The Dr. Hyman Show - The New Science of Brain Aging: What 200,000 scans reveal | Paul Thompson, PhD

Episode Date: October 21, 2026

How well is your brain aging? Your birthday tells you one thing, but your brain may tell a different story. Today, I’m talking with neuroscientist Paul Thompson, PhD, whose work with the global ENIGMA Consortium is revealing how brain health connects to what’s happening throughout your body. We get into what brain scans can tell us and why those findings matter to you. We discuss: What your “brain age” means and how it can differ from your actual age Why your metabolic health deserves attention when you’re struggling with mood or memory How sleep and nutrition support your brain’s ability to function and recover What having an Alzheimer’s risk gene does, and doesn’t, tell you about your future How brain scans, blood tests, and AI could help identify the right treatment for you It’s so exciting to see researchers like Paul looking across thousands of brain scans and uncovering connections between the health of the body and the brain. For me, it opens up a bigger conversation about how we care for ourselves and how our everyday habits can help protect our memory and support our mood as we age. View Show Notes From This Episode Sign up for Dr. Hyman’s Brainshaping Academy to learn how to nourish the biological systems that support your mental, emotional, and cognitive health https://drhyman.com/products/brainshaping?utm_source=dr_hyman_show&utm_medium=newsletter&utm_campaign=may_27&utm_content=link Get Free Weekly Health Tips from Dr. Hymanhttps://drhyman.com/pages/picks?utm_campaign=shownotes&utm_medium=banner&utm_source=podcast Sign Up for Dr. Hyman’s Weekly Longevity Journalhttps://drhyman.com/pages/longevity?utm_campaign=shownotes&utm_medium=banner&utm_source=podcast Join the 10-Day Detox to Reset Your Healthhttps://drhyman.com/pages/10-day-detox Join the Hyman Hive for Expert Support and Real Resultshttps://drhyman.com/pages/hyman-hive This episode is brought to you by BON CHARGE, Paleovalley, Timeline, Seed, BIOptimizers, and Fatty15. Explore red light products at boncharge.com/hyman and enjoy 15% off with code HYMAN. Shop nutrient-rich foods and supplements at paleovalley.com/hyman and save 15% off your first order. Support healthy aging and get up to 20% off when you subscribe on top of the new starting price of $79 at timeline.com/drhyman. Make your microbiome part of your daily routine with seed.com/hyman and save 25% with code 25HYMAN. Use bioptimizers.com/hyman and code HYMAN for 15% off, special bonuses, and a 365-day money-back guarantee. Head to fatty15.com/HYMAN today and use code HYMAN for 15% off your 90-day subscription Starter Kit. 0:00 Paleo Valley Superfood Bars 2:50 Enigma and Brain Mapping 10:30 Psychiatry Meets Brain Biology 18:35 The Brain-Body Connection 24:30 Mapping Mental Health Patterns 31:30 Brain Age and Biomarkers 36:59 Sleep, Nutrition, and Recovery 47:38 A Case of Brain Repair 52:50 Genes, Risk, and Protection 59:15 Brain Charts and Diagnostics 1:12:26 AI for Alzheimer’s Disease 1:20:06 Imaging and Prevention

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We pick one topic. We have one trajectory. We're working on our whole career. We're reductionist to a fault. And you've zoomed out and you created this extraordinary project called the Enigma Consortium, which is a global brain mapping collaboration involving 2,500 scientists across 47 countries. And you're looking at brain imaging all sorts. and biomarkers, blood biomarkers,

and you're kind of doing something that's kind of heresy in medicine, which is looking at psychiatric diseases by looking at the brain. The joke in medicine is that psychiatrists pay no attention to the brain and neurologists pay no attention to the mind. Yes, yes. And you're paying attention to both, the mind and the brain and how they relate, and they're not the same exactly,

and how the rest of your biology plays a role. And you're not just looking at the typical neurologic diseases like Alzheimer's and Parkinson's and so forth, but you're looking at psychiatric conditions, which typically have been just diseases of description. You get these symptoms, you get this to diagnosis. It's basically the DSM-5, which is a, we all call the diagnostic and statistical manual number five. It'll be a number six soon, I think. They used to have visitation from the gods and things like that, but they've updated it. But it's not any better than that.

Honestly, my opinion, I asked Thomas Insullo, who you probably know is the head of the NIH for the National Institute of Mental Health for a while. And I said, Thomas, what do you think of the DSM-5? He's like, well, he said, it has 100% accuracy, but zero-per-fidelity. I mean, it's very accurate in describing and putting people into groups and categories

according to their symptoms, but not at all about understanding the cause or mechanism of the disease. And for the first time, I think, I don't know too many people doing what you're doing, which is you're looking at the, the biology of mental illness in a way that's not just, it's a chemical imbalance and takes serotonomy uptake inhibitors,

but really a much more nuanced view of how the structure and function of the brain work together and how that can help us understand these conditions, how it can start to kind of bring about novel treatments that we haven't thought about before, make discoveries we never thought of before. I don't know how you got to do this, but like you were kind of a Greek and Latin major at Oxford,

and I don't even know where you go with that. becoming a classics professor. What took you down this road and how did you get this aha that we should be looking at things a bit differently? Well, first of all, I really appreciate your invitation to be here today. I admired your work for many, many years. And it's fun to be able to check. I was hoping you say, yes, I didn't even know you who I was. I was like, oh, I hope he comes on this podcast. He's a real scientist. I'm just kind of a quacky doctor. You do an incredible work, Mark. So I was just, first of all, in the classics, if we, we were joking about this. If we meet any ancient Greeks, we're going to be fine. We'll be able to

look after them. But I grew up in England. as you can probably tell from my funny accent. And I had the chance to work at UCLA during my PhD in my 20s here in Los Angeles. And they had a brain mapping center, a brain mapping center. And so what you could do at UCLA, and now this is available across the world,

is you could have a three-dimensional picture of the brain, not just what it looks like, but the activity of the brain, what is the molecular content of the brain, is the activity in the normal range, Is it depressed like in depression? Is it deteriorating like in dementia? So I just got absolutely fascinated by this.

I mean, you know, Mark, in your own work, you can use these technologies to give you insight into whether someone is doing okay, whether they need some medication or lifestyle intervention, or for that matter, in a drug trial, you can use these as a readout of whether or not the medication is working. That's incredible.

You know, and you know, you have been part of this consortium in collaboration across 47 countries, than 200,000 brain scans, which is a staggering number of brain scans, over 30 different brain disorders. What are you seeing? What are the patterns that are emerging? So I can tell you a little bit about the different brain diseases.

And I know your listeners are going to be very familiar with some of these, perhaps less so with others. So in old age, a lot of people get dementia. And one of the kinds of dementia, Alzheimer's disease, is a huge problem. And so, as you know, maybe among 70-year-olds, maybe 5% of them have this, but every five years after 70 years of age,

its incidence doubles. So that's pretty incredible. I mean, at 75, 10% of people at 80 years of age, 20% of people. So this is this looming epidemic hazard that is coming. So one of the early results with brain imaging that really showed its value was that if you scan people as they progressed with Alzheimer's disease, there was this wildfire. tissue loss in the brain. And you could take a scan a little like a polaroid. You'd take a scan, you know, a month later, two months later. And you could make a time lapse moving where you could see the propagation of the disease. So it starts in the memory system. It attacks your language systems. Eventually it attacks the frontal parts of the brain involved in planning and making

decisions. So that started to be used in drug trials. So people say, well, I'd like to see if a treatment, it could be a pharmacotherapy, it could be a lifestyle intervention. Does that slow this relentless, you know, forest fire of change? And so then we got into psychiatry. So Lily, just to tell you the story of how it came about, they... The drug company. The drug company, Lily. They were testing...

