Alzheimer’s Is Optional | Preventing And Reversing Cognitive Decline with Dale Bredesen, MD

Content By: Ari Whitten

In this episode, I am speaking with Dr. Dale Bredesen about the root causes of cognitive decline and how to prevent and reverse them.

In this podcast, Dr. Bredesen and I discuss:

Is Amyloid plaque the root cause of Alzheimer’s?
New tests for early Alzheimer’s risk detection
Can the brain’s conservation response to energy scarcity, influence performance decline?
The non-negotiable role of exercise in safeguarding brain health
The stress-inducing pathogens linked to diminished brain function

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Transcript

Ari: Dr. Bredesen, welcome to the show.

Dr. Dale Bredesen: Thanks so much for having me.

Ari: First of all, I have to say I’ve read your book and I’ve listened to many interviews of yours over the years. I’ve given your book to my parents, which speaks to how much I value your work and I’m giving it to my family and saying, “Hey, read this book. Here’s how to protect your brain.” One of the things that I remember you talking about from an interview I think I heard a few years ago was talking about your story in terms of how you thought about health and how you thought about brain health in particular, and batting dementia and Alzheimer’s disease, and specifically in terms of how your focus on drugs versus lifestyle.

I know that if I remember correctly, your wife fits into the story and you and your wife sort of had differences of opinion and then eventually you saw her perspective. Do you know what I’m referring to? Hopefully, I’m remembering correctly.

Dr. Bredesen: Oh, absolutely. Yes. I came through very classical training at Caltech and MIT and Duke and UC San Francisco and looking at how does brain disease work? I set up the laboratory actually way back in 1989 specifically to look at what drives the neurodegenerative process. This is such a common problem and you could argue that it’s the area of greatest failure.

As physicians, we have not been able to do anything about ALS, about Alzheimer’s, about Lewy body, about frontotemporal dementia, corticobasal degeneration, just go right down the list. It has been an absolute disaster. We wanted to go into what are the molecular mechanisms and we wanted to find what’s that one fold of one protein. My wife, who is an integrative physician, said to me it was now about 25 years ago.

“Whatever you guys find in the lab, it’s going to have something to do with energetics and it’s going to have something to do with lifestyle and how much sleep you’ve had and whether you’re under stress and whether you have had a horrible diet and all these sorts of things.” I said, “No, we’re going to find one fold of one protein. We’re going to create a drug that targets that. Everything’s going to be great.”

The new understanding of Alzheimer’s

Well, interestingly, the science itself, that’s what’s been so interesting to me. The science has led us away from the classical view. The classical view is turning out to be wrong and it’s led us into a view– and it’s actually a beautiful story in that we see that Alzheimer’s disease now is really a network insufficiency. You have this amazing network. You have about 100 billion neurons. Each one has nearly 10,000 connections on average. You have almost one quadrillion synapses in this amazing supercomputer you have inside your skull.

Of course, there are all these factors that are critical. There is a supply and there is a demand and when the supply is outstripped by the demand chronically or repeatedly, of course, it has to downsize. So you have this downsizing network over time. Of course, it turned out that the things that contribute to this are your sleep and your exercise, your energetics, your ongoing inflammatory processes, and all this. I had to realize I should have listened to her all those years ago because we would have gotten to the answer sooner.

Having said that, coming at it from the molecular basis, you can actually see the molecules that drive the problem and you can see exactly what to do to prevent it and to reverse it. It’s been such an exciting journey to see, and then, of course, the best of all to see human beings. We started with the first patient in April of 2012. She’s now over 11 years and sustaining her improvement. That’s a huge issue because when you have sustained improvement it means you’ve actually gotten to the root cause of the problem.

Whereas if you use your typical approach you don’t get sustained improvements. As you know, you get a little bump and then you go right back down. In fact, the sad part is studies of the various drugs like Aricept and Namenda that have been used for Alzheimer’s have shown that over the years they do worse than people who are untreated. That’s how bad it is. So forget sustaining improvement. They actually do worse than no treatment.

Amyloid plaques

Just recently a paper came out showing that the people who were treated with the antibodies, such as Leqembi and things like that, actually underwent more rapid brain atrophy than those who weren’t treated so that they actually had the size of a brain associated with dementia earlier than the untreated patients. It’s been a real problem. Again, that tells you they’re not getting at the root cause of this problem.

Ari: I think that this is largely a matter of paradigm more than anything else. I think what you’re describing is a microcosm of the entire field of what modern medicine and biomedical research and pharmaceutical development has encountered with its approach to almost all chronic disease that’s plaguing humanity right now. It’s this focus on the molecular mechanisms and then developing some kind of synthetic chemical pharmaceutical that’s designed to interfere or block that particular mechanism. It works really well in the context of antibiotics when there’s a clear bad guy in the body and we can attack it and kill it. It seems to work horrifically poorly in the context of almost all chronic diseases, as far as I can tell.

Tell me more. I’m curious if you agree with me that this is a matter of paradigm, like the access to this way of seeing things and this approach to treating it, you don’t arrive at it if all you do is study the molecular and genetic and biochemical mechanisms of the disease. If all you’re doing is focusing on the amyloid plaques and the neuronal degeneration and then trying to develop synthetic chemicals that interfere with those processes. I don’t think that you can go down that pathway of thinking and then ever arrive back at, oh, well, actually exercise and eating a good diet might be the answer instead of more synthetic chemicals poured into the system. Do you know what I mean?

Dr. Bredesen: Absolutely. You’re right. That has been really the crux of the problem. What happens when you become a physician? You’re told you have to do things this way because otherwise, people will die. It’s very much like being in the military. You do it this way, you better cut here, you better make sure that it’s an aseptic field or you’re going to kill somebody. You have this mindset that you’ve got to do exactly what you’re told. Then you’ve got a disease like Alzheimer’s where there’s no treatment. They’re telling you, “Okay, it’s about amyloid. Go find that thing that removes the bad guy.”

You need to start much earlier and say, “Well, what is actually causing this problem? Why is the amyloid there?” This old idea, the amyloid is there to give you Alzheimer’s is so silly. The amyloid is there for a reason. It turns out that it is a beautiful response to various insults. Just as you said, you have pathogens. The amyloid is a beautiful sequestrant and antibiotic. It is an antimicrobial peptide that’s been shown beautifully and first discovered actually by professors Robert Moyer and Rudy Tanzi at Harvard several years ago. It is killing and it’s interesting, it has antiviral activity, it has antibacterial activity, it has antifungal activity. It’s pretty remarkable.

Alzheimer’s is about energetics and inflammation

It also has this interesting property of being a sequestrant. You essentially coat these things, great way to keep you away from these, unfortunately, of course, because it is also part of the innate immune system. It is part of your response to inflammation, part of your inflammatory response, which is one of the reasons we’ve pointed out Alzheimer’s is about two major things, energetics, inflammation. Too little energetics, too much inflammation, you’re on the wrong side of the curve and you are downsizing. Unfortunately, because of that, it’s also doing things like, for example, it interacts with complement. Professor Ben Barres from Stanford showed a number of years ago that as you age, your synapses are often covered with complement, kind of remarkable. You’re in this kind of closed–

Ari: Just explain to people what complement is, because a lot of people won’t be familiar with that.

