Prevention Strategies for Neurodegenerative Diseases
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Coming up on this episode of The Doctor's Pharmacy. - Exercise has really emerged as one of the areas that has grown with real biological evidence that it can prevent and improve brain function and brain health. - Before we get into today's episode, I'd like to take a minute to remind you of some exciting news.

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Millions of Americans are affected by neurodegenerative diseases like Alzheimer's, dementia, ALS, and Parkinson's and more.

But the good news is that there's some simple steps that we can take every single day to protect our brains and reduce the risk for and even reverse the symptoms of cognitive decline and neurodegenerative diseases. Like in today's episode, we'll feature three different conversations from the doctor's pharmacy about why it's so important to take care of our brains when we're young and what to do

if we're experiencing a brain condition. I speak with Dr. Marwan Sabah about the role of ApoE4 gene. He was the head of the memories clinic at Cleveland Clinic. I also speak with Dr. Richard Isaacson, one of the pioneers in understanding how to reverse Alzheimer's disease with lifestyle modifications. It's quite amazing. And with Dr. Jay Lombard about bacteria as the cause of neurodegenerative disease. So let's dive in.

We're now seeing now a big push to move the calculus beyond the time of symptoms to much earlier and try to find people and identify people at risk.

Along the way, but most of that research has been focused on drug interventions to prevent, delay, or forestall the onset of symptoms. But along the way, of course, if I'm in my 70s and I know my disease started in my 50s or 40s, we can change outcomes.

drugs. We can change to say lifestyle interventions have benefits and there's now a whole new area of research. Exercise has really emerged as one of the areas that has grown with real biological evidence that it can prevent and improve brain function and brain health. And beyond that, we're seeing now

People are looking at things like diet and supplements and other ways to manage the disease. And so I think this is an area that's just relatively new, but very exciting. Yeah, I mean, there was a recent study called the Finger Study. The Finger Study is one of the ones that we're going to talk about. Which is fascinating. Which I talk about in the book. Yeah, I know. And this study was done in Europe, and it was a very large study where they did an intervention with diet and exercise and stress and addressing. Yeah.

Yeah, addressing cardiovascular risk factors. And tell us about the study. What did they find? Yeah, so this study is done at the Karolinska Institute. The geriatrician, her name is Mia Kivapel, to a really, really sharp, very thoughtful physician scientist. And she said, we're going to create a multimodal intervention, including diet changes, managing health conditions, improving...

exercise, improving all their parameters. And one group was randomized to the intervention and one group was randomized to just kind of passive intervention. And in an objective way, followed for over two years with aggressive intervention, the treated group did much, much better over the two years. Not only did they not get declined, they actually got better. Wow.

Wow. And so, and these are people not young. They were starting in their late 60s into their 70s. So these aren't people in the middle of life. They're kind of in the senior, running into the senior age. And they actually got better. And this has been published in the journal Lancet. So it's a very respected, you know, peer-reviewed scientific journal. Well, this is really remarkable. I just want to pause here because what you just said is pretty radical. Now,

Like I said, we've spent billions of dollars on hundreds of studies and none of them show this. We can't slow or reverse. Now you're saying just by eating better, exercising, optimizing your health, we literally can slow and even start to reverse the disease. That is correct. In fact, the U.S. is taking the finger study and in 2019, 2020, there will be the U.S. version of it called the pointer study, which is being rolled out in about six sites in the United States this year.

And the government has to pay for it because there's no drug involved. Well, this is to be very clear, the Poynter study, so far as I know, is being funded by the Alzheimer's Association. I don't know if there will be federal dollars behind it. But the fundamental issue is... But it's not a drug company. It is not a drug company.

company. But the fundamental issue is we want to answer an important question. Do these things objectively work? The signal, the way the evidence suggests the answer is yes. And so having more evidence, because I have to tell you, you and I are both physicians. Part of our day job is taking care of people with disease. Right.

So here we are saying, let's step back from that. Let's say instead of treating disease, let's treat health. Yeah. And did you take the course in medical school called Creating Health 101? I did not. No, I didn't either. I did not take that course. Yeah, we didn't learn that. We did not. But, you know, but the advantage of that is that it's not prescriptive. Then you can health recommendations that come up from consensus panels and then it can have effect change at a larger level.

This is actually easier to roll out if we can prove there's a signal than it is by just writing a prescription. It's unbelievable. Yeah, I think, you know, what you said is really remarkable that we need to focus on how do we create health rather than just treat disease or symptoms or pathways or

Some pathology and that's essentially what functional medicine is. It's asking the question. How do you create a healthy human being? What are the factors that knock you off that path and one of the things that actually? help create health and in those studies the finger study the point study are Looking at those factors and there and there are more right there are more and I think that's the exciting thing is that I think you know, I I have to be tell you I've been involved in all these clinical trials and

Every time there's a failure, it breaks everybody's heart. There is no ego involved. It's not like, ha-ha, I told you so. Because I will say to you, whether the drugs work or not, I'm going to clinic tomorrow or the next day, and I still got to look these people in the eye and say, you know, something good is coming. We just kind of hope that it's coming soon. And so I say this to you because if I can see a path forward, whether it's a drug, a device,

a lifestyle intervention, any way forward to help my patients either prevent, postpone, or delay. Well, let's talk about the disease a little more in a medical way because the understanding was from my training was that the brain seemed to be disconnected from the rest of the body. We learned about this barrier called the blood-brain barrier where nothing except some nutrients got in. That's correct. It was like this

thing that disconnected our head from the rest of us. Turns out that our body is one system and then our brains are connected to everything else that's happening in our gut microbiome, in infections, what we eat, everything is actually influencing our brain function. So can you share a little bit about how this understanding has changed the way we think about the brain and how some of these factors that are driving inflammation are actually causing this disease? Because it's a disease of brain inflammation.