Not your friend, Lily. No, my friend Lily. They were developing drugs for schizophrenia. So schizophrenia is very different. It's a mental-ness way. people hallucinate, they have a distorted perception of reality, they have so-called psychotic outbreaks. But there are some medications for it, not always successful, they're moderately successful. And with lots of side effects. And with lots of side effects, one of them being obesity,

which we'll get into. So Lily said, could you come up with a kind of brain imaging where we can see what the drug is doing? Because there was an older drug, haloperidol, it was an antipsychotic. And the results of that trial were that the medications seemed to be slowing down the spread of schizophrenia in the brain. And you say, well, what does it mean the spread of schizophrenia in the brain? You could see physical changes in the brain tissue. And if someone was scanned today and in three months, the people that were taking that particular medication would have a slower rate of tissue loss. So you can begin to see how, you know, in Alzheimer's where, you know, pretty much all scientists agree there's a degeneration of the brain. You could say, well, you're maybe 10% below the normal range for people of your age and background.

And the drug trials started to use these measures. So you're very pioneer in the area of biomarkers. So you can think of a brain image as a source of physical evidence of disease in the brain. And there are plenty of others. I mean, someone's not going to just use the image. There'll be clinical assessment. There might be blood marker assessment. There could be whole body physical assessment.

as you are doing. But the big picture of it all is that each of these is sort of an indicator, either to rule out or rule in a disease, and then even to see if an intervention is successful. Yeah, this is really important. I think, I think, you know, this is sort of novel, the idea that you can see schizophrenia on a brain scan, right? I think what's really interesting to me is,

and I always say this, the body has only so many ways of saying, ouch. And there are a lot of different things that happen, but often the pathology is similar. Some of the manifestations are different, right? So inflammation, oxidative stress, mitochondrial dysfunction, these are common phenomena across the spectrum of brain disorders.

Metabolic dysfunction is schizophrenia. These patients have inflamed brains. They have mitochondrial dysfunction in the brain. And there's different types of causes. There's scientists, for example, at Harvard and other places, doing metabolic psychiatry like Chris Palmer and putting people on keto diets and seeing schizophrenia resolve without medication. So that makes me wonder, sort of what you're looking at with these brain imaging, we can start to look at inflammation, we can start to look at mitochondrial

function, we can start to look at metabolic function in the brain through various kinds of imaging. Absolutely. And I think that line of work of functional psychiatry, metabolic psychiatry, I saw your interview with Ian Campbell, a terrific interview. I think it's opening a door to therapy for patients that they really haven't known about. I mean, if they've read your work, they know about it. But it's a new window on how to come into these disorders. And I'll give you an example. So a lot of the radiologists look at brain disease, as if there's got to be some lesion or very obvious visible difference. So the techniques that tended to be used, you know, an MRI would say, look, in a stroke, we see a vascular event. That's what we're looking for. In Alzheimer's,

we're going to use a PET scan. A PET scan can look up the buildup of amyloid, which is a toxic protein in the brain. And maybe in Parkinson's, which, as you know, as a disorder of motor function, where people have disturbances in their ability to walk or things like that. You look in the scan for an astrophy of the motor systems of the brain.

Yeah, the basal gang. So in neurology, that kind of works. It's not the full picture, but it kind of works. So you can say... Well, it tells you with the structure, not the function. Yes, it deals... Absolutely. Now, in psychiatry, and I think you hit the...

when we were first publishing neuroimaging studies of schizophrenia, there were a lot of skepticism. And these were studies with maybe a dozen people. And they say, look, it looks like there's a change in the memory system, the brain that had the campus. But I think what we were missing, and you said it, Mark, is that there are physical biological processes going on in the brain all the time. Some of them are functional. They have to do with the activity and the synchrony of parts of the brain. These are visible with newer imaging technologies. Functional MRI is going to look at the blood flow as your blood flow healthy, is your lifestyle enabling you to have the activity of the brain that you need. And I think part of the blindness to this was to treat the brain as

something that we could assess with an x-ray. I mean, you know, an x-ray is pretty good. If you break your leg, we're going to have an x-ray. But the brain is complicated. And if you are a pilot flying over Los Angeles, or you were trying to figure out what was going on. I mean, the map isn't all there is to it. You want to have a look at the traffic flow and is anything blocked or, you know, what's going on. And I think these functional neuroimaging methods,

functional MRI is one of them. Pat, which is another type of brain imaging, looks at the metabolic activity of the brain. And these are slightly less used. And certainly in psychiatry, So it absolutely is opening a whole new window into the synchrony of the brain. I've heard you interview people about the so-called resting state networks of the brain. On an x-ray, you're not going to see any resting-state networks.

And what we see is that in... An x-ray meaning an MRI or a C2-T scale. Exactly. Because those are really static images. There's static images. And that's the secret, isn't it? Because if someone is very depressed, it might not be evident in the physical. physical structure of their brain. I mean, they could, and I've heard your guest say this. I mean,

someone, I think Ian Campbell had a mental health condition. He went to a doctor. He had an MRI of the brain. And they said, well, this looks like you're fine. I mean, there's nothing any different than other people of your age. Can't fight bipolar disease on a MRI. That's right. But what he is doing and what we're also doing in our Enigma project is we're trying to collect assessments of the brain that can look at the metabolism, is your blood flow, as it should be. And it's complicated. I mean, in something like depression, maybe the interactions among the brain's networks are slow or they're sluggish.

And you've done a lot of work on bipolar disease. So at certain times of day, someone's brain networks might not be functioning exactly as a healthy person would. But with the right intervention, maybe a metabolic intervention, maybe a keto, interventional or even with classical pharmacology, which some people respond to, you could see a resetting. You know, they get back into the normal range. So they, I feel like these two things go together. One is having a giant reference of what healthy people's brains do, which includes getting the right assessments. Yeah. And then in a sense, you know, making sure that the therapy is,

as you know, is matched the kind of illness that they have. So if they have a neurodegenerative disease, something like Alzheimer's or Parkinson's, you know, there's particular treatments for that in pharmacology. There's also particular lifestyle interventions as you've pioneered for their metabolism. On the other hand, if you have bipolar or major depression, these brain scans can give you a readout of whether or not the intervention has been beneficial. Yeah. And I mean, it doesn't get more personal than that. You have a physical picture of the result of the... It's really a whole new era. I'm pretty consistent about the things I do for my health, but I also know that the easier something is to work into my day, the more likely I am to stick with it. That's one reason I like timelines,

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It's kind of a fallacy that they're separate because they're so connected. And what I find so fascinating is that and functional medicine is really good at describing us, what are the fundamental physiological processes that underlie all disease? There's not that many of them. There's the microbiome. There's the immune function. There's your mitochondria. There's your communication systems.

and networks, hormones, so forth, they're transmitters, there's your circulatory basket system, there's your detoxification system, there's a structural system, down from the membranes all the way to your biomechanical structures. Disturbosis in these fundamental processes

are what's driving all the downstream illnesses. Absolutely. And so when you look at the science, and what's interesting is, is a functional medicine doctor, like I'm not a, quote, specialist, but I'm a super generalist. So I'm looking at everything all I want.

It's like everything, all it was like the movie. And so I'm like, oh, gee, if you look at the literature on depression, it's brain inflammation and mitochondrial issues. If you look at the literature on Alzheimer's, it's the same thing. If you look at the literature on autism, it's the same thing. If you look at the literature on schizophrenia, it's the same thing. So all these diseases are like leaves on a tree and they have common roots and often common therapies. But that common therapies aren't, like, aren't like the same drug for the different diseases. They're like the fundamental lifestyle and causal, corrective causal systems.

And I think, Mark, you have the perspective to see all of the connections among these things. Because if someone is an Alzheimer's doctor and they don't necessarily see patients with diabetes or with other psychiatric conditions, they won't see the connections between the things that were helpful. And, you know, some of the people that you've interviewed, they said, you know, the dietary change that I you know, did, I noticed a big change. And that wouldn't have been on the radar for people that were doing the, you know, conventional treatment. What's interesting to me is that, you know, like Suzanne Goh has done a lot of brain imaging

around autism. And she's like, oh, there's a lot of mitochondrial dysfunction. Or you can look at the same thing around schizophrenia. So the manifestations in an individual depend on their genetics, lots of factors, some of which we understand, some which we don't. But it's, you know, like David Deutsch said in the fabric of reality, you can treat diseases, even if you've never seen them before, if you follow the fundamental principles and be successful. And that's what I've done in functional medicine.

