literature suggests the opposite. That said, I think we should back it up a little bit and ask how effective of a treatment is an SSRI for depression, for that matter? And we think that the literature would suggest that the answer is not very. And in fact, the effectiveness of SSRIs as it relates to

treating depression is only minimally, if measurably at all, greater than placebo. What does that tell you? Because placebo is somewhat effective as well. maybe, it used to say, well maybe we should give people sugar pills. Well I’m giving people sugar in any form. Maybe they could be pills of allulose or something. But that said, it tells you that there’s a lot going on with respect to

Dr. Heather Sandison, ND (50:24.538)
We.

David Perlmutter (50:43.806)
an individual for depression in terms of what they’re thinking. perhaps we should be not derogating the placebo effect. But here’s another way of looking at it. And what are SSRI drugs designed to do? They are designed to inhibit the enzyme that breaks down serotonin.

Well, actually the reuptake more specifically of serotonin, selective serotonin reuptake inhibitor. So this pathway whereby serotonin is gotten rid of is blocked. So there’s more serotonin floating around. And if there’s more serotonin floating around, well, by all means, we’re going to be healthier. If you believe this kind of myopic…

view of depression being a less serotonin happy chemical in the brain. It’s between friends, it’s a bit ridiculous, but nonetheless, if serotonin is playing a role, we should ask, well, then what is it that’s reducing the serotonin in the brain to start off with? And that’s an interesting question, because yes, we know there are some genetic factors that are involved in that, but

Inflammation reduces available serotonin through the complex pathway called the kynurenic acid pathway. But that said, inflammation diverts where tryptophan would have gone to become serotonin to a more destructive brain pathway. So that’s where we should be focusing our emphasis, our understanding and targeting where the inflammation is coming from in the first place.

Dr. Heather Sandison, ND (52:25.678)
And we see that people who get on the ketogenic diet, their mood often improves considerably. Right back to the brain energy Christopher Palmer conversation.

David Perlmutter (52:32.194)
You bet, as they do when they take GLP-1 drugs that target mitochondrial function, get their blood sugars under control, and reduce inflammation at the same time. I’m not advocating that, though I’m open to it. And I was very-

Dr. Heather Sandison, ND (52:36.196)
Great.

Dr. Heather Sandison, ND (52:47.064)
It’s a tool when used appropriately.

David Perlmutter (52:49.578)
Well, no, I’m open. Yeah, right for the appropriate indications. But as I said in the new book, Brain Defenders, if it gets demonstrated that this is a viable treatment for Alzheimer’s, will I be recommending it? And I said, yes. Surprising. You know,

It’s about keeping your mind open in the toolbox, right? You know, there’s no other way of generally, pharmaceutically, to unravel this problem. mean, you know, a multi-pronged, vis-a-vis Dale Bredesen approach and your approach has proven its efficacy. But in terms of, you know, wider population of a single modality, man, I mean, we saw it happen in Parkinson’s, at least in a 2024 trial published in the

New England Journal of Medicine using elixir cenotide, which is not an approved GLP-1 drug now in America. But Parkinson’s was stopped in its progression, dead in its tracks in this one year study of 153 people with Parkinson’s. That, we say karamba, say, you know, that’s, it’s breathtaking. So I remain open, pardon me.

Dr. Heather Sandison, ND (53:55.684)
and which GLP one was it?

Dr. Heather Sandison, ND (54:00.441)
Yeah, which GLP when? Which GLP?

David Perlmutter (54:04.802)
It was lixacinatide and it was not available in America now, but I hope I got that right, published in the New England Journal.

Dr. Heather Sandison, ND (54:15.992)
I’ll have to look that up because maybe there’s a trial or something to get some people into. I am curious, looking forward, what are you most excited about? know there’s gamma-light and olfactory enrichment and the hyperbaric oxygen and fasting and metformin and mushrooms and psychedelics and like, I mean, the list is long and there’s a lot of hope and I think there’s a lot of directions that we can go, but is there one thing that you’re really excited about as we look forward?

David Perlmutter (54:18.03)
Oh, I will send that to you.

David Perlmutter (54:42.606)
Oh, I hope I don’t have to do one thing, but I’m very taken by the 40 Hertz, you mentioned a gamma oscillation store that targets microglia. I think that has huge potential for broadsped application. It’s a flashing light for crying out loud.

Dr. Heather Sandison, ND (54:45.112)
Well, you could move three.