It is. So the, so the kind of the conventional wisdom that we're trying to look at is that inflammation is an, is a response to an injury, uh, or is it the injury itself? Uh, at the end of the day, you know, a lot of people think that there's an amyloid triggered event and then the inflammatory events occur, uh, because of the production of the amyloid. And amyloid is sticky, gooey stuff that gums up your brain. That is correct.

And importantly, but we used to think, as you said, there was north of the neck and south of the neck, right? And that everything in the Alzheimer's was north of the neck and nothing south of the neck was related to it. When in fact, now we know that things like gut microbiome can alter your immune system.

and having a healthy microbiome can keep you healthy and you can boost your innate immunity which might reduce inflammation across the body including the brain. Yeah, and exercise helps reduce inflammation? And BDNF. So the exercise, I have to tell you, I hated running. Oh no. But I've taken up running.

Because of BDNF. So what is that? It's brain-derived neurotrophic factor. It's like miracle growth for the brain, right? It's miracle growth for the brain. And the funny part about it is almost neuroscientists are runners. They don't do anything but run. They have to have something to do. It's the fastest way to raise your BDNF levels.

which is basically this growth factor that connects your brain cells together. So it causes neuroplasticity, which increases connections and helps neurogenesis, which is the development of new brain cells. That is correct. So we never thought that was possible. We never thought it was possible. We said, once you're born with your neurons, you're going to get it. But we now know that the brain's

making neurons throughout their life. Yeah, I mean, I read a study where they studied terminal cancer patients and they gave them this dye that only goes to dividing brain cells. And they found even at the point of death, they're making new brain cells. That's correct. We did a, when I was in Sun City, Arizona, at the Banner Sun Health Research Institute, we had a brain and body donation program. And we had scientists that could take

of patients who had just expired and culture out, bring out stem cells that were still left alive in dead brain. That's unbelievable. It's pretty cool stuff. So these things like diet and exercise and optimizing your gut microbiome

and stress reduction, they all in a sense work by regulating this inflammatory process. That's correct. That is correct. The inflammation, of course, is the unifying common pathway that we can manage. And you know, at the end of the day, that's what we want to do. But studies taking Advil never really worked. They tried it. Well, Cox inhibitors have not worked. So then the questions are scientifically, is it that pathway of inflammation or...

People are now looking at different pathways of information. Now they're looking at TNF-alpha, which is two-nucleosis alpha. They're looking at the fact that TNF-alpha might trigger enzymes related to Alzheimer's called BASE. So we think that there's links that inflammation is not just a broad category, but there's specific segments that seem to work and others that we've tried, like you said. We tried anti-inflammatories for years to treat or prevent Alzheimer's. It didn't work worth a darn. Right.

Well, that sort of goes back to the thinking in functional medicine, which is what's causing it in the first place, right? So if you're standing on a tack, it takes a lot of aspirin to make it feel better. Pull the tack out. So it's not necessarily the best logic, but it's something that we have to sort of begin to wonder about. I'm talking to one of your colleagues, Rudy Tanzi from Harvard, who said to me that they've done studies of patients who had brains full of this amyloid

but they had the genes somehow that didn't let them create inflammation and they were cognitively intact. They didn't have dementia. - Right, and that's the amazing thing is that you can go to your grave with a brain full of amyloid and not develop dementia. And we wanna study those people 'cause there's something protecting them against the development of symptoms. And of course, they may have just less inflammation as you commented.

Rudy Tanzi would be the guy to figure that out. Yeah, and he talked about the microbiome of the brain. I don't think they're still trying to figure it out, but they're finding microbes in the brain. We thought it was sterile up there, but it turns out it may not be. It may not be. There's a new one that you probably have just hearing about. There's a company out of the Bay Area that found there's an oral bacteria called...

P. gingivalis, which creates a protein called Gingipane, which may be a neurotoxin and trigger of neuroinflammation. And so they're looking at drugs to stop that. Maybe brushing your teeth, flossing, getting them clean is a good idea. Not just good for the heart, it's good for the brain as well. That's right. I mean, people don't probably know that, but one of the biggest triggers for heart disease is gum disease, right? That's correct. So let's talk about the genetics here for a minute. So, you know, most people think you get your genes, they're fixed.

Your fate is sealed. There's nothing you can do. It's not actually how genes work. You can modify these genes' expression, which ones get turned on and off and how they work. And I remember I had this patient years ago who was a 90-year-old woman. She was a dentist. She had APOE double four, meaning she had two...

of the worst genes you could have that are triggers or maybe predisposing to Alzheimer's. And she was 90 years old. She was still working and she was completely cognitively intact. And she was a health nut her whole life. She ate a perfect diet. She exercised. She never smoked. She never drank. She took her vitamins. I mean, it was remarkable to see that. Yeah. And this is what you talk about in this book with this woman, Jamie. She came to you because

She had a family history of Alzheimer's and you checked her genes and she had that dreaded APOE4 gene, which many people are afraid to test because they feel like it's just a, why bother? You talk about why bother. Tell us why bother. So I'll answer the why bother in a second, but Jamie is like your dentist patient. She's a 4-4.

She found her story, of course, she found out her genetic risk by accident. Now, you and I know that if you are two copies of the APUA4 gene, your lifetime risk is 91% that you're going to develop it. It's almost a matter of when, not if. And the problem is that

Fortunately, there's only 2% of the population that are double copy. 20% of the population is a single copy of the APOE4. But people are now finding out because there's commercial genetic testing by accident. Like 23andMe. 23andMe, right? And then they go to Dr. Google. It's me and my friend, Dr. Google. Yeah. And they're like, well, what does this mean? And they go and they...

So the Jamie's of the world are finding out day in and day out by accident and they're trying to figure out what does this all mean? So the story is on her half is how she found out by accident and how it affected her. My half of the book is, is it a good idea to be tested? What are the consequences of being tested? What does it mean?