I've treated diseases I've never seen before successfully because I just follow the fundamental laws of biology. And what we're discovering here, and your work is so key to this, is we're discovering these fundamental principles of human biology that we're here to fore never unpacked. And now they, and now they're like, wait, you know, what does OCD or schizophrenia have to do with Alzheimer. Absolutely. A lot. Absolutely.

And so... I think you're so, right, Mark. I mean, one example, and you've written about this is cardiovascular health. So cardiovascular health, and people are familiar with it, I want to avoid a heart attack, I want to avoid a stroke. I'm going to have a better lifestyle, better diet. I would kind of rephrase it as cardiometabolic health. That's better.

Now, a doctor who's treating Alzheimer's disease can say, oh, you know, the scan shows that you're not doing so well, there's amyloid plaques building up in the brain. The treatment for amyloid plaques is, I mean, there's a vaccine that's experimental. Do you want to try that? But you know, Mark, that at the same time, you know, 60% of people that are diagnosed with dementia have cardiometabolic issues and problems that, to some extent, are treatable. They may be very treatable. And even going over to mental health and mental illness, we had a colleague Thomas Hayek, and he treats a lot of people with schizophrenia and bipolar. And he said, do you know that the cardiometabolic health of these patients makes all the

difference in the world? And he said, some of the treatments for schizophrenia, as you know, you put on weight, it's part of this. And he noticed that it's all ironic, the very drugs that treats schizophrenia caused the very problem that causes schizophrenia, which is my condone response. Absolutely. And he noticed by looking at brain imaging, he said, look, I've seen the differences in people with schizophrenia on brain imaging.

this tissue loss. But the people with high body mass index or the people with with cardiometabolic problems, they have worse brain scans. And he was very interesting. He said, you know, in Enigma, let's start collecting that data. And I mean, Mark, you do this. So as well as the brain scan, let's collect data on their cardiometabolic markers in blood. And I mean, you knew this. And in your work, you pointed this out. In addition to whatever it is that is going on in their brain, systemic, their bodily health, when that is treated, it can make a whole world of difference to their symptoms. And this was true in depression. It was true in bipolar disease. It was true in schizophrenia. And just to be really precise, the amount of difference in their brain on a brain

scan was far greater if there was metabolic disease or if there was cardiovascular disease. And he said, you know, this is a revolutionary because we don't, I mean, we will certainly use antipsychotics, but we don't see all the time this other path to health. Yeah. And I mean, the patients are extremely interested in this, as you know, because it's another path. And he said it's a little like a bank account. I mean, let's say my bank account is getting low, but there's plenty of ways that that

bank account can be topped back up. And we used to use this one, and it worked for some people, didn't work so one another's. But if there's another route, as you know, to replenish or protect or. or bolster the other processes that are going on. I mean, that can make the world of difference. Yeah, and it's so true. And I think that we really don't think about treating the body to treat the brain. And that was the subtitle of my book, Ultra Mind,

which was picture broken brain by healing your body first. Or something like that. And you know this, but this is true in people that are sick and true in people that are healthy. So if you look in these brain scans of people with different mental health conditions, the people that have an intervention that protects their cardiometabolic health do better. The scan can show you it. So, I mean, we know that this is also relevant to, you know, everybody.

But particularly in these illnesses that we blamed on something else, it seems to make the world of difference. Yeah. You know, you studied the spectrum of psychiatric and neurologic conditions. You know, they have all these different labels. Yes. What's in common? Kind of interesting. So you mentioned the DSM-5, which is the way that.

doctors categorize a person's mental health condition. And people have heard of things like, you know, major depression, bipolar disease, schizophrenia. There's conditions like post-traumatic stress disorder, there's addiction. And they can be grouped. So there's a lot of mental health conditions with emotional blunting, lowered affect. There's sort of a depressive aspect of this. And on brain images, you very often see metabolic issues in. the so-called limbic system.

So the center of the brain, we often think of it as the gas pedal, the motivation. It's like the reptilian part of your brain. The reptilian part of the brain. And this is a deep part of the brain that you could maybe think of as kind of a gas pedal, the motivated, what drives us to get out of bed in the morning, what motivates us. It's the fight or flight or feeding. Exactly. We call it the four-ups in medical school.

Fight, fight or flight, feeding and reproduction. Yes, yes. The four-ups. Yes. Yes. So you can see this part of the brain on neuromaging, and a lot of the mental health conditions that are associated with poorer, your emotional flattening, I mean, loss of motivation and volition, and that would include depression. It would include, in some cases, anxiety. The depressive side of bipolar disease, which is very low emotion. You'll see on the brain scans that there is, in some cases, structural deficits there, but also metabolic. I mean, you know, gluten, For example, I mean, the neurotransmitter that's very important to brain excitation, you'll see your abnormalities in glutamate too. So that is one group of disorders where there's depression. We sometimes call them internalizing disorders because they're disorders of thought, their emotional disorders inside us.

There's another group of psychiatric disorders that are associated with compulsion, addiction, substance. OCD is one of them. I mean, these are disorders. And on brain scans, you can often see these compulsive, even aggressive disorders associated with abnormalities in the frontal parts of the brain, the frontal loads of the brain. So these are sort of two systems. There's the gas pedal, the motivator, the primitive brain. And the frontal part of the brain, you'll often see damage. And the brain scans show this in people that are disinhibited, that they might be manic, they might have even in ADHD,

where there's a sort of overactivity. And so these are, it's a very simple classification of the disorders into ones where there's depression, blunted affect, or the ones where there are compulsions. But you'll see similarities. So if someone who's addicted to a substance of abuse, you know, alcohol or meth or opiates or cocaine, you'll often see damage, and this is visible on the brain scan,

in the frontal lobes of the brain. And the frontal lobes are kind of like the brakes. So if the limbic system is the gas pedal, the frontal lovers is a little bit like the brakes. And if you've damaged the brakes, there's often an out of control aspect to behavior. So these patterns, they're not just physical pictures of how these brain diseases look. They're sort of becoming diagnostic tests as well. So if someone wants to know if someone has anxiety or depression. Are these not functional MRIs?

They're actually both. So to make a distinction, the functional MRIs are more useful. in psychiatry, because we tend to think of these are more disorders of behavior, of emotion. We may not see a physical loss of tissue. But like you said, Mark, there may be molecular changes, there may be physiological changes that we can interrupt or block or restore

that can the read out on the functional MRI shows a benefit. So for people, you just kind of help distinguish between what is a regular brain MRI? Yes. And what is a functional brain MRI? Okay. Okay, so a regular brain MRI, looks a bit like an actuary

and the reason we don't use x-rays is a fancy x-ray. The principle of how it works is a little different. So an x-ray is radiation wherever this bone or kind of fibrous tissue. I mean you can see it if you've broken your bone you can see the problem.

For the brain a lot of the issues are with the tissue, the nervous tissue. Obviously brain's not made of the material that bones are made out of so that's why we use MRI. And usually the types of things of structural MRI will pick up is if there's a tumor or a brain bleed, if someone has aneurysm, you will see on the MRI that there's a physical structural disturbance of the brain.

Now, what happened was around about 30 years ago, there were people tinkering around with an MRI and they say, wouldn't it be interesting if this depended on how active the brain was? I mean, it's just a picture, but I mean, it is measuring physical processes in the brain. And so they started to do experiments where somebody did a task in the scanner. Like they would tap their fingers or they'd look at a flashing light. And they found tiny differences in the oxygenation of the blood in the brain. And if you could subtract the image when someone was active from the image when they were at rest, you could pick up. And they just really took off.

And so in the 90s you'd get, you know, here's the map of language or here's the map of planet. or here's the map of vision. And the brain is a landscape. It's like a city. I mean, there's places that control these different tasks. So you're right. The functional MRI is looking at the blood flow in the brain, which for many reasons can be disrupted,

either because the blood vessels are blocked, as in stroke, or because there just simply isn't the metabolic supply to drive the blood into these key brain regions. So basically you're looking at the biological function of the brain versus just the structure of the brain. That's right. And you can tell a lot about the metabolic function, what's working, what's not working, how it's working.