Dr. Bredesen: Again, another part of the immune system, that helps you to kill bacteria and other microbes that actually you have a whole complement cascade that ultimately results in punching holes in the pathogens. Again, this is all part of your response to these problems. It is interesting because it’s part of a response where you’re trying to kill these bacteria and fungi and viruses, but it’s also part of, okay, we don’t have enough energy to support 500 trillion synapses, we’re going to have to downsize. It’s actually part of the downsizing.

One of the things it’s doing is inhibiting insulin receptor signaling. It is inhibiting some of the trophic factor signaling. It’s almost as if, imagine that you have a situation where you have 10 children, and they’re all 10 going to die of starvation, but you’ve got enough for seven. Then you may get rid of three of them, unfortunately, and sadly, and then the other seven can survive. That’s what it’s doing here. It’s basically saying, “We’re going to put additional stress. We’re going to down-regulate this support, and the weak ones are going to go, and then the ones left as we now are going to slowly get rid of that amyloid are going to survive.”

One of the intriguing things to me is, why would you lose memory early? That’s such a horrible thing to lose. Well, it turns out if I said to you, “Hey, you can wake up tomorrow morning, and you can either not remember new things, you can remember everything that’s come up till now, so you can live your life, do all sorts of wonderful things, but you’re not going to be as good going forward at remembering new things. Or you can wake up tomorrow morning, and you won’t remember how to speak, or how to read, or how to do your job. Well, that’s an easy choice. Most people can do extremely well with all the things they’ve learned up till the age of 45, or 55, or 65, et cetera.

I should add when I was training way back in the ’80s, in neurology, we thought of Alzheimer’s as a disease of your 60s, 70s, 80s, 90s. We now know is really a disease of your 30s, 40s, 50s, and 60s that’s diagnosed 20 years later. Unfortunately, it is moving into earlier people, we see people all the time now diagnosed in their early 50s, when we never used to see that when I was training. Things are changing. We’re beginning to understand a lot more about why that is and what to do about it. Actually, I’m writing a paper right now on these long-term sustained improvements, where we have people over a decade who’ve improved and then sustained their improvement, is really exciting to see.

Ari: I want to parse out a couple of things here that I think might be interesting and might be territory that I would guess you probably haven’t explored before with any other interviewer. You’ve described this process of downgrading, downsizing, getting rid, sort of culling certain circuits, and certain structures, and functions, and certain neurons in the brain, and saying, “Hey, we don’t need that, let’s do some resource conservation here, and try to engage mechanisms to conserve these functions because they’re more important, let’s get rid of these other ones.” In a way, this is–

Dr. Bredesen: [crosstalk]. Yes.

The influence of metabolic health and exercise on Alzheimer’s

Ari: This is the opposite of how beneficial hormetic stress leads to adaptations in the body that actually confer increased stress buffering capacity, increased resilience. The most simple example, of course, is if I lift heavy things if I create that demand on the system, I don’t shrink the muscle, it doesn’t downsize in response to that, it grows bigger and stronger to handle that demand.

If I do endurance exercise, we know that endurance athletes have 400% more mitochondria in their muscles compared to overweight people with metabolic syndrome or diabetes, for example, who don’t do endurance exercise. The body is engaging mechanisms to adapt to that stressor that confers an upgrading, an increased size and capacity, an increased robustness, and stress-buffering capacity of those systems that are being challenged. Can you parse out how it is the case and why it is the case that these particular kinds of stressors or forces that are acting on the brain are leading to the downsizing of the system rather than increased robustness and capacity?

Dr. Bredesen: That’s a great point. This is essentially a backup plan. What happens we see that, for example, if you normally have exposure to a pathogen, you have your innate system come in, you have a short period of inflammation, you then hand it off to your adaptive system, which now is going to go after the specific pathogen and part of the function of your adaptive system is to turn down the innate system.

Now what did we see with COVID-19? People who were dying of it were dying of cytokine storm. Their innate system would come in, but their adaptive system could not clear it, either because they didn’t have a lot of energetics, and that’s turned out to be a big issue. It takes a lot of energy to run your adaptive system, or because you’re overwhelmed. Unfortunately, COVID-19, the SARS-CoV-2 virus, actually has molecular mechanisms to prevent you from early interferon responses. You go for very little, very little response, and all of a sudden, oh, my gosh, I’m a wash in these viruses. That’s why you have this cytokine storm and why people die.

With Alzheimer’s, it’s cytokine drizzle. It is a long-term problem with mild inflammation. Now, you’re right. The first line is a more hormetic response, and that’s why, who gets Alzheimer’s? People who have metabolic syndrome, exactly what you just said. Who avoids it? People who exercise. Again, the problem is people keep saying, “Well, exercise isn’t a cure for Alzheimer’s.” No, it’s because you’re not looking at the whole equation. You’ve got to look at all the pieces. No question, exercise is a part of that, and no question metabolic syndrome is an important driver. It multiplies, in terms of time, three to five-fold your likelihood of developing Alzheimer’s.

Again, it’s this beautiful network. You have all these things happening, and they are mostly related to energetics and inflammation. There’s also some trophic support. There’s also stress issues. There’s also toxin issues. They again boil down to energetics and inflammation. You’re right, it is a response, but it’s a late response. It’s essentially saying, “My hormesis has failed. Now I’ve only got the resources to support this much, and therefore I’m going to have to downsize.” You can see immediately how to prevent it. You can see what we can do not to get to that stage.

Ari: Yeah. I should say that how the body adapts to stress is a specialty of mine. It’s the subject of my next book. I’m immersed in writing on this for about the last year now. I would say it’s a chronicity of stressors that are exceeding the stress-buffering capacity of that system such that it can’t adapt, and the only response now is to try to do its best to protect itself against the overwhelming force of these stressors that it can’t adapt to. Would you agree with that?

Dr. Bredesen: Yes. I would go one step further. Again, can’t go back to how this works at the molecular level. What’s really interesting, and, Dr. Alex [unintelligible 00:17:47] is one of my colleagues. We’ve worked together for many years and published a number of papers together. He’s pointed out that, again, if you look at amyloid, the thing that we vilify in Alzheimer’s as being part of the innate system, it is really even more part of the innate system that is innate system’s memory.

And was thought years ago, of course, you have an adaptive side memory where you have, your memory lymphocytes that are looking at, okay, are you getting exposed to measles again, or mumps or what have you? It used to be thought that there was no memory for the innate side. It turns out there is. Interestingly, amyloid is part of that. The innate system’s memory lives at three places. It lives in your bone marrow, it lives in your tissue macrophages, and it lives in your endothelial cells, which is, unfortunately, one of the reasons these people have increased clotting often and some microinfarcts as we see with COVID-19, of course. You have a situation where anything that can now tweak this memory.

For example, you have adverse childhood experiences, you’re now on high alert. You eat saturated fats, it’s inflammatory, you’re on high alert. So you’re going to respond, have a hyper response. If you are APOE4 positive, which is the most common genetic risk for Alzheimer’s, you are now on hyper-alert, is essentially you can look at Alzheimer’s as a chronic hyper response to these various insults. So stress plays a huge role in this, and in part, because it tweaks that innate system memory. Just as you’ve got someone, two people walk into a bar and someone looks at him wrong. The guy who’s had no ACEs is going to say, “Ha,” the guy who’s had a lot of ACEs and is on high alert is going to go punch him because he’s worried. He’s had that.