And so that's what my half of the book about it. It's a nice convergence of two storylines that help people to become informed because this is happening every day of the week. It's happening anyway, but what your book, Fighting for My Life, suggests is that by knowing that, it can motivate people to take control of their life and their lifestyle

and address the modifiable risk factors. That is exactly right. And I want everybody who reads the book to be like your dentist patient, right? Yeah. She was amazing. I have to say to you, I had one other. I'm not sure I would go to her at 90 years old to clean my teeth. Sure, but she got to 90. She was. Right? And working, still working. And I've seen only one other elderly person get to late 80s, 90s, a 4'4 who was unaffected. In my career...

I've almost said that if you have that genetic profile, it's almost a foregone conclusion you're going to get Alzheimer's, dementia eventually. But there was one exception to that. So we want everybody to be the exception, not the rule. Now, you know, one of the things we haven't really talked about yet is the role of sugar in the brain. Yes. And many people may remember Ronald Reagan's favorite food was jelly beans. Yes. And he got Alzheimer's. Now, maybe there's a correlation, but...

It turns out that diabetics have four times the risk of getting dementia. That is correct. And that we sometimes talk about Alzheimer's as type 3 diabetes. Yes, this is Susan Delamonte from the University of Rhode Island. From Brown, yeah. Yeah, Brown, yes. And the...

Truth is that we all have control over whether or not we get diabetes. This is almost 100% preventable and reversible disease by changing our diet. Right. And do you know that insulin resistance, of course, is the hallmark of type 2 diabetes and that we can see insulin resistance in the brain, and that's with the type 3 diabetes, even if you're not having insulin resistance in the rest of your body. And we think, of course, and I strongly believe, like you, that that's a modifiable risk factor, that we can alter that.

We can alter it, of course, the epigenome, which we're going to talk about. I hope we're going to talk about epigenetics. But the diet and reducing the sugar intake and the diabetes risk is something we can alter and have a positive effect on. So we all learned, I mean, I learned in medical school that your brain uses 25% of your glucose and it needs sugar to run. Yes, it does. And the PET scans,

show that you need sugar to make your brain light up. So the rule of thumb on a PET scan is you want your... South of the neck, you want to be dark. North of the neck, you want to be bright on sugar PET. Because if it's dark below, you got cancer. If it's bright below, you got cancer. If it's dark, that's why you put it in the brain. You want it to be nice and bright. You want that brain to light up because it consumes so much

of the sugar metabolism is in the brain. - But you also say in your book, in patients who have Alzheimer's, that people are exploring the role of ketogenic diets, which means no sugar and lots of fat, and the brain running on ketones instead of glucose. - And the issue that people are trying to decide is can you bypass insulin pathway mechanisms? So if you're relying on insulin and pathogen-related insulin to nourish your brain,

and you have insulin resistance, either you can pharmacologically improve that or you can dietarily improve that. Yeah, I mean, you know, I remember this patient I had at the Ultra Wellness Center, my practice in Lenox, and she came in, she was about 78, and she started having what we call MCI or mild cognitive impairment. And she had a whole bunch of things wrong with her. Her thyroid was bad, she had gut issues, she had low...

low vitamin B12. She had heavy metals and mercury. But she was able to fix a lot of these things and do a lot better for many years. And then she started to decline. And I'm like, well, let's try a ketogenic diet. And we got someone to work with her and cook for her. And it was like the lights went on again. It was pretty dramatic. And I think, you know, there's some preliminary studies that are showing that. And

And, you know, people have been looking at it. So the ketogenic diet all starts with the whole coconut oil conversation, which is coconut oil is controversial by itself. But the story behind ketogenic diets is that we do understand there's insulin resistance. The NIH actually funded a study looking at the ketogenic diets. So I think the science is there. It's just a matter of being able to prove it and, more importantly, to adhere to it. Ketogenic diets are not easy. Not easy.

you know, it's not new to neurology. We've been using ketogenic diet to treat childhood epilepsy for 30 plus years. So it's not new. It's new to Alzheimer's, but it's not new to brain disease. It's been used to treat other brain diseases for a long, long time. But, you know, fundamentally, it's really hard to diet to stick to.

Yeah. Well, we're finding, you know, more and more people are doing it. It's one of the hottest diet trends out there. If you look at all the best-selling books, it's not mine, it's the keto books. And we, you know, we're seeing just much more interest and we're running keto programs at Cleveland Clinic. They're our most popular programs, which is pretty amazing. So people seem to be willing to try it. I know you had Dan Perlmutter on a few weeks ago and Dan and I have... David Perlmutter. David Perlmutter. He and I have...

had an internet debate about this and I will say to you that I think it's more nuanced. I think that ketogenic diets that are insulin sparing make more sense in the symptomatic phase of the disease and I have to tell you I look at Alzheimer's disease in a dichotomous way. There's the pre-symptomatic and then there's the symptomatic.

Symptomatic disease means mild cognitive impairment and dementia. And I think there is some logic to a ketogenic diet in the dementia phase. I agree. I think an ounce of prevention is worth a pound of cure, as Benjamin Franklin said. I think the ketogenic diet is a pound of cure. It's a pound of cure. But I would not necessarily advocate for it in the pre-symptomatic phase. I'm more advocating for the pre-symptomatic.

Mediterranean diet in the priests and people. - And that's the beauty of your book is you talk about how to create resilience and health so you don't need the pound of cure. - Correct. - 'Cause the whole purpose of life isn't to be restricted and restricted, it's to actually be more resilient, healthy, so you actually are resistant to these diseases. - That's correct. - So it's actually exactly the right idea. - There are so many things that we can do

to put the ball back in our court, to write this script and tell our own story. You know, can you definitively 100% prevent Alzheimer's in every case? Well, no. I mean, there are certain pretty rare genetic causes where basically just about anything you're going to do, you're going to get Alzheimer's and it's going to probably start early. And that's unfortunate, but that is an exceptionally rare number of cases. Most cases of Alzheimer's, you can do something about it. Based on the 2020 Lancet Commission,

An amazing study. Based on 12 modifiable risk factors, we can – the person makes brain healthy choices –

prevent four out of every 10 cases of Alzheimer's disease. Wow. Like we didn't learn that in med school. Medical students now aren't learning that in medical school. It takes 10, 15, 20 years for something to be learned in medical science to be translated into clinical practice. And I think it's important for this podcast and people like us to share this news because there are so many things a person can do. So you asked me what can a person do? I want them to know there's so many things.

