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Episode 5 – Dr. Dale Bredesen and Dr. Craig Tanio on the Prevention of Cognitive Decline

Podcast The Rezilir Way

Hosted By:

Show Notes

Dale Bredesen joins the podcast for the fifth episode in our series, to talk about multimodal outcomes in Alzheimer’s patients to neurodegeneration, new therapeutics for Alzheimer’s. Getting to the root of what is flipping the switch and changing how we approach treatments and navigating the modes of the brain. What do you have to do, to get someone better? How do we diminish things failing over time? Dive deep as Dale Bredesen takes us on a thorough journey into increasing our understanding of Alzheimer’s.

 

– (2:00) Watching things change in exciting time. Dale’s background and his interest in why and what exactly goes wrong in the brain. The last thirty years in his lab. The breadth of the Alzheimer’s pandemic.

– (7:45) Entering clinical trials and persistence in finding the right drug. Getting a new view of Alzheimer’s. Identifying the contributors to target.

– (12:15) The difficulty in making things feasible. What’s actually driving the problem? Discoveries in changing APP. How can too many variables restrain a multi-variable issue? Getting on the right track.

– (17:30) Gathering anecdotal evidence. Looking forward to new drugs being tested. Opening up the dialogue on changing paradigms. Embracing functional medicine.

– (22:00) Acquiring a higher understanding to produce functional outcomes. Creating a registry. What are the critical pieces in all of this? Making Alzheimer’s a treatable problem.

– (30:20) The insulin factor and the branching paths toward cognitive decline. The six types of Alzheimer’s. Beta-Amaloyids.

– (40:00) Getting the resilience back. The reverse approach of how clinical trials are performed now. Gathering data to redirect where we are thinking. Manipulating our neuro chemistry.

– (51:00) The Ark Project. Difficulties with ALS.

– (55:00) Macular Degeneration findings

– (1:03:00) Lifestyle and dietary changes that can determine where an individual is in the protocol. All the different pieces that help in data. Using better technical logic to improve patient outcomes.

– (1:05:00) Diet and what seems to be working best. Getting you into ketosis and beyond.

– (1:08:30) Detoxifying and getting what we need daily.

– (1:13:00) Implementing the protocol.

– (1:25:05) The way forward and opening new modalities.

Transcript

Dale Bredesen:
We started to get these larger data sets on people. We said, “Okay, we’ve got to look at their inflammation, and we’ve got to look at their insulin resistance. We’ve got to look at the pathogens and the toxins and the vasculature.” We started realizing: “Ah. We’re seeing profiles where the main problem is …”

Jacob Gordon:
Wouldn’t you like to know? Well, you’re going to find out today in this episode. Hey, guys, and welcome. You’re listening to The Rezilir Way, with Jacob Gordon. I’m your host, Jacob, and I’m so excited to have you here today. On today’s episode, I have Dr. Dale Bredesen. He’s an internationally recognized expert in the mechanisms of neurodegenerative diseases such as Alzheimer’s. He’s held faculty positions at UCSF, UCLA, UCSD, and directed the Program of Anti-Aging in the Burnham Institute, before starting the Buck Institute. He is currently renowned for his latest books on reversing Alzheimer’s disease and preventing neurocognitive decline.

Jacob Gordon:
I’ve personally incorporated some of his ReCODE Protocol into my daily life and wrote about it, as well as all the mechanisms, on my website: MyBioHack.com. Today, Dr. Craig Tanio, Dr. Dale Bredesen and I will all be discussing multi-modal approaches to neurocognitive decline, his latest research study on Alzheimer’s disease, his upcoming books, mechanisms into Alzheimer’s disease, ALS, Parkinson’s disease, macular degeneration, and much more.

Jacob Gordon:
I had a fantastic time interviewing Dr. Bredesen and be sure to stick around until the very end. So, without further ado, let’s get started. Hi, Dale.

Dale Bredesen:
Hey, Jacob.

Jacob Gordon:
Thanks for being here with Craig and I.

Dale Bredesen:
I’m excited to be here. Thanks very much.

Jacob Gordon:
We’re very excited to have you here on the show today. I’ve followed your research for quite some time now and I know Craig has been practicing with you, so we’re both really happy to have you here on the show.

Dale Bredesen:
Great, thanks. This is an exciting time, I think, for all of us, watching things change. For the way people are treated for multiple different chronic illnesses, this is just a very exciting time.

Jacob Gordon:
It is a very exciting time. Craig and I, for the sake of our patients, we’d like to know a little bit more about you: who you are and what kind of research you’ve done, a little bit about your story.