You see the same thing with dogs, for example. The little guys that are really worried, they’re going to get upset very quickly. To some extent, you want to take that system and bring it down. How do you do that? You remove the pathogens, you start eating polyunsaturated things like Omega-3s you get resolvents. Now you’re bringing this down so that you don’t have that hyper-response.

Ari: Great stuff. I want to integrate one more layer to this story. Also, it ties into this story of stress and stress-buffering capacity on the system. As I’m writing the chapter of my new book on the brain, I stumbled across a recent study from September 2022. I don’t know if you’ve seen this, but it’s called Demand Coupling Drives Neurodegeneration, and it says a model of age-related cognitive decline and dementia.

Basically, the gist of this study, maybe I’ll read one little section of it, they said, “In addition to not yielding effective treatments, the phenotypically heterogeneous biological processes that have been the primary area of focus to date have not been adequately shown to be necessary or sufficient to explain the risk and progression of Alzheimer’s disease. On the other hand, a growing body of evidence indicates that lifestyle and environment represent the ultimate level of causation for Alzheimer’s disease and age-related cognitive decline. Specifically, the decline in cognitive demands over the lifespan plays a central role in driving the structural and functional deteriorations in the brain. In the absence of adequate cognitive stimulus, physiological demand-function coupling leads to downregulation of growth, repair, and homeostatic processes, resulting in deteriorating brain tissue, health, function, and capacity.”

In other words, they’re saying that lack of cognitive demands is a key driver of the downgrading of the brain. This plays into how cognitive demands on that system might be seen in the same way that weightlifting, that exercise would be seen to upgrade the muscular system, or how lack of exercise, sedentary lifestyles, would be linked to sarcopenia and muscle atrophy. Do you follow what I’m getting at here?

Dr. Bredesen: Exactly. They’re just restating what Professor Michael Merzenich stated 30 years ago. Of course, Mike showed that essentially the disuse you’ve got a plasticity that’s going one way or another, it is back to the kind of use it or lose it, which is what they’re saying again. Again, I think that’s part of the story. It fits very nicely within what we’re talking about, but it doesn’t explain the whole thing. For example, the idea there would be, “If you have ALS, you just need to go lift weights.” That doesn’t work. And, “If you have Alzheimer’s, you just need to stimulate people more.” It’s not that simple.

There’s much more to this disease than just lack of use. There are pathogens and in fact, part of it is over-demand. When you have this ongoing inflammation, there’s a tremendous demand. When you’re trying to trigger your adaptive immune system, there is a high degree of demand. Actually, it is a piece of it, but it does not in any way explain this disease. It doesn’t explain– There have been over 150,000 papers published on Alzheimer’s. It’s clear, for example, that chronic infections, interestingly play an important role.

This is concerning to all of us because COVID-19 is in the wings now. So many of us have been exposed to it. I had it back in 2021, so I am at increased risk in the future for cognitive decline because I have had COVID, and so there’s this chronic inflammation, and hopefully, I have gotten rid of it. I don’t have a long COVID. I’m very happy about that, so hopefully my risk is minimal. You have to look at things like P. gingivalis. Having P. gingivalis, which is from your oral microbiome in your brain does not in any way represent a reduction in stimulation. It is a challenge. It is a pathogen. It is an inflammation. In that sense, it is increasing risk for cognitive decline.

I’d say that so many of these simple theories leave out many of the findings that are already known. Yes, in a certain area, very good. For some people, that may be the problem, but there are many other people where it’s about P. gingivalis, or it’s about herpes simplex or HHV-6A, or it’s about, interestingly, a hypercoagulable state, we see that fairly frequently, or it’s about mycotoxin exposure. There are all these things that have in common, that the energetics are reduced and or the inflammation is increased.

Ari: In this case, the question is, how much do you think cognitive challenge, like having a cognitively demanding life where you’re asked to use your brain to solve problems, to figure things out, to focus, to use your memory, to do things that involve solving challenges and problems, even if it’s something simple like crossword puzzles, this is the emphasis on doing things like Sudoku and crossword puzzles and some of these brain games that are now emerging. Given what you just explained, that there’s many layers of causation here of course, what percentage do you think is attributable to– or maybe another way of saying this is, how common is it for people who don’t have cognitively demanding lives? Is it more common for those people to develop Alzheimer’s than someone who is working into old age and doing cognitively demanding job, for example?

Dr. Bredesen: Yes, and that’s been known for years. Interestingly, it’s been attributed to cognitive reserve. It’s very clear that your level of education, as it goes up, decreases your risk for Alzheimer’s. Now the interesting point there is, let’s imagine that the people who are doing more, who have had more education, have been stimulating for longer, which is certainly not to say that education is always the way to stimulate your brain. There are lots of other ways. Let’s say that they have more synapses, they have a farther way to fall before they get to the point that you can recognize they’re not hitting on all eight cylinders here.

That actually makes some sense. You’re starting somewhere. Some people are going to start lower, some people are going to start higher, and then over time, of course, the ones that started lower are going to hit that threshold where you can notice something’s not quite right here sooner. Interestingly, it has been suggested by some in the past that when the ones who start higher finally do hit it, they actually tend to go downhill more rapidly. Again, if you graph it out, you can see why that would be, that the people who are up here by the time they finally get there because this accelerates with time.

Ari: Accelerates with age.

Dr. Bredesen: They’re now hitting it and they’re now have a more negative slope. I wouldn’t be surprised if that is indeed the case, but you have to have a certain number of synapses to keep things going. It also tells you the actual pathophysiology starts many, many years before the symptoms. It’s really important for us to remember just as people used to study diabetes and then they said, “Wait a minute, there’s a pre-diabetes and then there’s a pre-pre-diabetes where you have insulin resistance,” it’s the same with Alzheimer’s. There are things going on early on that lead to a diagnosis way down the road, and it’s been typically said at least 20 years from when you start the changes that’s been shown with a serial PET scans and with serial spinal fluid analysis until you get to the point where you actually have a diagnosis.

Now the good news is there are new blood tests and just as we all want to know our blood pressure, we all want to know our LDL particle number, things like that. Our lipid panel, our L-P-little-A, our Apo B, it’s also it behooves all of us to know our Alzheimer markers in our blood. The first ones that have come out are P-tau181 and Aβ42/40 ratio, and these tell you whether there is ongoing activity in your brain. A lot of people say I don’t want to know because I don’t want to know if I’m headed for it. Yes, you do want to know because you want to do the very things that you’ve been talking about. You want to have a mild stimulation. You don’t want to go crazy and stay up three nights in a row. That’s not good for you, but you want to have some stimulation. You want to do all the right things.

We have not had a single person yet who went on active prevention when they were asymptomatic and yet developed dementia. It may happen someday. We haven’t seen it yet. The people who then go, so there are four stages you go through. One is asymptomatic, the second stage is SCI, subjective cognitive impairment that lasts on average 10 years. As you can see, you have a tremendous window of opportunity. It’s just that people don’t do anything about it at that point. The SCI people, virtually 100% of these people get better when they go on the protocol that we developed.