At least 12. At least 12. Well, so in our study- I think there's more, but there's at least 12. At least 12. In our study, we recommended on average 21 different things that a person can do, and those were individualized per person. In our whole universe of our study, we recommended almost 50 things that a person can do. 50 things that influence the brain that you've identified. Yep. And this isn't radical. This isn't rocket science. This isn't like

You know, I'm a simple man. I did not graduate first in my med school class. I did pretty good and I worked pretty hard. But, you know, I try to just see things from the patient's perspective. And there are so many things that are evidence-based and safe. The two categories I would start with.

just to kind of set the stage, are pharmacologic and non-pharmacologic. And I want to get granular because the word pharmacologic doesn't just mean drugs and prescription drugs. It also means- You mean food is medicine? Well, food is definitely medicine, although that got sidetracked to non-pharmacological. But I can- Vitamins are medicine? Oh, vitamins are medicine.

I would actually challenge you, Richard, because I think that food is actually real medicine. The phytochemicals, compounds in food are biological response modifiers or signal transduction changers. And they have

similar effects as drugs in fact many drugs come from the phytochemicals in plants so i would just kind of well make us think about that a little bit well actually so i'm glad you brought that up i i would say that traditionally speaking and let's let's talk through this this is this is a great opportunity so traditionally speaking i've always framed it and i'm open-minded so this is great yeah um as pharmacologically i'm just teasing this is

This is exactly why we're doing this. This is exactly a meeting of the mind. Gloves are off. Let's go. So drugs, vitamins, supplements, and medical foods are the classic things that I personally have categorized in the pharmacologic session. And then in the non-pharm section, I've included diet, exercise, sleep, stress, a whole bunch of things, learning new things.

But what you bring up is important. And I have a colleague named Dr. Robert Krikorian. And he's an amazing guy. He's a neuropsychologist. And he's fought the good fight.

you know kind of like us he's i don't say he's had yeah in some ways that contrarian views because he's tried to do randomized studies using nutrition he's done studies on the ketogenic diet and alzheimer's and parkinson's and he's done you know studies on blueberries and omega-3s and what he's done is he's taken the food and he said okay it's not just about the blueberries we did the study and wild blueberries are better well why because of this it's called anthrocyanin and

And then he gets down deep into it. So I completely agree that food is medicine. A hundred percent agree. I completely agree that the specific, uh,

chemical nutrient compounds can be isolated but i think it's it's too reductionist to just say let's just put a pill of anthocyanins and and prescribe that because it's it's the milieu it's right it's like with caffeinated coffee is good for brain health well is it the caffeine is it the coffee well no they think it's like some substance x during the brewing process right so so you know depending on which way you look at the science i would prefer that food is

- I agree with you. I understand the bucket. So I'm just kind of playing with you. - I love it. - But I think, I mean, when I put a patient, for example, on a ketogenic diet with Alzheimer's and they wake up and their brain becomes alert and they remember their son and their daughter and I'm like, well, how is that less a disease?

a drug than some other drug that doesn't work that we're using like Aricept, right? It's impressive. Yeah, no, I mean, I just feel like all of the different paths, like, you know, some people call like nutrition, I don't know,

Not mainstream medicine like that to me as a Western doctor that doesn't make any sense to me nutrition is Like I got very little nutrition education in medical school, and I think that's a terrible thing I learned a ton

And I had to – my better half has a master's degree in nutrition from Columbia, and she's taught me a lot, I think, through osmosis. That explains everything. Ah, there we go. It's always the better half, and she informs the less enlightened one. So, you know, I guess what I'm trying to say is nutrition –

is the cornerstone of how we practice. Physical exercise and precision exercise, precision nutrition, these are all the things that are developing and really become the cornerstone of our care.

So you're talking about the 12, then the 21, and then the 50. Maybe there's going to be 100. Tell us more about the granularity on that. Sure. You were using these, you know, and I just want to sort of frame it for people. You did a study that you published, I think in 2019, which surprised even you. We're using this approach, looking at a personalized assessment of these biological factors that could be modified, and then individualizing the treatments.

that you not only slowed the decline, you not only stopped the decline, but you reversed the decline.

which is something that has never really been seen except in a couple of trials like the finger trial. And I think there's a new one coming out, the pointer trial. So those are also lifestyle trials. And so you really have sort of cracked the egg and published something that should have been on the front page of every major newspaper, the lead story in every evening news. And yet it was like, "Frick it."

Yeah, well, I mean, we got the Wall Street Journal and CNN and this mother. So I'm OK. I'm OK. But for me, it was like it was it should have been like the NIH should have gone. Oh, Richard, here's 10 billion dollars to get going on this. Like, that's what it should have to be careful. But, you know, the NIH doesn't really fund what we do.

And that's been, it's very hard. And listen, the NIH, I've engaged with the NIH over the last year or two, and there's definitely been more interest. But, you know, I, you know, talk about crickets years ago, a decade ago, when I started this whole thing, more 15 years ago, there was nothing. There was no, there was no funding for any of this. So, you know, what I would say is, what our work shows is that when you individualize care and you

give people a plan. And I know you've asked me at least three times now, what should people do? What I'm trying, why I'm delaying things is because it really truly needs to be individualized. And what we use is a term called the ABCs of Alzheimer's prevention management. Based on the data, we get data on A's, the B's and the C's. A stands for anthropometrics. Anthropometrics is basically a fancy A word for body composition.