And that tells you so much about the psychiatric disease. So it's a way of like using imaging for psychiatric illness. Absolutely. When you look at so many brains, like what are the things that you're finding? Because you're not just looking at brains. You're also looking at lifestyle factors. You're looking at blood biomarkers. What are the factors that seem to have the strongest influence

over brain function, brain health over time? Because, you know, we all know, okay, I know for my heart, I should not necessarily fat, that's not right. Or I know I should exercise. I know I shouldn't smoke. I know these things are important for my heart health. But people go, how do I take care of my brain? Yes.

Well, those same things as you know matter for the brain. So when we looked at brain scans of people that were maybe obese, overweight, their brain would look eight years older. And you know, there's this very interesting measure of brain age. So you've talked about this concept in your work. So the brain age would be, you know, how old does my brain look? And not just an opinion. I mean, a computer can identify the different features of the brain, the changes we age and give you a score.

And what are those measuring? Well, they can be based on a few different kinds of measures. So the ones based on brain MRI are usually measuring the structures of the brain that change the most as we get older. And so, you know, your kids' brains grow, they reach a peak in your 20s. Obviously, there's a gentle loss of brain tissue throughout the brain. I mean, even helping people. The shrinking of the brain. So you can make a brain chart.

So you can sort of say, you know, a pediatrician has a chart of how, you know, the height of a child should be at different ages. And they're not all the same height. There's a range. So what about if we were to make a chart of the size of the brain's memory system? Like the hippocampus. Like the hippocampus. And for a long time, even in drug trials, that single measure was used. So if someone was designing a drug trial of an anti-dementia drug, it would be common to say,

well, the primary endpoint of this trial is the person's memory function doesn't decline as much. I mean, that's the clinical endpoint. But we're interested in a physical biomarker as well. So they would pick either the size of the hippocampus, which is a little two teaspoon. It looks like a sea horse. It's like a sea horse. Over the course of time, I think people realize that, you know, just a single measure, it wasn't really going to cut it.

It's not going to cut it. So even if you stay within a brain MRI, you can say, well, okay, what are the other things that decline as we age, you know, maybe the language area and the visual area and other things? Let's measure all of them. So what people do when they talk about brain age is they say, well, okay, in a particular person, let's measure them all. and we're going to see where this person is on a chart, like a percentile chart,

and if the hippocampal volume is kind of low, maybe in the lower 5 percent, let's look at some other things as well. Let's look at the white matter connectivity of the brain. So there's another type of brain scanner diffusion image. If those neural pathways are intact, that's another measure. And you could even put in functional imaging. You say, well, the structure looks like there's a little bit of a problem. What if we look at this other measure of blood flow?

So what will happen is all of these individual biomarkers on their own, they can certainly flag an anomaly on their own. But imagine how great it would be if there was a holistic picture. I mean, even just with imaging, all these cool types of imaging. And that has led to the notion of, for example, brain age. And so you could say, well... It's a composite number from a multiple different structural aspects of the brain. Yes.

Yeah, absolutely. And you, I mean, you know this, Mark. Just for your listeners, you could have a blood age. So you could say, look, we can measure proteins in the blood. We know things like cholesterol and lipids are very important to healthy function. We want to look at hormones like estrogen and testosterone, maybe homocysteine, which is sometimes a sign of bad metabolism. Let's make a score.

And there's several scores from blood. I mean, blood, I mean, you know this. you can get a blood panel readout and flag things that are off. But you can also have a summary, as you know, of cardiometabolic health. Are there any signs of Alzheimer's? Are the endocrine markers within range? And so I think, as you've said, the perspective, the hormones as well. Nutrients, hormones, everything.

And these are also evident in a brain scan. So people who had below normal estrogen and testosterone, their brain aging was faster. And I mean, that kind of makes sense. If their thyroid hormone was too low, their brain aging was faster. Too low, like low normal or low? Out of range. And that's a good point. So there's some markers where they're too high when they're bad, something like homocysteine.

So if someone was taking folate or the B vitamins and it can lower your homocysteine, and these have been used, as you know, in clinical trials. I mean, there's been tests that have said, look, if somebody has some of these nutrients, out of range, there's not just a health benefit of fixing them, but there's a physical measure in their brain scans that their brain is getting better. So brain age is a useful tool to sort of see how you're doing. I want to take a little digression around this because, you know, we often think that aging is a linear process. Like we just decline gradually over time and then we die. Sure. It doesn't turn out that that's true. I can tell you that from personal experience.

aged backwards and forwards many times. And not obviously willingly. I've had various conditions or illnesses that have knocked me back. But I recently went to Mexico where there's a compound called Ibegain, which is legal. And I took it as a sort of as a way to enhance my neuroplasticity. Because I met with Governor Rick Perry, who was the 15-year governor of Texas. And we had a dinner. And he's like, you know, Mark, I did this.

and my brain size increased on MRIs. And that got my attention. Like, oh, okay, well, I'm 66. I'm like, I can use all the hell if I can get. And I was like, let me try it. And I went down there and I was methodical. I did a brain imaging, a quantitative brain image because they're different on MRIs.

You can do MRI just a regular one and then you can measure ones that look at specific brain structures and actually measure quantitatively the size of them. And I did a quantitative for a week after and three months after. And my cortical thickness, which is sort of the size of your brain, essentially, like went up 8%.

And my white matter lesions, which is the level of inflammation, which tends to get worse as you get aged, went down 22%. I'm curious if you've seen this kind of phenomena happen before. Yes. And what can you talk about that can explain that? And what other things,

lifestyle factors or other things, drugs that you've seen that can help do this? I mean, you know this, Mark. They make a huge difference. So there's dietary factors, there's physical lifestyle factors. And, I mean, you saw this from your own experience and in the scan. It's just not regularly studied. And I think, you know, you're seeing this sort of missing.

By the way, I didn't tell the neuroradialologist what I did. I just had my scans and they were like, what the heck's going on here? Yeah, absolutely. And there are so many lifestyle factors as well. So one example that, I mean, Mark, you've written about is sleep. So having good sleep. And sleep, I mean, we think of it, you know, brain isn't doing anything at all. I mean, when you're asleep, that's just downtime.

But on imaging, neuroimaging, the images kind of had a surprise recently. There's something called the glymphatic system of the brain. And neuroscientists kind of knew a little bit about this, but they'd never really seen it in action. And what happens is when you're asleep, there's these sort of waves, almost like a car wash, where the brain fluid is cleansing out toxic products from the brain. And I mean, this wouldn't be a surprise. Thinking creates a lot of waste products. It creates a lot of waste products.

It's like, God, you've got to poop at the end of the day. That's right. And your brain essentially has to get cleaned out at night. Absolutely. And we have a lymph system for cleaning out our waste from our body. But our brain has its own lymph system. We call the lymphatic system. I mean, it comes back to what you said, Mark.

If you weren't thinking about that or weren't knowing that there was other thing there, I mean, you'd miss it. But what started. it's happened is people said, well, if you have bad sleep, how does that affect brain decline as you age? I mean, something like Alzheimer's. And a lot of these things are circular. If someone starts to have Parkinson's or Alzheimer's, their sleep is going to be affected. And as you know, if you can fix their sleep or if you can fix the lifestyle factors, some of these other things come back into line. So we were able to see in these brain scans the effects of bad sleep. But until you think about the mechanism,

this sort of detoxification of the brain that goes out during sleep. You don't realize how important it is. So in Enigma, our consortium, we have a sleep group. And they look at insomnia. I mean, people have a sleep disorder. Then they have people that, you know, would benefit from better sleep. Maybe their job is very stressful. And you see these biomarkers come back into line.

Wow. And as you know, I mean, you see them restore. And so sleep is important. As you know, good quality diet is important. And I think the important thing you said, Mark, your brain restores. I mean, we were looking with brain imaging at people with eating disorders, people with anorexia. And it had the greatest effect on the brain of any disorder that we've studied in psychiatry. So we studied depression, bipolaris, it's free eating disorders.

Now, you know that this is common sense. I mean, the food is the fuel of the mind. But when they were treated, when they went to the hospital, when their nutrition was back in balance, all of these brain systems were restored. And one of the things that you're taught in medical school is the brain, you know this. The brain doesn't regenerate tissue. Do you think, wait, wait a minute, the brain scan, like you said with Ibogaine, the brain scan shows physical evidence list. So I think people shouldn't be so pessimistic about the potential for the brain. to recover because it's just not true.