Then the third stage– and this is why by the way, I tell everybody, if you’re 40 years of age or over, please get a cognoscopy, just as we know you should get a colonoscopy when you turn 50, get a cognoscopy if you’re 40 or over. Find out where you stand, and then now you can include P-tau181 and Aβ42/40 ratio. Pretty soon we’ll be able to include GFAP, which is even an earlier marker not as specific for Alzheimer’s, but it’s an early marker. So if it’s normal, you’re in pretty good shape because it’s such an early marker. It’s a marker of astrocyte activation, so you want to do this.

The third stage then is mild cognitive impairment. It’s too bad they called it that because it’s a horrible term. It’s like telling someone, “Don’t worry, you’ve only got mildly metastatic cancer.” It’s a relatively late stage of Alzheimer’s disease, the third of four phases. Now the good news in our trial, 84% of those people still improved even though they were relatively late. By definition, that means you’re now starting to do poorly on cognitive testing, whereas FCI you’re still able to score in the normal range, but you know something’s not quite right. With MCI, you’re not scoring well.

The Bredeson protocol for reversing Alzheimer’s

Ari: When you say improve, these people are actually having fewer symptoms or less degree of severity of the symptoms. They’re not just slowing down the progression, they’re actually reversing, correct?

Dr. Bredesen: So glad you mentioned that because the success with the drugs has been not to make people better or even keep them the same, it’s to slow their decline a little bit 27% for Leqembi. In our studies, we saw people actually improve and then they sustained their improvement, so what we’re saying is these people actually do get better. Their MRIs got better, their cognitive testing got better, their symptoms got better.

The judge from their partners, their spouses, or their significant others, was that yes, these people are definitely better, so in all ways, they were improved. Then the fourth, if you don’t do something about MCI, about 5% to 10% of those people each year will convert to the fourth and final stage, which is dementia. Where now by definition, not only are you scoring poorly on cognitive tests, but you’re having problems now with activities of daily living. Whereas with MCI, you can still do your activities of daily living, you can still drive, you can still balance your checkbook, you can still live, you’re just not scoring as well on the cognitive testing.

Precision medicine for dementia

Ari: Let me ask you this, in your protocol, what you would prescribe to someone with, let’s say MCI or early stages of dementia, or where you measure some of these biomarkers that you mentioned and you see that they’re elevated and you see that there’s APOE4 and there’s a risk of Alzheimer’s even if there isn’t a large presence of symptoms, and you prescribe a particular protocol for stopping the progression or reversing the progression into neurodegeneration and dementia. Are there, in your protocol, drugs that would be harmful to someone who doesn’t have any problems with neurodegeneration?

Meaning somebody who’s perfectly healthy, a 50-year-old person with no signs of dementia, if they followed your dementia protocol exactly as you outline it, would they suffer any ill effects or side effects from following your protocol, or would it be also healthy for them?

Dr. Bredesen: Great point, and I think it’s important for everyone to understand this. What we’re doing is called precision medicine. We are looking for each person, okay, do you have P. gingivalis? Do we need to help your oral microbiome? Do you have herpes simplex? In which case we should give you some Valaciclovir, which is a very benign drug and actually gets rid of herpes and dramatic reductions in risk for decline.

The answer is, no there are no problems except a couple of areas where you have to keep your eye on and say, “Okay, wait, is this the right thing for me?” Here’s what they are, first of all, when we treat this, we start with two pieces, so we’re going to do a core piece which is seven things for everybody. Just some of the things you mentioned, diet, exercise, sleep, stress, brain training, detox, and so many of us are exposed to toxins, it’s a huge issue, and then some targeted supplements.

These are all benign, so the main side effect of our protocol is better health. People are going to live longer, they’re going to have more energy, they’re going to have a better mitochondrial function, they’re going to have better sleep. They’re going to get rid of their sleep apnea, all these things. Then beyond the core, we’re looking at, what specifically? Okay, so for example, do you have exposure to trichothecenes? If so, we need to get rid of those. Do you have exposure to mercury? If so, we need to get rid of that.

Now here’s where we come into the things that could be borderline, people have to think a little bit. For some people, they have a hypercoagulable state, you can pick that up on genetics, and we treat them with nattokinase and or Pycnogenol, sometimes lumbrokinase. If you have a bleeding tendency, you don’t want to be on those things. You have to decide, am I more on the hypercoagulable side, or am I more on the bleeding tendency side? You wouldn’t want to take nattokinase if you’re on to that.

The other thing that, again, you have to decide is bioidentical hormone replacement. If your hormones are low, you’re going to do better with your cognition, because again, this is a network insufficiency, by having the appropriate levels of estradiol, progesterone, testosterone, pregnenolone, DHEA, all those neurosteroids. Again, for people who have breast cancer, for example, we have to be very careful about which ones and for how long.

I do think the future is going to be combining precision medicine, personalized protocols that we’ve been doing, with specific drugs. In fact, in the lab, I work with Dr. Vargas John, for years and years, we set up the Alzheimer’s drug discovery network way back in 2007. There are some very exciting new classes of drugs coming out from there that I expect will be part of the future. Again, you want to know, when you do something that is non-physiological, and any drug is non-physiological, you have to look very carefully, what are all the things I’m doing to this system? We want to do as much as we can physiologically. You talked about stress earlier, critical part of physiology. It’s important to have it when you need it. It’s important to not have it chronically, as you know.

For these drugs, you want to be very careful. As an example, inhibiting the cleavage of APP to go toward the side of downsizing, you can do that mildly and help to do better, but you don’t want to shut it down because it is there to respond to pathogens. Again, I think in the long run, we’re going to be able to do better and better and better with really addressing all of the things that are driving the cognitive decline, we’re already getting unprecedented improvements, that I think we’ll be able to do better and better and better.

For example, we’ve had people go from MoCA scores, MoCA’s go from 0 to 30, it’s Montreal Cognitive Assessment. We’ve seen people go from 18, which is the fourth stage, early dementia, all the way to 30, which is a perfect score. We’ve seen people go from 0, which is end-stage dementia to 9. We’ve never seen anyone go from 0 to 30, that’s the goal. We’d like to be able to take someone who’s in the end stages of dementia and make them normal again. Hasn’t happened yet, it’s probably going to take some stem cells, it’s probably going to take some intranasal trophic, peptide support, we don’t know yet but that’s the goal.

Making normal cognition better

Ari: Okay. As someone moves more and more, as you were just alluding to there, as someone moves more and more into the disease state, we see more and more layers of dysfunction in more and more physiological systems. More things are out of whack basically, and to the degree one tests for it, in somebody with severe Alzheimer’s, you could probably find almost as many layers of dysfunction as you’re capable of testing for. With the emergence of things like metabolomics technology, where we can test for thousands of metabolites instead of just the 50 or 100 or so that are commonly tested for, I suspect we’ll probably find hundreds or thousands of more layers of things, pattern, different biochemical and cellular mechanisms that are dysfunctional in the gut, in the brain, in the muscles, in the blood, wherever you test for it, I suspect you’d find it if you’re capable of testing for it.