What is your body fat? What is your waist circumference? What is your muscle mass? Depending on these factors, we're going to change the recommendations we give. The B stands for blood-based biomarkers. We're going to look at markers of lipids, cholesterol markers, also advanced markers that preventative cardiologists use, for example, that most neurologists honestly don't really pay attention to. We look at metabolic markers, insulin resistance. We look at inflammatory markers. We look at nutrition markers. Instead of

know saying okay well go eat fish it's good for you we're going to look at the markers in the blood we're then going to tell you based on your blood and based on your genetics how much fish you should be eating what types of fish so so the the take-home point is we're going to get granular with every patient the other thing we do is in the blood-based biomarkers we look at genetics we look at the apoe4 variant it's the most common risk gene doesn't mean you're going to get alzheimer's if you have the variant but it increases your risk well

if I know that you have the APOE4 variant, they check for this in 23andMe and millions of people have gotten this checked.

I'm going to personalize your care differently. If you have the variant, I'm going to give you plan A, B, and C. If you don't have the variant, I'm going to give you a little bit modified plan X, Y, and Z. If you have two copies of the variant, you have a different plan altogether. That's only 1% of the population. So the take home is we take all these markers and then the C is cognitive function. And we understand a person's cognitive baseline. We look at memory function, language abilities, learning abilities,

speed of processing, attention, and executive function, which is higher order processing. We take all of this and the patient's medical history. We learn about the patient. We learn everything we can about them, about their family, and then we personalize a plan. So those 21 different things are based on that person individually. And there's a lot of overlap. If you want me to say, okay, well, what are the core things? Well, exercise on a regular basis. Okay, well, exercise on a regular basis is good, but every person gets a different plan.

If we're putting someone on a plan for body fat loss, we're going to give them a different plan. Steady state cardio, for example. Some people would call that zone two training. Steady state cardio at 60 to 65% of your heart rate. There's different ways to do this through lactate testing, through a variety of things that we do more precisely in our clinic. But we put people on these steady state cardio plans.

fasted in the morning as long as they can tolerate it because that way it jumpstarts body fat loss. If we have people that don't do any muscle strength training because they don't like it, we educate them to say, I don't like it either. I'm not Mr. Big Muscles over here, but I have to do strength training once or twice a week minimum because if you don't have muscles, you can't boost metabolisms.

So we put people on these very specific plans, high intensity interval training. I really believe that high intensity interval training is almost necessary for people with at least one copy of the APOE4 variant. And this is what has been studied now in a couple of studies. And yes, we need more. We need more research and studies out of Norway were good, but we we need to personalize an exercise plan.

We need to personalize a nutrition plan. We need to personalize a vitamin and supplement plan. In some people, we do use drugs. Drugs are actually not commonly used at all in our research, although we do use them on occasion. We'll use a variety of drugs, usually at much lower doses than maybe the regular community uses. But when it comes to

you know, management, um, equal opportunity. If there's data and it's relatively safe, um, you know, I'll, I'll entertain it. So we recommend, um, you know, cognitive activities that will have a spillover effect, learning something new, learning how to play a musical instrument, learning a new language. These are things that may have a protective effect, build backup pathways, believe it or not, even learning how to play a musical instrument in midlife has protective effects on cognitive

outcomes in late life. And that's hope for me yet. There's hope. There's hope for me yet. I got my bass guitar over there. I got blisters on my fingers. I'm dying to learn to play the guitar. I'm dying, but I just love song. But my big problem is I don't know how to tune it. And I don't, I am so musically inept that I, I probably, there are good apps and things to do it. There's, there's a website. It's called, you got a pen. It's called YouTube. YouTube.

YouTube, you may have heard of it. I heard of it. Almost as many people watch YouTube as listen to your podcast. So you can learn how to play guitar on YouTube. I think you can do it. Okay, I'm going to try. For sure. That's my December. Excellent. And January and February and March. So the take-home point is engage your brain. Treat your brain with respect. Love your brain. Make a plan for your brain. What does that mean? Make a plan for sleep.

If you exercise and exercise and exercise, some people say colloquially that that loosens the amyloid, the bad protein that gets built up in the brain of a person with Alzheimer's. But if you're burning the candle at both ends and you're not sleeping during sleep, especially deep sleep, that's when a person...

has the trash come. The trash man comes, they pick up the garbage and they take it out and they take it to the trash heap. That is the restorative part of sleep. And if someone isn't sleeping, you know, at least seven, seven and a half, eight hours of sleep is usually the goal. As we get older, it's

you know, harder to sleep that much. But making a plan for sleep, prioritizing sleep. You know, we have people that track their sleep, that track their exercise. I'm wearing a wrist device here. I have nothing to disclose, but we've done, you know, several research using this device. I track people on my phone. I have my phone right here and I can check,

How much exercise they've been doing, how their sleep, how much deep sleep. I can see their blood sugar control. I can see all these different things on my phone because my patients share their data with me. And when I talk about data sharing, it's not just about tracking sleep. It's not just about doing exercise. It's about tracking it.

determining the response, talking to your physician about it. Granted, it's hard to find physicians that will take the time to talk to you about this kind of stuff. Tracking your blood sugar, there's at-home devices called continuous glucose monitors. In our program, we take a very, very deep dive and we learn about all of these different metrics and we refine or fine tune the plan that we give them based on their real-time measurements. So I can keep going. There's

Stress modification, you know, transcendental meditation. Bob Roth's taught me a ton about this. What about mindfulness-based stress reduction? You can take a course online. Mindfulness-based stress reduction has amazing outcomes when it comes to brain health. The list goes on and on. There's no one magic pill or one magic cure, but there are a variety of

I was going to say pharmacological and non-pharmacological, but you're reevaluating how I say this now. There are a variety of interventions that are evidence-based and safe that I think all of us need to learn about. Whether we talk about fasting, and I like the term time-restricted eating better, meaning not eating for 12, 14, 16 hours overnight, at least four or five days a week.