Dale Bredesen:
Yeah, sure. So, yeah. I was very interested, actually, in mathematics when I was a kid. So, I went to Cal Tech and actually worked at MIT also, and got interested in the brain. When I was a freshman, I read a book called The Machinery of the Brain, all about how the brain is similar to a computer. I got very interested, and then ultimately interested in why the brain goes wrong, why you get these various diseases.

Dale Bredesen:
Of course, it turned out … When I went to medical school, and then neurology residency, then neurology fellowship to study neurogenetics and molecular neurobiology, it turned out, of course, that this is the area of greatest biomedical therapeutic failure. You know, we can do a lot, even with … there are many cancer survivors, but as they always say, there’s no Alzheimer’s survivors. And so, whether it’s Alzheimer’s, or ALS, or frontotemporal dementia, or Lewy body disease, or PSP, or CVD: You just go right down the list of all these neurodegenerative diseases, and they have just been untreatable.

Dale Bredesen:
It’s really been, unfortunately, a death sentence. I actually was a postdoctoral fellow in the laboratory of Stan Prusiner, who won the Nobel Prize for studying and discovering prions. And so, I set up a lab, and we’ve been working for the last 30 years in the lab, looking at what actually drives neurodegeneration. That’s when the question, what are the molecular drivers of this process of neurodegeneration? Why is it so common? You know, Alzheimer’s is now the third leading cause of death, according to Professor Kristine Yaffe from UC San Francisco, now the third leading cause of death in the United States. Just an incredibly common problem.

Dale Bredesen:
Just for perspective, the projection is that somewhere around 500,000 people in the United States will die of COVID-19. It may be more, but we’re up to over 300,000 currently. For perspective, almost 100 times that many of the currently living Americans will die of Alzheimer’s disease. So, as large of a pandemic as COVID-19 is, the Alzheimer’s pandemic is actually much larger. And so we really need to work together, all of us, to develop ways to prevent and reverse this very common problem.

Craig Tanio:
Dale, when you … I’m just really curious. In the research that you were doing, when did you first come on the notion that a multi-modal and a more holistic approach would be a better answer to Alzheimer’s?

Dale Bredesen:
Yeah, that’s a really good point. Just for clarification, let me say this. People often say, “Oh, this is just about lifestyle, or just about this, or just about that.” The whole point of this is very straightforward, that all the previous trials of Alzheimer’s have been predetermining what you’re going to treat it with. So, you say, “I’m going to treat it with this drug, or I’m going to treat it with this lifestyle change.” Whatever. All we’re saying is, “No. You have to flip the script to the opposite.” You have to say, “What is causing this problem?”

Dale Bredesen:
This is truly root cause medicine, as so much of functional medicine is, but people have not been doing this in Alzheimer’s in the past. So, we need to look at a whole set of variables. We look at 150 different variables currently: some historical, some biochemical, some genetic, of course, in looking to see this. What happened was, we were looking at a very reductionist approach, and looking at what are the things that actually cause the death of the cells? We were focusing on the function of amyloid precursor protein because it is the parent. It gives rise to the amyloid that we all know is part of the brain in Alzheimer’s disease.

Dale Bredesen:
What was really surprising is that when you look at this molecule, APP, it is cleaved in one of two alternative ways. It almost functions like a molecular switch, and so when things are good, you’ve got enough nerve growth factor, brain-derived neurotrophic factor, hormones, nutrients, energy, oxygenation, all of this. It is cut at a single site, which is called the alpha site, so therefore you get two pieces: one that goes outside the cell, one that goes inside the cell.

Dale Bredesen:
These things turn out to signal synaptoblastic activity. You’re making and keeping synapses, so things are good. When things are bad, when you have a reduction in hormones, and a reduction in nutrients and a reduction in trophic factors, reduction in energy, or you have inflammation, ongoing pathogens or toxins, this same molecule is now cut at three different places. So, you get four pieces, which are called sAPP-beta, A-beta, the amyloid that we all associate with Alzheimer’s, but it’s a much bigger story than that, Jcasp and C31.

Dale Bredesen:
Those four actually tell the system, you’ve got to downsize. So, what’s interesting is, it’s actually a protective response. This switch is going back and forth between two modes: one mode is, things are good, we’re going to grow. The other mode is, things are bad, we’re going to protect ourselves. So, your brain is not trying to give you Alzheimer’s. People have said before, amyloid is bad. No, it’s simply you’ve got insults ongoing, and so therefore this molecule is now trying to help protect your brain.

Dale Bredesen:
You’ve got to identify those insults, so we’re actually sitting … We had developed a drug that we were going to have tested, and it did ultimately go into clinical trials, that will change the balance and flip it over from the good side to the bad side. But I was sitting at the board, this was about 2009, right in there, and I was sitting at the board saying, “What if there are other problems? What if there’s insulin resistance, or …?”