Yeah, and I think what your work is doing by kind of mapping the brain with imaging, by mapping the biomarkers, by looking at metabolic things and nutritional factors, hormonal factors, and probably, I don't know what else you're looking at, which I'd like to unpack. You know, you're actually seeing how the brain can repair. And many of these conditions can be treated in a different way. Absolutely. And, you know, the thing that's so interesting to me is that even you're seeing that there's like some distinct patterns in different conditions,

but there's a lot of shared patterns. Can you talk about that? Yeah, absolutely. Cross- Disease brain patterns describe them. Yeah. So one of the puzzles about the brain's function is very, very complicated. And the more imaging that's done, I mean, the more complexity you start to see.

And it's like layers of detail. So one of the things that you see is that the brain has synchronized activity in so-called functional resting standards. networks. And in something like depression, in something where someone's brain activity is less, even the switching between these networks is slowed, it doesn't work. And we talked about the x-rays. I mean, you would never see this other x-ray. It just has to do with the ebb and flow. But if we were at the ocean side and we were watching the waves come in, there'd be something about the dynamic balance of these things. And we see this in depression. We see it in bipolar.

The treatments are usually either pharmaceutical medication, you know, antidepressants, SSRIs. There's something called TMS, transcranial magnetic stimulation, which attempts to kind of reset the brain activity in a certain way. It's been very effective in treatment-resistant depression or neurofeedback. I know you've talked, Mark, about this in other episodes where a person try, so it may be a patient with chronic pain or a condition that is really severe. they try and train their brain activity in a certain direction. And then, as he said, there's the lifestyle, metabolic, and other sources of fuel to the brain.

And very often, you know, some of these things are like turning the dial way up. I mean, a stimulation is going to have a very radical effect on the brain. In fact, initially, people wondered whether that was safe. But the ability to influence your relative contribution of these networks is really important. And I'll give you an example. So there's a network of the brain that's active when we're ruminating. So if you don't feel good about something, maybe you just regret something. Your brain kind of fixates on this.

So what is happening in the brain when you're doing? Well, I mean, it's not we have a brain lesion. It's that there's a certain kind or pattern of activity. And this has been discovered to be something called the default mode network. It's a network that's kind of active when we're not really doing anything. You could say, well, that could be useful, but it could become, it could interfere ego, right? Yes, yes. So one of the ways that the treatments are being evaluated for things like major depression,

and as we said, there can be kind of behavioral therapy, seeing a psychiatrist, there can be direct brain stimulation or neurofeedback, which is kind of jolting the brain's activity, or lifestyle and cardiometabolic approaches as well. every one of these has a role to play in shifting that balance of brain activity back into action. But it's very complicated. I mean, as you said at the beginning, this isn't something that would be evident from a standard brain scan. It has to do with the ebb and flow of activity.

And I mean, there's even AI methods that are trying to identify exactly what it is about the brain synchrony that's off and then tell us when it's back in balance. This time of year, your nervous system can be under a lot of pressure. family obligations, holiday travel, end-of-year deadlines, all piling up at once. And here's the thing. Stress can increase magnesium loss. Caffeine and alcohol can add to those losses, and poor sleep can put even more strain on your system. That's one reason so many of us hit December wired and tired. And that's why I recommend magnesium breakthrough, advance 10 from bioptimizers. It's their most complete magnesium formula yet with 10 bioavailable forms of magnesium designed to support

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That's what convinced me to take fatty 15 every day, and it's what'll convince you to. Head to fatty15.com slash hymen today for an extra 15% off your 90-day subscription starter kit. The discount will be applied automatically at checkout. I had a case of a patient. I'll show you the image and we'll put it up on the video on YouTube and link it to it in the podcast. But this was a patient I had a long time ago who was an ADD patient, ADHD, really bad. He was 12 years old, really intractable, kicked out of kindergarten, on Ritalin for years, you know, just a mess.

And he had all these other behavioral issues. He had anxiety, had insomnia, but he also had the health issues, like gut issues and asthma and skin issues and just gut issues. It's a mess. It's on seven different medications. And his mother came and I treated him. And I basically gave him, you know, Whole Foods diet. He was eating only junk food, processed food.

This is only diet. He's in so many nutritional deficiencies that I corrected with diet and supplements. His gut was a mess. I helped his gut restore. He had some lead. We kind of got rid of that. But even before we did that, I basically just did diet and lifestyle, a few supplements. He came back two months later.

And his mother brought his homework. that was before he saw me, and then two months later. And the original homework was illegible. It was 12 years old, and it was what we call dysgraphia, which was the common, you know, common symptom of people with brain dysfunction and these kids with learning disabilities or, you know, ADHD and so forth.

They have bad handwriting. It's basically bad hat, right? Like really bad. And he comes back two months later, moms bring his homework in, and I'm like, Wow, it was perfect, perfect penmanship. And I was like, that was the aha moment for me.

I was like, what is going on in the brain? Like, this wasn't a kid who had handwriting lessons for two months. He had something go from chaotic and coherent and disynchronous in his brain to coherent and synchronized and organized. And I was like, oh my God, this is something that nobody's talking about. And that's what led me to write the book, The Ultra Mind Solution, which was this case. And I wrote about Alzheimer's and autism and many other things that are kind of, quote, incurable that were curable. If you understood how the brain worked and how all these factors from diet, exercise, sleep, stress, environmental toxins, gut health, nutrient deficiencies, all these things play a role.

And it's so important. And the things you're looking at. So like, you're doing this massive study, getting massive NIH grants. You're looking at 47 countries, you know, thousands of doctors and scientists. and just so much work. And you're coming back to the same freaking conclusion, which is these fundamental things that matter and that we can modify, that we have control over,

that can change not only the function of our brain, but the structure of our brain. And I'm glad you said that, because it's so critical for mental health. I mean, whether someone's generally well or whether they have a mental health condition. I mean, you've described examples where this has made the world of difference.

And I think one of the reasons that neuroscience sort of went in the wrong way. Everyone's like, well, you know, everything is neurotransmitters. If we could just get the level of the chemical right for dopamine or adrenaline or serotonin. And, you know, there's some validity to that. I mean, there could be an imbalance, maybe a drug. I mean, an example might be, you know, if you're anxious, you could take a drug like propranol, a beta blocker, and, you know, you'd feel a bit better.

But that's missing the whole channel and stream of fuel that's going on in your brain. your body. I mean, we know this. I think, I mean, you've pioneered this line of thinking, treating those things as well, the psychiatrists that we've worked with, and they all say the same thing, it can make the world a difference when all of the common remedies have already been exhausted. Yeah. I mean, the drugs don't really solve these problems. It's like you're treating, it's like you're treating, you know, a problem with a symptom suppression drug. And we talk about this and functional medicine, we call it the tack world. So we're standing on a tack, it takes a lot of asthma

and make it feel better. Take out the tack, right? If you have schizophrenia and your brain's inflamed, treat the source of the inflammation. Don't give them antipsychotic, right? Change your diet, get them on a keto diet, whatever the science is showing. And you're seeing, you know,

your work is so important because there's very few scientists as far as I can tell that, as I said, the beginning of this show, that are not just reductionist. You're like zooming out, and you're like, what are the common patterns? What are the, what is like, you're looking at tons and tons and tons of data. You're like, what are the emerging patterns?

And you're seeing these patterns and these common patterns they've run across all kinds of neurologic and psychiatric diseases. And there are common treatments that really work. And I think, Mark, you, I mean, in your writing, you have this perspective where you see that something is effective across so many different conditions.

And it's because you're treating this systemic issue. Right. And, you know, you're just looking at the brain. You say, well, I don't see anything wrong here. And I mean, can you imagine the times when people have been told their brain is fine? Yeah. But there's something else that could be the source of the melody. So, I mean, it makes a whole of a sense.

Yeah, I treat the system, not the symptoms. Yes, right. Yes. In terms of Enigma and the work you're doing, how much is determined by genetics versus lifestyle environment? I mean, both genetics and lifestyle are usually important. And just to give some examples, it depends on the disease. So there are some disease of the brain that are genetic diseases.