I use the term fasting for a more prolonged fast, 24 hours or more, and that's a different discussion. There's the ketogenic diet. There's the Mediterranean-style diet. There's the mind diet. There's components of each diet, green leafy vegetables, wild salmon, grass-fed beef better than non-grass-fed beef because of the omega-3s. There's so many devils in the details, half a cup of blueberries and strawberries two to three times a week.

you know, leads to better brain health outcomes and cognitive outcomes in the nurse's health study. You know, many years later on there's dark cocoa powder. There's so many things that I can drop in as, as key things, but the take home point is all of these things need to be individualized. So, so let me, let me ask you this because I mean, you know,

First, I want to just kind of feedback because what I'm listening to you thinking, you're a neurologist, but you're also an immunologist, a cardiologist, an endocrinologist, a gastroenterologist, a nutritionist, right? You're breaking down the paradigm of medicine, which is we should stay in our lane, focus on our organ, and leave the rest to everybody else. And your insight here is that the body is a system.

that everything's connected to everything. You can't just pick out one thing and work on that, like amyloid or tau or whatever, and get to the problem. It's sort of like trying to

bail the boat while there's holes in it. You gotta fix the holes. And essentially the holes that you're talking about are all these ways in which our brain gets injured by our lifestyle and by our environment. And you didn't mention toxins, but that also plays a large role. And so all of a sudden we have to sort of rethink our whole approach, which has really been a reductionist approach. Single disease, single drug,

with a single outcome. There was an article in JAMA a number of years ago called Shifting Thinking in Dementia. You probably saw it. And they said in that article that we combine categorical misclassification with etiologic imprecision. And in English, for those listening, that means we categorize dementia according to symptoms, not the causes. And we categorize

we are not very focused on the etiology or the causes. We're focused on the symptoms. And we say, well, you can't remember this and you fit this profile on your neurocognitive testing. You have Alzheimer's or you have this kind of dementia or Lewy body or blah, blah, blah. And the reality is that you could have 10 people with Alzheimer's who need 10 different treatments.

And that's exactly what you're talking about. That's heresy, Richard. That's heresy in medicine, honestly, because we really have a very, very restricted reductionist view of disease that doesn't let us actually even study these things. And I've literally had arguments with top leading researchers, like heads of research at major institutions saying, these are all the factors that affect the brain. We want to study them together.

So, oh, no, you have to study one thing at a time and then see how that works. So study exercise, and then study nutrition, and then study vitamin D, then study fish oil. I'm like, no, that's not how things actually work. It's like you have to use the whole picture. The other thing I sort of wanted to sort of touch on was that you're sort of introducing a concept of

the personalization which again is is very different in medicine it's not one size fits all and and you're talking about very sophisticated personalization based on a whole set of biomarkers and tests and things that are easily accessible but that aren't normally looked at and that aren't normally tested you know you get your typical panel you get your thyroid your b12 you get your spinal fluid done you get your mri and you go okay you got alzheimer's like it sort of

A little bit more complicated than that, but it's really a fairly narrow window of biomarkers and metrics. And there's bazillions of them. And I think we're just sort of touching the sort of tip of the iceberg on this. And I've seen in my patients, when you start to apply these

concepts of personalized care around food, around exercise, around sleep, around stress, around supplements, around everything that you really begin to see dramatic changes in brain function. Yeah, I

you know i i often joke that i'm like a one-third neurologist but a preventative neurologist at that i'm a one-third um make-believe i will full disclosure i'm not a preventive cardiologist but i may make believe preventative cardiologist i'm a one-third primary care doctor and make-believe preventative endocrinologist

I don't even know any preventative endocrinologists. If you find one, introduce them to me. I was trained in an environment. I went to a six-year medical program where I was in med school from day one, University of Missouri, Kansas City. I knew I wanted to be a doctor when I was five, 17 years old, wearing my white coat. And I did so much internal medicine during med school. I had like an extra year of medicine because that's the way our training was. And I don't know if it was that or I'm not sure exactly what it was, but Alzheimer's disease is a medical disease.

Yeah. Full stop. That's it. There's this thing called the skull and it's a hard thing that affects you when you fall. But it's just like it. It's like when you have medical conditions, you can affect your kidneys. When you have medical conditions, it can affect your eyes. It can affect your heart. The same thing. It can affect your brain. And I couldn't agree with you more. People can take different roads to Alzheimer's.

And you have to figure out what word they're on and get them the heck off that road. Women, for example, are unfortunately many times in the fast lane to Alzheimer's. Women, two out of every three brains affected by Alzheimer's are women's brains. And five, 10 years ago, I would say I didn't know why. And

Now, I think I can answer that question and it's related to the perimenopause transition, it's related to specific life factors, it's related to women being maybe a little bit more at risk if they have the APOE4 variant. So the take-home point here is if you understand a person's individual risk factors, whether it's biological sex, whether it's medical conditions, whether it's what's floating around in their blood, whether it's what is their cognitive function at baseline,

You have to figure these things out and then you have to target that plan and personalize that plan. And I mean, I,

Alzheimer's disease and brain health needs to be treated in a medical way. Because if it's not, if you're just targeting amyloid, you're missing the boat. You know, amyloid is a marker. And I think hopefully one day we're going to have just like we treat diabetes with lifestyle interventions and exercise and as well as certain targeted drugs that honestly, some of them actually do tend to work pretty well. I'm not the biggest fan of insulin like that doesn't that's maybe band-aiding to me. That's probably too late. I mean, I'm not the best.

Whatever, but some of these new things that are pretty interesting. I won't get into specifics, but I hope that one day we treat Alzheimer's disease and cognitive decline like any other chronic disease of aging where we hit things with a multimodal evidence-based and safe approach that requires a medical intervention.