I think you could probably go endlessly down that pathway of precision personalized medicine, especially in the context of somebody with severe disease, and come up with lots and lots of different specific ways of treating all the things that you find that are wrong in that person from, as you said, their oral microbiome, to their gut microbiome, to their leaky gut, to neurotransmitter imbalances, to nutrient deficiencies and lots and lots of layers to that story. But let me ask you this going back to my previous question, let’s say you applied your generic protocol, the non-precision, personalized one that you would apply to someone that you’re working with one-on-one and actually doing tests for. Let’s say you took, just as a thought experiment, all 40-year-olds on the planet, and they followed your generic protocol. Would that mostly eliminate the problem of dementia and Alzheimer’s disease?

Dr. Bredesen: You’ve hit on so many good questions there because this is about making normal cognition better. The beginning answer to your question is, number one, they would mostly get better cognition. All of us are operating with the vast majority of us, suboptimal cognition. We could do better if we did those basic things. If we had better metabolic flexibility, which so many of us are losing in our 30s, 40s, and 50s. So much better. If we found that we had mild hypoxia and a nocturnal SpO2 was decreasing, so that the beginning to answer is yes, just about every would be better.

Second piece, though, is you’re getting to what we have proposed, which is how does public– Let’s say that we decide. There’s a cancer moonshot from President Biden years ago when he was vice president. I’ve been surprised there hasn’t been an Alzheimer’s moonshot. It would be great. We can do so much better with Alzheimer’s than we could just 5, 10 years ago.

Let’s say that we set up an Alzheimer’s moonshot. We said, look, we’re going to make it so that as few people in the world develop Alzheimer’s as possible. We can’t do a million-dollar workup on every single person. What we’re going to do is just what you suggested. Everybody is going to do the basics. When you turn, let’s say, 40, you turn 40. You could start at 35, but let’s say you’re going to start at 40. You’re going to do the basic seven, you’re going to make sure you do the right things. The vast majority of those people will never develop Alzheimer’s, but a few of them will. Now, those people go to the next phase, and we catch them at the SCI phase. Now, they’ve taken that next.

By the way, their GFAP will be available soon, but you can now follow their pTau-181. I was fascinated by a woman who had a pTau level when it was just becoming available and actually tried to do some of our protocol and did pieces of it, not everything but pieces. She went back and got it tested it again, and it was lower. Fantastic. It’s showing, the signaling is now moving. You’re going in the right directions. The idea would be that this would be a multi-tiered public health approach, just as we think of with vaccinations, but here you don’t have to have a jab. You just go and you do the appropriate things. Then what you do is once a year, you test your cognition.

Most people are going to do great, but a few of those people are going to fall through the cracks. Something didn’t go right. They had exposure to something. They had the wrong genetics. They did the wrong things. They had undiagnosed sleep apnea. They had a leaky gut that they didn’t know about. Sensitivity to something, a chronic pathogen. Okay, they’re going to fall through the cracks. Now, those people have a more extensive evaluation, more extensive treatment. Most of those now are going to be fine. A couple of those people will still go the next stage, so we want to still catch them. They’re going to be continuing in their SCI. We catch them later. Now they have a more–

The goal then is nobody– and I’ve been saying to people recently, Alzheimer’s is now optional. If everybody were to get on appropriate prevention or earliest reversal, virtually nobody has to become demented. Think about that for a minute. We’re talking about dementia, which currently costs the US over $300 billion a year. The average person spends his or her own money, $350,000, before dying of Alzheimer’s. Of course, most of that is in nursing homes and nursing care and things like that. Spending much, much less than that, you can make sure that you never get it, and everybody should.

Ending the Alzheimer’s pandemic?

Ari: That’s really what I’m getting at is, to some extent, going back to the initial thing we were talking about, this is a matter of paradigm. Is the Alzheimer’s epidemic–? Should we treat it in the way we think about this problem? Should we treat it as a deficiency of drugs that we haven’t yet found and that the real problem is that we just haven’t synthesized the right chemical in a laboratory that will interfere and block these pathways in the brain that lead to this disease?

Alzheimer’s, are we thinking about it as a deficiency in a pharmaceutical, or are we thinking about it as a breakdown of health, a breakdown of the optimal physiological function of the various systems of the body, because that’s what your formula is really all about. You’re teaching people– You’re not saying, “Here’s the drug to fix your Alzheimer’s,” you’re saying, “Here’s the program to make your body and brain healthier,” which happens to result, and we can look at the mechanisms at the level of the brain as they relate to Alzheimer’s. One of the effects, one of the many, many physiological effects of that program is that it also happens to prevent dementia at the same time as it prevents dozens of other diseases. Is that correct?

Dr. Bredesen: Absolutely. You started this whole discussion by talking about paradigms, and I couldn’t have said it better. This is about paradigms. How do you look at health? How do you look at medicine? I came from the old-fashioned paradigm and was trained in the old-fashioned paradigm. What’s the drug we’re going to get that’s going to get rid of Alzheimer’s? That’s a tall order. Man, what do we start thinking? Now when you look under the hood and you start looking at what’s everything, how is it connected? I think of this as the medical internet. Back in the 1960s, DARPA said, “Hey, we can all connect up our computers. We can communicate,” so communication, information, recreation commercialization, this has all happened through the birth of the internet going way back to the 1960s.

Well, now what’s happened is we’re seeing the medical internet, which is that the many, many nodes of interaction between your gut and your brain and your pancreas and your liver and your bones, all these things are connected with this amazing, beautiful physiological internet. That now they’re all connected, and so what we’re saying is, what’s happening with these connections? Why? You have to ask why. In the medicine I learned in the 20th century, it was about what it is. We learned to make a diagnosis. It’s measles, it’s a broken leg, whatever, and then we try to fix it. The 21st-century medicine is about why, not what. Why is it? Yes, you have some drugs. If you want to use them at some point, fine, but remember that they’re going to mess up physiology, so be careful. Use them appropriately at the right amounts in the right ways.

The bottom line is you want to know why. It’s been so surprising to me. If you look up functional medicine on Wikipedia, it basically says this is hokey stuff that doesn’t work. Oh my gosh. Jeffrey Bland is a hero. He created a new way, a new paradigm of understanding medicine by saying, “Let’s look at what causes the problem, the root causes.” If you’ve got hypertension, don’t just take a calcium channel blocker, figure out why you have hypertension. Maybe you’ve got some unresolved stress issues. Maybe you’re eating too much sugar. We’re learning the molecular mechanisms of these.

I would add one more thing, which is so common. Professor Rick Johnson has done beautiful research over the years, and Dr. David Perl Mutter has published a nice book on this called Drop Acid. The point is that when you have fructose exposure, it fits exactly with our model, the fructose, as Rick showed, is telling your body, “Winter is coming, drop your ATP levels, drop your energetics by about 15%.” Well, when you’re developing Alzheimer’s, nothing could be worse than dropping the support to your brain, so you’re getting ready for hibernation, you’re dropping these things down. Strangely, fructose actually decreases your energetics and contributes to your likelihood of developing cognitive decline.

You’re absolutely right. You have to change the paradigm. You have to address what’s actually causing the problem.

How sugar impacts health

Ari: How much do you think that relates to consumption of fruit versus things like high fructose corn syrup and soda and other processed foods?