Not many of them, but there's a few. So something like Downs Syndrome, Fragilex Syndrome, William's Syndrome. These are usually developmental abnormality of the brain where sometimes somebody's DNA, their genetic code, has a deletion, and it doesn't develop in the way that we would expect. Now, usually, what about the more common disorder, you know, Alzheimer's or Parkinson's or stroke? Now, there's some puzzles there. So something like Alzheimer's disease, there's one form of it that is genetic.

So only 2% of patients have this. It's the pre-synaline gene. It's the pre-synaline gene. So that's interesting in itself. So if there can be a form of the disease that's genetic and you can point to a gene, I mean, that's already very interesting. And there is, as he said, pre-synolin, there's an amyloid precursor protein gene where someone has a really serious genetic anomaly in that area.

The brain overproduces these amyloid plaques. and that can lead to dementia. But for the 98% of the other cases, the genes sort of tilt the scales a little. They're not deterministic. It's not deterministic at all. And there are some important ones. So I'll give you an example.

So in Alzheimer's disease, there is a genetic variant that triples your risk. And it's not rare. And so there's something called APOE, the apollo protein. APOE4. You have two copies, yeah. Absolutely. And around a quarter of a.

quarter of us have one copy of this, three quarters don't have it, around 6% of us have two copies, and the risk can be nine to ten times higher, just from this gene. Now that doesn't mean that someone's going to get Alzheimer's if they have this gene, it sort of tilts the scales. And a lot is beginning to be known about these genes. So one puzzling thing is in people of African ancestry, the APOE doesn't matter as much, in people of Japanese and Chinese ancestry is really bad. And people of European ancestry somewhere in between.

Interesting. And it was originally sort of speculated that maybe in those countries, other things determining health. But more recently, it's been found that even the gene sequence, in East Africans, there's a genetic variation that's near the APOE gene that seems to neutralize it. Protect it. It seems to be protective. Now, that's interesting, because if,

you could somehow switch that on or introduce it. I mean, maybe there's a kind of direct genetic approach to doing this. And so when we started to look at the genomes of people that had Alzheimer's disease, we knew that this gene, I mean, number one, it's not deterministic at all. I mean, you can have people that have this gene and they're fine, which is already interesting. There is a protective form of the APOE gene, a little bit rarical, APOE2. But the problem with that is they often have cardio-metabolic problems. So they don't get the Alzheimer's, but they tend to get these other problems. But going back to your question, there are genome-guided drug treatments today. So there are treatments that are being developed that target these genes. They won't necessarily

target the root cause of all these other things. They just don't look at that one. Yeah. Now, I'll tell you a little bit how they work, because it's kind of interesting how they work. So there's something called polygenic risk. And you know this. You can look at somebody's genetic code, You can add up all of these different genetic variants that matter for a particular disease, and you can get a score. And within these polygenic scores, there's different subtypes. So there might be a particular set of genes that have to do with inflammation or amyloid or tau depositions, proteins in the brain, or immunity. Maybe it has to do with immunity.

So there are actively approaches, one of them in our AI-3-D project, that essentially take... And that's a research project that's using AI to help understand... Yes. We'll get into that in a minute, yeah. Absolutely. So you could say, well, okay,

how do we influence these genes? I mean, the gene looks like it's destiny, as we know it isn't, but can we influence what the gene is doing? So some of these genes produce protein products, and there are known drugs, there are known drugs that are already approved by the FDA that influence those genes.

Off-label uses, yeah. That's right. Some of them, I remember your interview with Ian Campbell, you talked about the repurposing of epilepsy drugs in bipolar disease. It was very interesting. I mean, again, these drugs are not the whole story they can help. Depico or some people. Exactly. And so genome-guided drug repurposing has exactly that goal.

It tries to find a drug that's already on the market. It's known through these databases of drug gene interactions to suppress a particular kind of. of your protein product. And these are very interesting because if you could pair up a patient's genetic profile with a particular treatment that might be effective for them,

it may be less effective for them. This is personalized treatment. It's personalized treatment. It's precision medicine. It's precision medicine. And I started to look at the work. There's a person called Gianca Chun. She's a neuroscientist at Boston University.

And she, amazing, she makes these genetically engineered stem cells that express a certain genotype, the genetic risk for Alzheimer's disease. And this sounds like science fiction. It's kind of science fiction. They make these pluripotent stem cells that turn into brain cells called astrocytes and neurons. And they apply these treatments and see if it is effective at suppressing the gene products

of the risk genes. So this is an active genome-guided drug repositioning. Really, this is medicine by thinking rather than just by reaction. This disease, this drug, it's like, what is the pathway? What's the mechanism? What are the gene products? What are the protein made? How do we modify those?

What are the other things we can do? And it's just creative thinking about the biology of a human being that's not just so linear. It's fascinating. I mean, I want to jump to brain charts and diagnostic tools in a minute, but I just want to sort of double click on the APOE4 gene conversation. Because people are scared. People don't want to test it. And we offer it at function health.

We also offer Ptow testing, which is a biomarker that actually looks at progression and brain degeneration around Alzheimer's. And it's kind of like a cholesterol test. You can modify it by lifestyle. All right. So let's talk about this concept that you've kind of developed called brain charts. And also what kind of new diagnostic tests are you actually discovering from this large-scale brain imaging and genetic data and biomarker data? So the first one, it focuses on the brain scan. And we'll talk in a minute about the blood markers as well. The ones that focus on the brain scan. So let's say you and I go and get a brain scan. And you could get an MRI at most hospitals.

Now you can get it with function health. You can get a brain MRI and all the blood bar markers we're going to talk about. That's terrific. So the uninterpreted brain scan, I mean, we could ask a radiologist, but I mean, what can we do with the brain scan? So you can measure the components of the brain, you know, including ones that, you know, an automatic program can identify. And this idea has been around for a little while. So there's a company called neuroquant. Yes.

I mean, this is an accepted method. I mean, you will basically say, let's run this on a huge range of people. And, you know, people have very different backgrounds. You want to make sure you include people from, you know, other countries, people that have different backgrounds. You know, people who are, you know, they live in a city. I mean, you've got to have a very representative population to make this chart. And then just like a growth chart for a kid. you say, look, you seem like you're doing pretty well.

And the beauty of these charts, and you know this mark, is you can come back again after making a change and see whether or not your percentile or, you know, where you are on this chart has improved or gotten worse. And I remember, you know, my first encounter of these things, my daughter was born prematurely. She was born at 30 weeks. And they would plot her weight, or, you know, you don't say height for a baby, the length of the baby. And it would go back towards the healthy kids. And in much the same way, I mean, like you said, with your experience with iBegaine, you can make a quantitative map of how you are doing relative

to this chart. And it can either be for a particular brain measure. It could be for your brain age, which is, again, it's sort of a overall summary of how old your brain looks. Now, does the brain scan tell you everything, no? So, The brain scan is a tool. There are other... So the brain charges based on these quantitative measures of the brain, like with a neuroquant or... Exactly.

And one of the reasons in Enigma we do this is that we have access to a real large number of brain scans. So obviously... You can reinterpret it through the quantitative analysis. Yes, yes. And it helps to have a representative population. So if you were going to use these charts in India or Africa or Britain... They're different.

I mean, you want to make sure that, you know, comparable people are going to... be in there. You know, maybe men and women are all different. You have to have a chart that's adapted. So the more data, I mean, you know this. The more data that goes into compiling, the more accurate they are. And so, you know, with 100,000 brain scans, you have a pretty accurate picture of what is going on. The other angle to this, as you know, is the blood panels. So in research, clinically is a little bit different, but in research, there are panels that measure 11,000 proteins in the blood.

Yeah, we talked about proteomics. Proteomics. And we talked about measuring, you know, people know about cholesterol. You measure cholesterol in a standard test. You can look at inflammatory proteins. You can look at measures of, you know, general hormonal or endocrine health. You can even look for teletale signs of dietary, as you know, dietary abnormalities that are fixable. And also toxins.