So essentially what you're saying, to paraphrase, is that Alzheimer's is not a brain disease. Correct. It's a systemic disease that affects the brain. Yeah, I really believe that. I have to be careful saying that. Is this being recorded? Yes. And it's going to be broadcast to billions of people around the world. Great. My field. I was just gaining some...

from some fans in my field and now it's all, last decade of work. - Oh, no, no. You were at the forefront of a paradigm shift that's happening throughout medicine, which is the breakdown of the old concepts of disease from simply this reductionist organ-based symptom-based model to systems thinking and network medicine. And that's really all you're talking about. - There's very strong compelling evidence at this point

that bacteria are the cause of neurodegenerative diseases. Not my research. Yeah, we talked about Rudy Tanzi, who's a Harvard scientist, one of the discoverers of some of the presenilin genes, which are the genes that show that people are at risk for early Alzheimer's. He actually said they were discovering all these microbes in the brain, which we thought...

was impossible and that we had this blood brain barrier that protects us and you're saying and he's saying that that barrier is not always 100%

And this stuff can leak through. Not only can you have a leaky gut, but you can have a leaky brain. Look, bacteria, not to scare people, bacteria love the brain. Why? 25% of the body's glucose is used by the brain. They know where to eat. They're going to, you know, Le Pen or the fancy restaurant is downtown. Like everyone else is eating downtown. They're getting, you know, our brains. Can bacteria live on ketones?

- 100%, but not, wait, that's very important. They prefer simple sugars. Why? Because they're lazy, right? They want instant gratification. So they like sugar better than ketones. - But ketones and ketotic diets work for some of these neurodegenerative diseases, like Alzheimer's and even LS and brain cancer. - That's right, that's right. And I think one of the mechanisms, to be honest with you, is that ketones actually,

First of all, they improve mitochondrial function, but they're not a good substrate for bacteria. They're a great substrate for us. Bacteria don't like them because they like eating fast food, basically. Yeah, so feed them sugar and we eat fat. That's right. Okay, so...

This is just a breakthrough idea. And this isn't just an idea. You've actually treated patients using this approach and seen some really extraordinary things. Yes. So can you share with us a little bit about this case you were sharing with me earlier about ALS, which is a horrible condition. Stephen Hawking had it. It was called Lou Gehrig's disease after the baseball player. Essentially, it's where your nervous system is affected by ALS.

the killing of the neurons in your spinal cord, which makes you basically paralyzed. You get fasciculation, which is twitching. You eventually can't move your arms and legs. You're in a wheelchair. You can't breathe. You need a respirator. You wouldn't worship on your worst enemy. It's like a slowly getting paralyzed. Yep, that's right. And never has there been a treatment that has stopped or reversed it. Right. And you're saying that you've seen patients where this has actually happened.

- So, well, we are in the process of validating that sort of, that data, yes. - So, yes, we need more studies. Yes, we need to do research on multiple patients. But even if there's one patient where you've seen a change,

It raises the question. Oh, by the way, it's made me go crazy, by the way, because, you know, I am so, I'm finally glad to be a neurologist. You know, being a neurologist is like being a nihilist or a masochist. Diagnose and adios, right? Well, it's worse than that. It's like, diagnose and let me, you know, let me not tell the patient that they have ALS. Let me treat them for, you know,

like a CIDP picture, 'cause they don't wanna actually make that diagnosis for people. It's the hardest diagnosis you could make for a patient. 'Cause everyone knows ALS is incurable disease, right? I mean, it's 100%, even pancreatic cancer is better. Well, you have a 5% chance of living with pancreatic cancer. You have zero chance of living through this disease, zero. - So based on your hypothesis that it's infectious, that plays a big role, if not is the main role, you know,

I personally shared on this podcast that I went to a place in Mexico called Santa Viva where I and my wife both went through this treatment called hyperthermia, which essentially is where they heat you up to 107 degrees, which sounds crazy and is scary. But actually we did both fine and it,

Killed a lot of infections that we had. Yeah, it's amazing. Lyme, my wife, her viral loads of very tough to treat infection called CMV came plummeting down. She felt much better. I felt much better. And so this is a therapy that is not much used...

in the United States, but is used widely in Europe, is used in Mexico and other countries as therapy for some of these types of infectious diseases and even cancer. So how does the theory work behind this with something like ALS? Well, the idea is that fever,

is the way of actually denaturing spores. So... Okay, that's a big sentence. Can you unpack that? Sure. So human cells have their proteins that, you know, either...

Fold properly or not fold properly at a certain temperature, right? Bacteria have their own temperature zone, like their ideal climate. And spores have another ideal climate, right? Meaning that to kill a spore... A spore is like a baby bacteria. A spore is a baby bacteria. And that's what I believe personally is the reason...

that patients have amyloid accumulation, that the spores are creating this protective cover against antibiotics that actually is in fact the amyloid being produced. - So the amyloid is like the armor for the bacteria. - Yes, they're like the bomb shelter. The biofilm is the bomb shelter for these little baby bacteria, yep.

And so how does hyperthermia work to disrupt that? And what is that procedure? Well, so it works, hyperthermia works by, it's a very narrow window of temperature. Meaning if you give too much temperature, you can actually hurt normal cells as much as

you know, bacterial cells. If you don't give enough temperature, you've done nothing. So it's like Goldilocks. It's like Goldilocks. You got to get it just right. You have to get it exactly right. Okay. And that's part of the way that the hyperthermia technology has been developed is by really understanding that the brain itself is

can provide feedback on the tolerability for human cells because brain cells are going to tell the brain, hey, this is pretty hot in here. You don't want to fry your brain. Right. Can you turn the thermostat off now? So part of the device actually is to get the brain temperature back into the feedback system where it's self-regulating so that you never reach a point where the temperature is harmful to your own cells. Okay.

And so, you know, often in places where they do this, they'll give, at the peak of the temperature, they'll give antibiotics or antivirals.