David Perlmutter (55:01.71)
and can be constructed in such a way now that you don’t even know it’s flashing, because there’s a way of, in the off period, putting a different light in there such that you don’t really see that it’s flashing. And one of the leaders in this technology is Dr. Li-Wei Tsai at MIT, who’s published a lot of the work. And she talked about in her TED talk the idea that these lights could be in schools and in public places and in airports.

to target microglia. Think about that. And I’m also very taken, I guess you said what’s the number one, but I’m taken by the trend of emphasis away from ultra processed foods. I think that’s got a lot, will have a lot of traction and a lot of play. So I’m feeling quite positive about where this can go.

Dr. Heather Sandison, ND (55:53.168)
What brings you joy at this stage in your life?

David Perlmutter (55:59.279)
What brings me joy? I’ve never been as happy as I am in life and in my marriage. We’re 39 now on our 40th year. So that brings me incredible joy. I am over the top joyful that I’m gonna be a grandparent in September.

Dr. Heather Sandison, ND (56:20.144)
Congratulations.

David Perlmutter (56:23.214)
unbelievable. So I find a lot of satisfaction and I guess you you could say joy from the discoveries that I get the opportunity to make and publicize and hope will gain traction. I love the opportunities I have to be in these situations to speak to smart people like yourself that is you have no idea how much that lights me up.

You know, that really brings a lot of meaning to my life and that brings me joy. I also get a lot of joy from my bird feeder, which I fill up every two to three days. I know it sounds hokey, but I really enjoy watching the birds come to our bird feeder every day and knowing what they are. So little things like that.

Dr. Heather Sandison, ND (57:11.728)
What do you do day to day to protect your own brain health?

David Perlmutter (57:15.79)
Well, my dad died of Alzheimer’s. So I know, you know, beyond my professional experience of, you know, 35 years of meeting with the families and seeing the patients, you know, what that does, you know, how that is, I watched him go. And I, so I have that family experience that is so tragic for the 7 million families in America right now, the 55 million families in the world right now.

So, you know, I double down. It’s not do as I say, not as I do. I don’t eat till one or so in the afternoon. I exercise every single day. I eat twice a day. I’m very careful with what I eat.

You don’t want to know my supplement list because it’s very compelling, but it is highlighting obviously things like vitamin D, DHA, K2, the B-convex that I must take for my MTHFR and elevated homocysteine, urolithin A I’m a fan of, you know, and various other components, probiotic, et cetera. I have a 40 Hertz light on my desk that I use when I’m working and it’s on.

try to learn new songs to play on the guitar as often as I can. And, you know, I dedicate to brain enrichment. And I’m careful about protecting my brain. I stopped playing pickleball, which I don’t, which I miss a lot because I was getting injured and almost had a concussion. I said, I can’t do that. And so a friend of mine suggested I play pickleball wearing a helmet. I don’t know if I can necessarily do that, but maybe I will. Who knows? I certainly wear a helmet on the bike.

And those are the things. Dramatic reduction in alcohol over the past few years, that’s for sure. Not that I was drinking much before, but my reduction is down to almost none. I mean, might have a glass of wine once or twice a week before, and that’s almost completely eliminated. Not fully, but almost completely. And that’s it. I’ve dedicated to being a little bit more diligent about following my blood work.

David Perlmutter (59:25.486)
and adjusting my lifestyle to make sure my blood sugar is under tight control. My LDL is where it needs to be. My homocysteine is now 8.1. know, my p-tal 217 was less than 0.1, which was good news. Maybe as a manifestation of all the things I’m doing well. So those are the things I do.

Dr. Heather Sandison, ND (59:48.13)
Well then, if people were to remember one message from brain defenders, what would you want it to be?

David Perlmutter (59:54.316)
You can do this.

Dr. Heather Sandison, ND (59:58.208)
agency. Dr. Perlmutter, thank you so much for this conversation and also for the decades of work that you’ve done to move the fields of brain health forward, particularly that last

That last takeaway, it’s really giving people back control and agency of their health, their brain health and their whole body health, their ability to age gracefully. You’ve helped us see that the brain is not isolated from the body, that Alzheimer’s and other neurodegenerative diseases are not simply about plaques or tangles, but that our immune system and especially these really incredible cells called microglia may be one of these most powerful levers that we can pull to protect our brain.

So for everyone listening, Dr. Perlmutter’s new book, Brain Defenders, is available now for pre-order and will be coming out August 18th, 2026. This is a practical, powerful science forward guide so that you can protect your brain health for life. Dr. Perlmutter, it is a honor to have you here. Thank you.

David Perlmutter (01:00:58.007)
I

I appreciate the opportunity. Thank you.