I mean, maybe someone was exposed to a toxin. And, you know, you know, this disorders like Parkinson's disease. Very much toxic. It is thought to be, and this is a puzzle, it's thought to be, you know, people that were exposed to a lot of pesticides or a lot of hazardous chemicals have a higher incidence of Parkinson's disease. So these blood panels, I mean, they have multiple uses. One of the uses that is beginning to use AI, and I mean, you know this, Mark, is,

you know, we talked about how on a bracelet, and there isn't a single measure that on its own is going to, you know, tell us the difference between, you know, recovery or not. I mean, there's a profile. So I really believe that within the next five to ten years, we're going to be able to at least diagnose all of the major neurological and psychiatric conditions using a combination of scans, the brain scans we talked about, and blood markers. Now, the blood markers are not going to tell you everything, as you know, you know, if you have a stroke, maybe the scan is the thing to use.

If you have a metabolic abnormality, maybe both or maybe the bone, blood is going to be the things you use. But what's amazing about it is this data accumulates and the references get better and the abilities of either, you know, AI or the charts or some way of combining this to flag the anomalies. It not only finds people where these treatments are going to be useful, but measures the degree of improvement as well. It's really personalized sort of brain treatments, the effect psychiatry and neurology that are combining brain imaging with blood biomarkers that are looking for patterns that are unique among them. Absolutely. Absolutely. And so what are the suite of blood biomarkers that you're looking at that are most important?

So there's been a huge revolution in the last year in the dementia field. And so, I mean, you know all of the relevant processes to dementia. There is a test for amyloid beta, beta amyloid. Forty to 40. Exactly. And the FDA. approved that. Now, as we've said, that is just one process. And some people with dementia have that as the main thing that's going on. But plenty of other people may not have any of that going on at all. So there are other inflammatory markers. There's also a measure of neuronal integrity, neurofilament light. There's another measure. There's glial fibroary, GIFAP, which is looking at your astracitic helper cells. How are they doing? And this idea,

that for each one of these channels of abnormality, there could be a targeted treatment. I mean, you know this, Mark. I mean, you've written about it for a long time. The dementia field is just coming around to this. And Ptow 217. And Ptow 217. A lot of these you offer function to help, the AB40 Q40C, NIRFM light chain, Ptow 217. Absolutely.

So let me ask you, Mark, so are these tests you would recommend for everyone who's elderly or just people that are showing signs of a... I think if you have a family history, if you, I think it has a baseline at some point to get. Maybe when you're 50 or 60, I think we don't really know. Like when you should you check your cholesterol? When you're five, when you're 20, when you're 50. Like, you know, we're seeing kids with abnormality. You didn't mention earlier, but, you know, from brain imaging, we can see change in brain imaging

30 years before you have some of Alzheimer's. Absolutely. So something's going on and you can see the smoke signals. So I think, you know, we're going to be learning more and more about. about these biomarkers, but I think there's a continuum of abnormalities from optimal to fully abnormal. And I think it's just like blood sugar. Our blood sugar cut off as 100, but we know from the data that if blood sugar over 85, you're starting to see a linear increase in risk of cardiovascular disease. So it's not that normal is normal. I think that's such a great way

of looking at it because let's take something like Parkinson's, a fraction of people with Parkinson's, which is a movement disorder, have a lot of vascular abnormalities in the brain. And like, You said, well, I mean, that didn't happen today. I mean, the scan that shows vascular damage didn't happen on the day of the scan. And so there has to be a whole period of time, maybe years, maybe decades leading up to that. And I think it's a very different perspective. If someone had a scan that revealed that at an earlier time point, you know, maybe, I mean, some of the methods that you've been talking about could be proactive rather than just reactive to the same.

You're talking about things like Alzheimer's and dementia with these new biomarkers like neurofilament light change. A-2-40, P-touch 17, G-FAP. Those are emerging biomarkers, and we're adding those in function or they're already in function. What about psychiatry? Yes. What are the biomarkers you're seeing?

Because I think there are a lot of biomarkers of mental health. I think it's a whole unexplored area that I've been checking it for a long time, and I think I'm curious to see what your research is showing. Yeah, I think many of the same systemic biomarkers that you've been referring to,

I mean, things to do with inflammation, all of the metabolome. I mean, this is a whole new landscape that's ripe for study. But I'll tell you a story. So one of my lab managers, Chris Wheelan, he worked at Biogen and Pfizer. And we were using a data set

called the UK Biobank. They assessed half a million people in the UK. And Chris said, what you said, why didn't they collect blood redouts, proteomics? I mean, all of these things that we know are useful to do. And he managed to get a group of people together

is called the PPP, I think it's the plasma proteomics project. And you can look at exactly about what you said. I mean, did the people that had a mental health issue who recovered or had a particular diet or lifestyle? And I think a whole landscape of discoveries is going to be made using that kind of data. So these are like proteomic, metabolomic test. They're not things that are clinically used now. They're not used now.

And I think, you know, some of them need to be developed. And so there could be, as you've said, a melanocel. process or an inflammatory process, good or bad immune process, that is dysregulated. And as you know, there are many, many ways of nudging that back into the zone it should be. But by looking at this data, you could even have AI. I mean, I'm sure you do this. You even have AI. Find what is the signature of people that did well with this treatment?

What is the signature that did well with a different treatment? And then is there a signature for just not great outcome? And it's immensely useful for people doing drug trials or interventional trials Because if they have a plasma readout and there's a pretty good chance that these people will do well Or that these people will have a side effect You know ahead of time you can kind of pre-screen and neuroimaging is useful This if there's a drug trial You can often have neuroimaging be kind of a gait

It says this treatment is probably going to be good for you We think you know in Alzheimer's also in depression You know this brain scale can means that the probability is this is probably going to be the right thing. So I think that's a great way forward. That's true. And I would say that, you know, there's going to be emerging set of diagnostics to come out of things that are not typically clinically measured now like metabolomics,

proteomics, proteins, and metabolites. And we're just kind of hitting the surface of that, the microbiome, so forth. But I think there are existing biomarkers, and we include these at function health, that not necessarily like are directly correlated to mental illness, but to play a role in mental health, like vitamin D, like iron, like omega-3 fats, like heavy metals, like your insulin levels, and metabolic health, like hormones, like thyroid, like sex hormones, all these things we can actually measure, and we do homocysteine, methamotic acid. These are measures of B-vitamin status. And these are all

things that play a role in brain health, brain function, and mood and cognitive function and all of it. And they're available to us. And doctors aren't checking them. You know, you mentioned that the database in the UK. There's an American study that's called N. Haynes, which is the National health and nutrition examination survey done every year on a set of people it's about 5,000 people measure about 40 blood tests function health we have over half a million people we measure 160 a blood tests a year in a longitudinal fashion that look at much deeper levels of these these biomarkers that nobody's looking at and i think you know we're discovering all sorts of things and that the how sick our population is and we have a health foreign population these people are proactive want to join

want to know about their health, and they're not the average American typically, although we hit a broad demographic, there are people who are more proactive. So even within that population, we're seeing such massive amounts of problems that are fixable. And I think, Mark, I mean, you collect the right data. So you have to ask the right question. You have to collect enough data. And if these panels hadn't been assessed, you'd miss this whole perspective on what's going on. We should collaborate because we're now doing a lot of imaging now.

We're doing brain imaging. We have Ezra, which measures brain MRIs, full body MRIs, we can do neuroquantum MRIs, brain age. And I think we're just beginning to kind of unpack all this. And we want to come up with, I think, you know, like you can get a cardiovascular risk score. We should get a brain health. Brain health score.

I like it. And I really like that. I think it should combine blood biomarkers, genetics, and imaging in one, you know, informed data set that we can watch over time and learn. And it'll be a vehicle for scientific discovery and understanding. and it's kind of an exciting time. And I just want to finish by talking a little bit about your project called AI4. AI4 AD, which means artificial intelligence for Alzheimer's disease.

And, you know, we've hit a dead end. I mean, we've spent billion, literally billions of dollars in federal money on hundreds and hundreds of studies and have come up with buckets as far as I'm concerned. Like just failure, failure, failure, failure. The, you know, great drugs now maybe extend the time to get a nursing home by a few months. That's like a win. That's ridiculous. So we're basically failing.