Dr. Bredesen: Well, as Rick points out it’s 99% about high fructose corn syrup and other things, because fruit has the appropriate fiber in it.It has all sorts of wonderful nutrients. As he pointed out, the only time fruit activates this is when you’re an animal that’s eating 200 pieces of fruit, because winter’s coming. Yes, okay, in that case, but for those of us who are eating fewer than 200 pieces of fruit, we’re not going to have a problem. Eat an apple, it’s not going to hurt you. Eat some berries, not a big deal. To be fair, you start eating fruit, you can see yourself coming out of ketosis. You can also check your ketone levels with breathalyzers or with or with blood stick, and you can see, and you may have to adjust a little bit.

What you really want is that metabolic flexibility. Again, another thing taught to me by my integrative physician wife, when I was first telling her that, “Hey, we got to get these people into ketosis,” because when you look at their energetics for their brain, it really has to do with four things. It has to do with their oxygenation, it has to do with their cerebral blood flow, it has to do with their mitochondrial function, and it has to do with their ketone levels.

Her point was, no, wait a minute, it’s the ability to burn both, and unfortunately, as you know, you can burn ketones or you can burn glucose, but as we become insulin resistant, we lose both of those because the high insulin levels make it so you can’t make ketones anymore. When I see patients with cognitive decline, to me this is an energetic emergency. I get them going initially on just exogenous ketones, just at least give them back part. Then we make them insulin sensitive, and then we make them so that they’ve got wonderful metabolic flexibility and they do very well.

Is ketosis good for brain health?

Ari: How much do you think ketosis is a necessary part of this eating a ketogenic diet, and is it specifically necessary in the demographic you just described, in insulin-resistant people more so than it is in the general healthy population, non-insulin-resistant people?

Dr. Bredesen: Yes, it is a good point. It depends on where you catch it. Again, when we see people, they’ve usually lost both, and you need to restore both. You need to be able to make ketones at the appropriate time. You need to be able to be insulin sensitive. Now Dr. Anne Hathaway gets her patients into ketosis very quickly. I worry if you push too hard because again, this is an insufficiency, but it’s an insufficiency born of excess sugar in many people’s cases and excess simple carbs.

I worry for frail people about going into fasting too quickly. This is why I like Professor Steven [unintelligible 00:52:00] approach of just start with some exogenous ketones. At least you’ve given them some energy. The answer to your question is for people who are asymptomatic, you don’t need to worry about that. You just need to optimize things for them. For people who are already struggling, any day that they have without those energetics is a bad day. They are going to continue to downsize.

That’s why I just say, just start with some exogenous ketone, get them some energy. Then it takes a few weeks, as you know, to get into it. By the way, exercise is an important part of this, getting those energetics back, becoming insulin sensitive again. Then you can ease them into endogenous ketosis. As long as you’re flexible, you’re in great shape, but again, when you’re having trouble, you’ve typically lost both of those avenues.

Vascular dementia and neurodegeneration

Ari: Talk to me about the vascular aspect of dementia and neurodegeneration. I know that there’s something called vascular dementia, but this has also been implicated that the vascular supply issues are also implicated in lots of other types of dementia so there’s a lot of overlap. Tell me about that aspect of this story and I assume it probably also relates very strongly to exercise and cardiovascular fitness.

Dr. Bredesen: By the way, we’ve had a number of people, when we introduced them to EWOT, exercise with oxygen therapy, where you’re now getting better blood flow and better oxygenation, they improve dramatically. It just shows you, yes, we’re on the right track. This is about energetics, this is about inflammation. We see that as well when people go on resolving.

When I was training, we were taught to calculate something called the Hachinski score. It was a thing where you’d look at people and say, okay, did they have a sudden stroke-like decline? Okay, then that means it’s going to be one point for vascular. Did they go down slowly? Okay, that’s one point for the nonvascular. There was this idea that you had vascular dementia or you had Alzheimer’s. As you indicated, yes, there are people that have a pretty much pure vascular dementia, but for most people, it’s not that simple. You have some degree of vascular compromise that is part of Alzheimer’s disease. You see it all the time, and improving vascular support helps Alzheimer’s, and making it worse, makes Alzheimer’s worse.

As I mentioned earlier, we see a number of people, and especially some of the younger ones, where they have an undiagnosed hypercoagulable state. They may have Factor V Leiden or they may have changes in some of their clotting factors, for example. They may be people who are doing a lot of work where they’re going in planes for many, many hours with lower oxygenation, with sitting still, and they’re actually getting microthrombi. They may have had COVID. That’s one of the important reasons for microthrombi. All of those things contribute.

Absolutely this is a part of the disease, and targeting it is part of it. Interestingly, some very important work out of University of Southern California. Professor Savkovic and his group have shown that abnormalities and changes in the vasculature of the brain are some of the earliest changes you see in Alzheimer’s. From all those perspectives, vasculature and vascular support in Alzheimer’s is huge. Of course, we talked earlier about where does the innate immune systems memory live? Part of it is in the endothelial cells, and it does give you a more coagulable state. By the way, where do you see amyloid? One of the places you see it is lining the vessels. One of the things, as again my colleague Dr. Aleksey [unintelligible 00:55:55] has pointed out, it is a flocculent. It is actually patching areas in the blood vessel that are leaky.

Again, these things, you have to remember, this is not black and white. This is your body trying to do the right thing. Unfortunately, at some point, it gets to a pathophysiological consequence. We need to go upstream, be physiological to undo the things that are driving this process.

Ari: How much of that vascular story relates to whether you’re sedentary or whether you have a high degree of fitness and exercise regularly?

Dr. Bredesen: Oh, absolutely, a fair amount of it. Could I give you a percentage? I don’t know. I think what I can tell, here’s the way I could give you an estimation of the importance of it. A study was done years ago that showed, here’s the degree of change you get with one copy of a APOE4. If you have zero copies of a APOE4, and that’s three-quarters of the population, your lifetime risk is about 9%. If you have one copy, and that’s 75 million Americans, most don’t know it, you should find out because you can address it, your chance goes up to 30%. If you have two copies, your risk goes up to about 70%. Most likely you will get it. Helpful to know you can absolutely prevent the problem. Julie G, who’s one of the people with APOE4, has done a great job, has founded a website, which is called apoe4.info.

What was found in this study, though, was that the magnitude of the effect of exercise to reduce your risk was about the same as the magnitude of one copy of APOE4 to increase your risk. That’s a big effect. In fact, exercise has a large effect on the prevention of cognitive decline.

Oxygen delivery and hypoxia for brain health

Ari: I would also be curious to know what specific exercise intervention they did because one of the things that’s rampant in exercise intervention studies is they do very inadequate exercise protocols. Very simple, like two times a week of 30 minutes of very gentle activity, something that’s totally inadequate, and you still see massive reductions in risk of diseases, even based on those inadequate exercise protocols.

Dr. Bredesen: This is, again, why I think the mechanistics are so important. What are you actually doing? When you do strength training, as you know, you are doing a number of things. You’re improving your insulin sensitivity. Interestingly, you’re increasing your ketone levels, which then go to the brain. Interestingly, these enter the brain, and one of the things they do is impact specific histones that reduce the ability to inhibit the production of BDNF. Now, the exercise is ramping up your brain-derived neurotrophic factor, which is a very important anti-Alzheimer’s effect. There are intimate relationships between BDNF and APP signaling, it’s really remarkable.