Dale Bredesen:
So, I thought, “Well, okay. Let’s add a little list.” And then I thought, “Well, we should probably do some brain training.” I started putting this on a big whiteboard, actually, and after about the third one I thought, “Well, why would we exclude anything?” I thought, like, duh. Kind of that “duh” moment, and I thought, “Oh, my God. We’re developing a drug, and a drug is not going to deal with all the reasons that you have this problem.” So, then we proposed, in 2011, the first comprehensive trial, and it got shot down. They would not let us do it.

Craig Tanio:
It’s interesting because the question is, are you trying to develop a drug, or are you actually trying to change the disease? You could see all of these factors and say … It sounds like it just kind of hit you one day that a more comprehensive approach was going to be the right way. Is that because this balance was just being affected by all of these other physiologic factors you could see?

Dale Bredesen:
Yeah. When we realized that, okay … because there’s all sorts of published literature on what changes APP from producing the two good guys, or what we used to think of as the four bad guys and the two good guys. We would try to get drugs that changed that. And then, again, I realized, “Wait a minute. There are all these other things that are going to affect this.”

Dale Bredesen:
So, when we were trying to go through that we realized, “Okay, this thing that we call Alzheimer’s, we’re getting a new view of it. We’re realizing it’s really, at its most fundamental nature, it is an insufficiency. That’s the problem.” Again, it’s like, well, isn’t that obvious? It’s an age-related problem that’s associated with not enough support, and too much demand: too much inflammation, too many pathogens, too many toxins. So, it should have been obvious to me years ago, but it wasn’t. That this is fundamentally an insufficiency, and so you have to identify both the supply and the demand.

Dale Bredesen:
So, we realized that what this disease is all about is not meeting the demand with the supply, so we’ve got to reduce the demand by reducing the inflammation, reducing the toxicity. And we’ve got to increase the supply by increasing the hormonal support, the NGF, the BDNF, the nutritional support, all the energetic support. This is really what this disease, at its most fundamental nature, is.

Dale Bredesen:
Then we realized, “Okay, we’ve got a new handle on what these … We think, maybe, the major neurodegenerative diseases are all mismatches.” So, there are different subsystems within the brain. Alzheimer’s is all about neuroplasticity. That’s why, of course, memory is affected so commonly, whereas, for example, Parkinson’s is more about energetics. It’s about motor control.
But it has its own subset of requirements, and as you know, mitochondrial complex 1 is a critical part of that. So is ubiquitination and proteasomal degradation of proteins. So, each of these subsystems … And, of course, there’s a third subsystem for macular degeneration, or even a fourth for progressive supranuclear palsy, another one for Lewy body. Each of these has its own Achilles’ heel that we tend to kind of overstep during our lifetimes if we’re going to get that illness. Therefore, we need to, for each of these, identify the numerous contributors, both on the supply and the demand side, and then we can target those with a prescriptive, personalized, precision medicine program. That’s the idea.

Craig Tanio:
I remember reading your first book, and thinking this is really a different way to practice medicine, and if we’re going to address chronic disease, we just have to really organize the system around such a different approach. Because so much of healthcare is just kind of geared towards the single solution, the silver bullet, and not the silver buckshot, as you say.

Dale Bredesen:
Yeah. It’s a really good point. Let me just comment on that. You’re absolutely right. A lot of this has been, okay, the theory is now beginning to emerge. The interesting thing, the theory tells you how to treat people. It tells you who’s going to get better, who’s not going to get better. But to make it practical, to make it feasible, has been not easy.

Dale Bredesen:
Just as you said, this is very much like when people first brought computers to their homes years ago. It’s like, okay, now wait. Where do I print? And how do I communicate with other people? It’s going to get better and better over time. Same thing, by the way, with Zoom conferences and things like that. They were clunky 10 years ago, or five years ago, even. But people keep solving these. And we’re at the same sort of situation where, what do you have to do to get a person better> How do you get them into ketosis, and how do you change these biochemical parameters that are currently shutting their brains down?

Dale Bredesen:
It took us a while to realize how critical nocturnal oxygenation is, how many of these people have reduced oxygenation. Because, as you know, usually when you get evaluated at a typical center for Alzheimer’s, they’re not checking that. They’re not checking your mycotoxin exposure. They’re not checking your insulin resistance, typically. They might check an inflammatory parameter like hs-CRP or something, but they’re not checking 90% of what’s actually driving the problem. So, we all need to start looking at these things.