And we're not basically looking in the right place. The same is true with this amyloid hypothesis. We're just barking up the wrong tree. I'm wondering, you know, with your work with AI4D, you're trying to look more broadly at genetics, brain scans, biomarkers, kind of not having such a prejudice view of what the causality is to be able to understand actually maybe we're thinking about this wrong. How do we rethink this whole problem?

So what would be learning about this and tell us about like the fact that, you know, Alzheimer's is a name of a syndrome, but there's many causes and there's many subtypes that you're finding. And this is classic and functional medicine. We like, you just be, because you know the name of the disease, you don't know what's wrong with you.

It's just a label that we give to people who share a set of symptoms or pathology. So it's medicine by pathology and geography, not by mechanism or cause. So tell us about like briefly, what is this AI-4D project? What are you finding? What are we learning?

Well, I think, I mean, you saw the full perspective of this at a very early time point. I mean, you know the theory behind it and the evidence behind it. And each of these new observations coming from neuroimaging or from blood tests is sort of, you're validating and proving this is true. And one of the points that you made on subtyping dementia. So if somebody has amyloid building up in their brain, I mean, that's one particular pathological process. But if you look at autopsy of people that've donated their brain to science, there's a number of things going on. I mean, some of these people don't have amyloid. They don't have these deposits that are the target of a lot of the therapies.

They have other things. There's something called Louie Bodies. There's a protein called sinuclein, which is typically. It's kind of like a combo of Parkinson's and also. Yes. And there's another one that's very, very recently discovered TDP 43. So there's something called late. It's a type of dementia that has a different pattern in the brain.

So rather than the memory system. and being hit first, you know, the frontal in other areas. And on a brain scan, you can say, well, look, that doesn't look like the same thing as the amyloid treatments are able to treat. That looks like a different thing. So one of the ways that AI can help, I mean, AI is terrific at seeing patents. Humans are pretty good at seeing patterns, but AI doesn't tire. It can look at millions of scans.

I mean, it's got a lot of time on its hands. So you could say, look, could you tell me if there's anything in the scan that would have found these louis bodies or the sunucan or i mean you you mentioned the metabolic i mean also evident and the i can compare these things in vast numbers i mean vast numbers and you know you know if you go to an airport and you come back in and there's a biometrics thing that tells it's you it tells it's you well the i i i mean it's using a lot of information it doesn't just say how tall is this So in much the same way, it can use the scan, pair it up with the pathology, same kind of technology. So the reason I'm saying that that's very important is if the diagnosis is refined and personalized and subtype, I mean, you know this.

The treatment that it's most sensible to offer a patient with that particular type of dementia may be very different than what they're being offered today. If they have a malaria, sure, if they have a primarily vascular type of dementia, You know, the cardiac, the metabolic, the lifestyle factors are going to be important. And you said this, even being proactive, if we know a certain fraction of people are likely to get these vascular diseases. I mean, you have exactly the right approach, and it's something they can do today. It's not something they're going to find out later only. I mean, they can look at this today and look at the readout. It's amazing.

So this whole project is using AI and large-scale brain data, biomarker data, to maybe genetic data, metabolomic data, proteomic data, basically to look at how to diagnose and create prognosis and treat a broad range of neurologic and psychiatric conditions. It's really a new era. You know, the joke in neurology is that the typical neurologist's basic way of practicing is diagnose and adios.

Oh, no. Have you heard that? No, I haven't heard that. I haven't heard that. Because there's nothing neurology. They're really good at diagnosing. But there's not a lot of tools in the toolkit. You have Parkinson's, you have Alzheimer's, you're kind of screwed.

And so now we're in a different era. It's no longer diagnosed. I think Marks through your work as well. Diagnose and Buenos Aires. It's good news. And you have readouts that you can demonstrate the correction of many of these processes. I think it's true. And AI is helping us because, you know, so much data.

It's so much information. It's so much noise. Like it's, you know, a human brain can't process all that. And so I think this is why it's such an exciting moment in medicine and science because, you know, we've been in the dark ages, like really dark ages. I mean, just to paint a picture. Like, you know, the average doctor is still practicing like Norman Rockwell's doctor in the painting where, you know, just the set of the scope, listening to the different parts of the body,

maybe a physical exam. Okay, we have some imaging. A few blood tests, like maybe 2030, maybe if you do a little more. I mean, we're really not looking at the scope of what's going on. We have 20,000 genes. We have 5 million variations in the other. genes we have 6,000 metabolites, we have tens of thousands of proteins, we have a microbiome that's got 40 trillion cells with 10 times much genetic material as our

own genes, we've got the metabolized from all that in our blood, we have all these biomarkers we can measure now that we couldn't measure before, it's just so much data and any, including me, I mean I've seen more data than most doctors because I've done so much diagnostic testing on so many people for so many decades and I I have my own little AI pattern recognition thing, but it's very limited when it comes down to it in terms of what AI can do and what it actually understands. And I think we're literally just at the beginning,

and I think function help is really leading the way, I believe, to disrupt all this thinking and to collect large data sets. I mean, you, I would imagine, like, to get the data that you've got has been billions of dollars of investment to get all this imaging and genetic material and all the, right?

And yet, and yet people now are paying $365 and giving us the information and it's their data, but we're able to kind of go, okay, well, what can we learn that can help you? How do we use this data to help you? Learn about your body and what to do about it. It's such an exciting moment.

I'm just, I think you're right, Mike. I mean, you know to collect the correct data. Like you've got to look at the right things. Like you could collect a lot of information that is tangential. But if you look at these blood markers, if you have a database that is so rich that the patterns that matter can be pulled out.

And then all of these different corrective actions, I mean, it's wonderful for scientists. I mean, it's a really great idea to be able to... I believe that people should get their blood work, and that's why I create a function of health and should get a detailed panel. Imaging is a little more controversial, and this is your life.

What do you say to people who are saying, oh, you shouldn't bother looking, and it's a waste of money in time? because I do think that it's valuable to get imaging on yourself. I think you're right, Mark. I mean, people who care about their health, who are healthy today might want to look into their future health, what is the downside? I mean, you've said this before. You know, if you have a brain scan and it finds something that you can treat, I mean, why not?

I mean, that seems like a useful thing to do. I have had countless times when I've had a blood test, and it's revealed something that is fixable for me. I mean, either, you know, vitamin is off or cholesterol was too high and now we're fixing it. And I feel like, you know, nobody would claim that you should just go through life oblivious to all of these things that you could fix. Now, people have different points of view on this, but at least you've made this landscape available to people who are interested in availing themselves of it. Yeah. And you have positive proof that it's, I mean, there's testimonials. That's true.

It's pretty rewarding to see how much. many people's lives have been improved and saved just by knowing their data. And I'm really proud to have co-founded Function Health and be working with our team of 500 people to make this a reality for everybody. And, you know, I hope we can collaborate in this. I'm excited to kind of share more what we're doing. And thank you so much for your work. And Enigma is such an incredible project. I just sort of overwhelmed when I first learned about it. And I think, you know, you're, you know, the fact that you're coming to the same conclusions that I did 20 years ago or 25 years ago. It's like so rewarding. Well, thank you, Mark. Thank you for what you do. I appreciate it very much.

Thanks so much. And people can learn more about your work where? They can look up Enigma. So if they put it into the internet, Enigma and Brain, and there might be a disorder or disease that they're interested in that they'll find us. Nigma. So it's Enigma, just go enigma what? Enigma. Well, enigma.coma.com. I and I, because it's the Institute of Murrow Machine and Informatics. Dot USC, University of Southern California.org.org. Okay, we'll put that link in the show notes, but it's an incredible project. Thank you for doing it and thanks for all your work. Thanks, much. Much appreciated it. Thank you. Hey, everybody. It's Dr. Mark here. I'm so excited to

share that my new book is officially available for pre-order today. After more than 30 years of practicing medicine and caring for tens of thousands of patients, I've written the book that brings everything together that I've learned about helping people get healthy and stay healthy as they age. It's called 100. What to do today to live 100 healthy years is a whole body guide to living 100 healthy ears. It's grounded in a new understanding of how our body's work. It's the new map of the body. And inside, I walk you through the seven core systems that drive your health from your gut and hormones to how your cells make energy and help you understand the signals your body's been sending you all along. Now, a lot of what's in the book, I learned the hard way through my own body.

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