These things are critical. Again, you get now aerobics, you’re increasing blood flow, you’re increasing oxygenation, you’re improving vascular tone and status. Then, of course, hit is another good one. By the way, the reason I like EWOT so much is because it is hitting multiple mechanisms. You’re now improving your ability to do exercise. You’re also improving your blood flow, and you’re also improving the oxygenation going out to the far reaches of the brain, which haven’t seen optimal oxygenation, perhaps, if you’ve had a sedentary lifestyle. It’s also the reason that I’m so interested in making sure that each person doesn’t drop their SpO2 while they’re sleeping.

People who have sleep apnea or upper airway resistance syndrome. So commonly I hear people say, “Oh, this person, they don’t snore a lot. They’re probably okay.” Had a patient just recently who did very well for six years, APOE4 amyloid-positive PET scan, unquestionable Alzheimer’s. Got her MoCA score up to a perfect 30. Did beautifully, and after six years, started to have some problems. We said, “Something’s been missed.” We started looking. She did have some mycotoxin exposure, but to my surprise, and what had been missed before, was she had severe sleep apnea. Addressing this, boom, she’s doing better again.

This is not magic, it’s just biochemistry and genetics. You’re looking at these things and exercise, no question, is a critical. All the different kinds of exercise, you’d like to do all of them at some point. Of course, you want to move up to it slowly, you don’t want to give yourself a myocardial infarction on day one.

Ari: You mentioned EWOT. I just want to mention a couple things to you that you might be interested in exploring. One is intermittent hypoxic training, which is essentially the opposite, but with a hypoxic air machine. Vince Giuliano, I don’t know if you know him, he’s a longevity researcher, physician who’s now in his 90s still working hard on this. He’s exploring and they’re finding amazing results that he’s raving about with what he’s calling [unintelligible 01:01:18] oxia which is alternating between exercise with oxygen therapy and intermittent hypoxic exposures as you do the exercise. They’re finding it– the way they describe it is that it pops open the vasculature and really, really causes a lot of adaptations in the vascular supply of the brain and the other tissues.

Dr. Bredesen: This is a very good point, and I’m well aware of this work. This work out of Israel where they showed that with– In their case, they were using HBOT, hyperbaric oxygen. I like EWOT in part because it includes the exercise component, and I think that’s an important piece of this, but I recognize some people are getting good results with HBOT as well. What they showed was you take up the HBOT, and then what they said was, “You get the best of both worlds.” You give the oxygen and then you simply let it drift down toward normal. That is a relative hypoxia to where you just were. You’re never truly getting hypoxic. I worry in patients about giving them hypoxia because already they have a problem which is a network insufficiency.

What I would say to people who want to do true hypoxia, if you’re asymptomatic and everything’s good, fine. Do some of that. That’s training for bicycling in the Alps, that sort of thing, or in the Rockies, fine. If you are already having symptoms, let’s wait till we get your MoCA back up to 30, everything’s great, then do a little hypoxia. Until then, just do the relative hypoxia where you go from high to normal. That’s good enough.

It’s the same thing I worry about with too much fasting in someone who’s frail. You’re starting with a pathological situation. There is frailty there. The system is falling apart. I don’t want to do anything to make the system fall apart more quickly. When I’ve gotten it to be resilient, everything’s great, then challenge it a little bit. For now, someone’s coming into me saying, “I can barely make it. My brain is literally dissembling.” I don’t want to say, “Well, you know what? We’re going to challenge you harder and make it disassemble quicker.” Again, I think that’s for people who are asymptomatic or people who have now become asymptomatic. For the others, I want to be very careful about pushing them too hard.

Mitochondrial function

Ari: You never want to take somebody who’s been sedentary for the last 10 years and tell them to go run a marathon. The Goldilocks zone of what is the appropriate dose of a challenge to their system, whether it’s their body, their muscles, with exercise, or with fasting, or with cognitive challenges, or EWOT, or hypoxia, is that zone shrinks to a very small zone of an optimal dose when the person has a lot of symptoms or is already in a state of chronic disease, as you’ve described, so agreed.

You’ve mentioned bioenergetics a lot. At the beginning of this discussion, you mentioned energetics and inflammation, mitochondria being a big part of this story. I’m wondering what your main approach is to improving mitochondrial health in the brain. What specific things maybe you find most effective or how would you describe maybe how your protocol works to improve mitochondrial health in the brain?

Dr. Bredesen: Great point. Again, you have to look at where are these mitochondria living? What are they asking for? Like everyone else, I start with supporting the mitochondria. Things like ubiquinol, although it was very interesting to me that the paper that came out showing that ubiquinol basically just gets oxidized to CoQ. Whether you’re taking ubiquinol or you’re taking CoQ, you’re going to end up with CoQ, which is then going to be reduced to ubiquinol. I think that’s interesting.

Then increasing your NAD levels, whether you like NMN or whether you like nicotinamide, riboside, or niacinamide, there are multiple ways to get that NAD level up. Then, of course, there are co-factors like vitamin B6 and things like that. I use a standard– Dr. Roundtree has a great list of things that are supportive of mitochondria, and I like his list. That’s the first piece.

The second piece is, yes, you’ve got to have the blood flow. You’ve got to have the oxygenation. My argument is a lot of us are having mitochondrial poor function because we’re simply not delivering the blood flow and the oxygenation that you need. It’s like having a plant and you are giving it all sorts of great food and then not exposing it to the light. You’re going to kill the plant anyway. You want to make sure that it has the appropriate oxygenation.

So many people– There was a beautiful paper years ago showing if you just look at the average SpO2 through the night, that correlates beautifully with the size of your hippocampus and other nuclei in the brain. Look, if you’re starving your brain for oxygen all night, which so many people are, your hippocampus is going to shrink. Let’s get that up, let’s get the blood flowing. Let’s get the oxygenation. That’s critical. Let’s give you the ketones that you need at times. Let’s make sure you are– If you look at this, the metabolic flexibility, it’s largely about care and feeding of your mitochondria.

Then the other piece of this is these things all doing all the right things don’t help you that much if you’re sitting there living in mitochondrial toxins. So many of us are. What is Parkinson’s? A big part of Parkinson’s is mitochondrial complex 1 inhibition. If you’re exposed to paraquat, if you’re exposed to MPTP, if you’re exposed to trichloroethylene, if you’re exposed to a number of the mycotoxins, you’re poisoning your mitochondria. It’s about supporting them. It’s about giving them the oxygenation and the blood flow. It’s also about, let’s get rid of the toxins that are sitting in there.

There’s some nice work out of Igl out of Germany where they’re looking at epigenetics. I do think epigenetics going to be so helpful to us in the long run as they get better and better and better. We already have things, we’re looking at biological aging. By looking at the epigenetic programming, you’re going to be able to say, “Look, this program is the program we see when people are exposed to trichothecene A, whatever, what have you. There are already a little bit of that going on with Igl looking at what toxins are actually sitting on your DNA. Now we’d like to know what toxins are affecting your mitochondria, and what pattern does that lead to?