Right. Does that make sense? To give antivirals? Or, yeah, to give antimicrobial treatment to patients when they're at the peak of the fever because the idea is that it sort of flushes out the... Oh, I see. Yes, for acute infection, yes. I would argue that... Like Lyme or... Well, if Lyme is acute, certainly. I mean, I don't think that... I mean, I think you'd be weary of the issue that by, you know, robbing Peter to pay Paul, for instance. Let's say that C. diff...

is let's say let's for obvious sake say this is a polymicrobial disease okay as opposed to a like lots of different bugs lots of different bugs as opposed to just one ring leader everyone else is following okay so lombard believes it's it's that that c diff is the ring leader okay and all these other guys lime hsv they're just they're tagging a ride because it's such a great killer that's like okay great well we'll take the leftovers no problem here

We'll take the leftovers. So my concern is clinically that if we start treating patients with bacterial drugs like Rocephin, whatever it is for chronic Lyme, yes, you're addressing chronic Lyme. I mean, the C. diff gets worse. Yes, exactly. Yeah. Exactly. So the heat alone is enough to disrupt the C. diff?

Well, we haven't demonstrated that yet, to be quite frank. But what's been demonstrated is that by applying hypothermia,

that we're able to actually see improvement in clinical symptoms of patients with ALS. - So people's muscle strength, this is a progressive disease, so it gets worse and worse and worse every visit, they're worse. You're seeing patients, it stops or it gets better, which never happened. - Correct. - So this is a major breakthrough. - I think so. - Major breakthrough. And this is not something new, this has been around for a long time. So where in the world is most of the research being done on hyperthermia?

- For ALS? - Period. - Most of the research on hypothermia actually is cancer research. They call it chemo-thermia, chemo-hypothermia. So people can look up a lot of data on how hypothermia affects cancer, but as far as I know, there's zero data until now

hyperthermia for ALS. We will be the first people to actually talk about applying hyperthermia for treatment of ALS. What about things like Alzheimer's or Parkinson's or MS? Well, the difference in those diseases are that, um,

In Alzheimer's, right, it's very difficult to induce hypothermia in a patient with Alzheimer's disease. Why? Because you need to be compliant. The treatment itself is, you know, it's fairly rigorous as you know from your experience. They put me to sleep. They put you to sleep, right. We don't want to put them to sleep though, right, because we're concerned about protecting their brain.

So, you know, you have a patient who's got, you know, end-stage Alzheimer's disease, for instance. I don't see how this is going to be helpful for them. But early. But early, 100%. Early. Early. In fact, I will talk later, not about the case now, because we're really just in the beginnings of this case.

But yeah, I think it would be applicable for Alzheimer's disease as well. - Have you seen any patients reported or in the literature or anywhere? - No, definitely not, no. - But you serve as a theory. - Yes, still a theory. - And MS, what about MS? - MS, there's data on actually the opposite, right? Which is how do you induce hypothermia, right? Because an MS, it's an inflammatory disease obviously, right?

which by the way I also believe is caused by Clostridium but not C. diff, where it's especially important to actually identify at that stage that this is bacterial. So there, I don't know what there... - Yeah, so what is the idea with MS? That you wouldn't want to use hyperthermia? That you wouldn't want to use heat because it makes it worse? - Well because remember, when you heat up a patient with MS, what happens?

they usually get worse so the the trick is but maybe not enough right maybe it's not enough that's right maybe you haven't reached the threshold to actually you know use the body's fever mechanisms against because there's links to ms and epstein virus and other infections there's links to alzheimer's and herpes virus infections right so yes the whole principle is applicable for all those diseases but we don't know yet if it is applicable yet until we clinically demonstrate that right

But yeah, I think that this is gonna be a treatment that's gonna be very important for a lot of different diseases, Mark. - So there's this whole theory that the body has a mechanism for dealing with this and it has these own proteins that are produced in response to heat. And there are things we learned about in medical school. They're called heat shock proteins. - I learned something very important about heat shock proteins from Dr. Lessler.

Because remember that, you know, people are looking at how to induce hypothermia, right? So there's all sorts of research. There's actually even a drug in clinic for ALS that is the mechanism of action is based upon increasing heat shock protein through a pharmaceutical agent.

So I was at this lecture and I thought I knew everything, basically. And I learned that actually you can induce each other. Because you thought MD stood for medical deity, is that it? Medical deity, yes, exactly. We all got that training. The truth is we know close to nothing. That's why I said at the beginning of this talk, thanks for inviting me, but I really know nothing.

Just disclaimer. But anyway, so yes, actually in MS, the goal is to induce heat shock protein through hypothermia. Hypothermia. So you get people cold. Not people, the brain. The brain. Right. How do we do that? Chill the brain. Chill the brain. How do you do that? Ice blocks around the head? No. No. Well, I'll invite you up and you can see for yourself what that looks like. All right. Dunk your head in ice water? Nope. Nope. Nope.

Nope, none of the above. Okay, so we have to be in mystery here? A mystery about what the device looks like, you mean? Yeah. It's basically the same concept as building a hyperthermia device, except remember now that technology itself was developed basically for anesthesiologists. This was developed at Yale by Dr. Abreu, who's the person who actually discovered

of measuring brain temperature objectively externally. Okay, so that's kind of where this whole thing started from, to be honest with you. Yeah.

And we don't just stick electrode in your brain. You can literally map it out from the outside. You can map it out from the outside. So the, the ability to do that now allows a clinician to not only, you know, heat the body to create hyperthermic states, but through other types of modalities to actually cool the brain safely externally with the same, in the same way, meaning that you can actually apply a small device, uh,

to a region of the skin, it's periorbital location. And you can actually change the temperature of the brain through this, what's called the brain thermal tunnel. - Thanks for listening today. If you love this podcast, please share it with your friends and family. Leave a comment on your own best practices on how you upgrade your health and subscribe wherever you get your podcasts. And follow me on all social media channels at DrMarkHyman. And we'll see you next time on The Doctors Pharmacy.

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