As we do this, now we’re looking at all these things that you and I have been talking about, we’ll get better and better. We’ll be able to focus more and more and say, “Look, this is the main one or two things that are driving this person’s cognitive decline.” Now, we’re dealing with 5 or 10 or 15 things, but it will ultimately be able to say, “This is the thing that’s driving this person, and if we just get rid of that, they’re going to do pretty well.” I’m very excited about the future of epigenetics because I think it’s going to get better and better and better at telling us what’s driving this.

Those are the sorts of different pieces that we use to make sure that your mitochondrial function is optimal. You’re absolutely right. One of the big problems we have is there’s not a simple way. Now we can look at P-Tau and things like that. There’s not a simple way to say, “What is wrong with your mitochondria? Tell us exactly what’s wrong. Is it a complex one? Is it a complex four?” You got to do some pretty sophisticated biochemistry to get there. I would love it if you can now do a simple clinical blood test and say, “Aha, this is because of poor oxygenation, whatever.

Ari: To add to that complexity of testing for mitochondrial function, one of– the big challenge is it’s not just whether the mitochondria that are there are highly functional or not highly functional, it’s that they literally atrophy and die off. As I mentioned earlier in this discussion, if you look at athletes who are doing lots of endurance exercise, they have 400% more mitochondria in their muscles than somebody who’s got metabolic syndrome and who’s sedentary. The main way you assess it is by sticking a hollow needle into somebody’s muscles and taking a biopsy and looking at the mitochondria under a microscope, which is not a fun test for most people to do.

Dr. Bredesen: Exactly.

The latest research on the Alzheimer’s drug efficacy

Ari: I’m often struck, I’m reading Peter Attia’s new book on longevity right now. Your book, I would also put in this category. It’s like MDs who spend such a long time studying pathology, studying disease, and pharmacology, the drugs that one prescribes for those disease states, ultimately ending up in a place where now what you’re really doing is teaching people about health, which isn’t even something that you learned about in medical school, ironically. You’re teaching people about nutrition and exercise. For most MDs, they didn’t even take a single class on those things.

It’s an interesting transition to go from realizing that the most potent medicine in existence for disease prevention and extending longevity isn’t one of the 19,000 FDA-approved drugs that have been developed over the last century of hundreds of billions of dollars of medical research. It’s moving your body vigorously for 20 or 60 minutes every day, which is an interesting place to end up after decades of studying the mechanisms of disease.

Dr. Bredesen: You’re right. We have to go from the current approach where we call things by pathology. Alzheimer’s disease is just pathology. You look under the microscope, you see the plaques, you see the tangles. You say, “Ah, Alzheimer’s disease.” You see the loss of synapsis, that sort of thing. We have to now move this to a model of pathophysiology and physiology to understand what changed from normalcy, from normal homeostatic principles. What changed?

I do think the pharmacology will be much more successful when it is applied in an appropriate physiological way. When we say, “Okay, we’ve done all the things we can do with the basics. Now we’re going to just have to tweak a little bit at this APP base cleavage, or at the tau phosphorylation stage,” things like that, instead of moving there immediately. You really want to understand the disease principles. That’s what’s driving us back to exercise and sleep and some of these basic things.

Ari: The last thing I want to finish on is a point that we’ve touched on at various times in this conversation, but I really want to emphasize for people to get this as a take-home point. I know there was a scandal that came out recently with regards to the Alzheimer’s drugs. I would maybe like you to touch on that a bit first, but what I really want you to do is talk about the bottom line of the efficacy of the drugs that have been developed to treat Alzheimer’s disease.

We’ve had decades of research and development of, I assume, hundreds or thousands of different potential compounds to try to combat the mechanisms of Alzheimer’s disease or what we think are the mechanisms. A lot of them have been based on combating amyloid plaques. What is the efficacy of those drugs, and how does that efficacy compare to the efficacy of your lifestyle-based treatment approach to Alzheimer’s?

Dr. Bredesen: I would say what we do is not just about lifestyle, it’s really about precision medicine saying what’s causing the problem. I have a nice graph that just shows you, you go down on average three and a half points per year on a 30-point scale if you have no treatment. If you have treatment with one of the drugs, such as Leqembi, that slows that by 27%, almost not at all. Very minimal effect. You don’t get better, you don’t stay the same. With that, you are likely to have some brain bleeding or some brain swelling. There were a few deaths as well. You’re really accepting these horrible side effects for something that has a minimal impact. It’s because of what you said earlier, the paradigm is wrong. You’re going after a response to the problem, not the problem itself.

In our studies, we actually see people improve, and as I mentioned earlier, the most important thing is we have people who have s`tayed improved for over a decade now, which is completely unheard of. People, it is because we’re getting at what’s actually causing the problem, and you see people actually improve. Now, when you mentioned scandal, I wasn’t sure which scandal you meant because there was a scandal about amyloid, as you’ll recall, out of the University of Minnesota, and actually from a superb professor there. It looks like one of the postdocs was doing some questionable reporting on the results.

That was one scandal, but then there was a second scandal with one of the drug approvals, where there were some backdoor discussions with the FDA that were inappropriate and ignoring data, all sorts of things. No question, when hundreds of billions of dollars are at stake, you cannot expect people who stand to gain billions and billions of dollars, you can’t expect these people to go buy the book. They’re not going to. They’re going to do everything possible. We’ve seen a lot of that.

As we report these positive results without the drugs, everything is done to marginalize these, to push back, to say that this is crazy, on and on and on. What we’re showing is head to head, the approach we’ve taken is far, far superior to the approach. Again, in the long run, there’ll be some sort of combination that will actually make specific drugs work much better.

Ari: Dr. Bredesen, thank you so much for your time. Thank you so much for the work that you do. I really appreciate it. I think you’re doing amazing work. I’m very much honored that you came on to the show to have this discussion. It was an absolute pleasure. Let people know where they can follow your work, get in touch with you to work with you, or wherever you want to send them.

Dr. Bredesen: Let me just before we end say, we’re just starting a clinical trial, randomized controlled trial at six sites. It’s in Miami, Nashville, Cleveland, San Francisco, Sacramento, and [unintelligible 01:17:09] Bay. Just six absolutely fantastic physicians, Dr. Christine Burke, Dr. Ann Hathaway, Dr. Kat Toups, Dr. Nate Bergman David Haase, and Craig Tanio. Very, very excited to be working with the six of them, just fantastic, integrative, and functional medicine physicians who have gotten excellent results with people with cognitive decline.

You can see more about this at Evanthea Dementia Reversal Trial. You can see more on my work in the books you mentioned, The End Of Alzheimer’s, The End Of Alzheimer’s Program, and The First Survivors of Alzheimer’s. You can also see on Facebook live and Facebook at Dr. Dale Bredesen. Again, appreciate you having me on. We all need to get the word out. Alzheimer’s is now optional. Let’s not continue this ridiculously high rate of dementia that we’ve been suffering for years.

Ari: Thank you so much. I look forward to our next conversation.

Dr. Bredesen: Thank you. I do as well.

Show Notes

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Links

Book: The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline

Book: The End of Alzheimer’s Program: The First Protocol to Enhance Cognition and Reverse Decline at Any Age