Dale Bredesen:
Again, people will say, “Well, it’s not reimbursed, yet.” Okay, but the problem is, the average person spends about $350,000.00 over their lifetime with Alzheimer’s. In other words, the nursing home costs, the medication costs, the doctor visits. It’s horrible. And so, you can cut that dramatically by getting in early and treating people, and getting good outcomes. We’ve got people now who are over eight-and-a-half years on the protocol, and doing very, very well still. So, once you improve, you sustain your improvement. Now, that doesn’t mean everybody improves. We still need to understand why that is, but we see patterns. People who are very, very late, of course, are harder. People who are not doing the right things, of course, are not going to do as well, people who have severe toxicity. But we do have people who are doing well for many years.

Craig Tanio:
Take me back to 2011. You’ve got these ideas around how the practice could be revolutionized, and you’re going to the IRB, the Institutional Research Board. What happens there?

Dale Bredesen:
Yeah. We had both of the … For the original one, we actually were going to do with that drug I mentioned. It was called Tropisetron, that we had discovered in the lab, makes this interesting change in APP. Interestingly, it turns out to have effects on the nicotinic cholinergic systems, so it helps memory. It has effects on inflammation, so it turns out to be helpful once again. Interestingly, it also binds directly, interacts directly, with APP.

Dale Bredesen:
So, we were enthusiastic about this, and we thought, “Okay, we’re going to have four arms, so we’re going to do a placebo and the drug, okay, as we always do. But then, we also wanted to do a whole program with placebo, and a whole program with the drug.” So, I was excited about the idea that maybe the two were going to be synergistic. Well, actually, if you put the two together, we could get a big impact.

Dale Bredesen:
We actually had to do it in Australia, because this drug was available there and not available in the U.S. Both the public and private IRBs said, “No, we’re not going to allow you to do this, because it’s too many variables.” And we said, “Well, hey. This is a multi-variable disease.” How can you … And I think this is one of the problems with our trials. Everybody wants to change one variable, but that’s not how the disease works for the vast, vast majority of people.

Dale Bredesen:
I got a call, actually, from a philanthropist who had supported some of the work and said he was really angry, and how come we didn’t get this thing approved? And if I had been his employee, he would have fired me. Oh, my gosh. It was horrible. So, I was really depressed. Like, what are we going to do? How are we going to get this through? Right shortly thereafter, I got a call from … who turned out to be patient zero, who had been sent out by her friend from the east coast. So, I just told her, “Look. We just got turned down, and so I really can’t do anything. All I can tell you about our research … I can tell you what we were trying to do.”

Dale Bredesen:
So, we spent hours going through all these different things, and she took all these notes. Then she called me three months later and said, “I can’t believe how much better I am. I’m back at work full-time. Everything’s great.” And she is, now, over eight-and-a-half years. That was April of 2012. So, I was really excited when she called back after three months, and I thought, “Okay, this is telling us we’re on the right track.” We thought, okay, if we get enough anecdotal evidence, maybe we’ll be allowed to do a trial.

Dale Bredesen:
So, over the last eight years, we’ve collected anecdotal evidence and, as you know because you helped us, thank you for that, we were turned down again in 2018 to do a comprehensive trial. Then finally, in 2019, we got approved. Although interestingly, these IRBs are so far behind, even though they approved us in 2019, they said for this first trial you’ll not be allowed to do a control group. Well, how silly is that? So, we have to do as controls, it’s going to be a historical control. Luckily, there’s so much data, as you know, for the years and years … You know when people have Alzheimer’s, they’re not going to improve on their own. They’re going to go downhill. That’s well-documented and we know about the rapidity, although it varies from person to person. So, we’ve just completed the trial, and we’re actually working on getting all the data together. But very, very exciting, and looking very much like what we’ve all seen with the anecdotes. So, very excited, and it gives us a denominator, which is nice, and so things look very, very promising. I think this is going to be the way to test even new drugs in Alzheimer’s. I think of many of these drugs that have failed and, as you know, there are over 400 failed clinical trials with Alzheimer’s. It’s just been horrible. Testing these as part of an overall program actually makes much more sense.

Craig Tanio:
Just tell us about the study right now. I know you can’t give the exact results until it’s published, but how many people ended up getting studied versus historical controls?

Dale Bredesen:
Yeah. This beginning is a small proof of concept trial, just 25 people went through. But good news for the vast majority of them, so that was very exciting. Again, we’ll have something published, I hope, in the next few months.

Craig Tanio:
Oh, great. We’re really looking forward to hearing that. I’m curious, just the dialogue with the research community. What do you think it will take to kind of win people over? Sometimes when you’re changing paradigms, it can be a little bit of a lonely battle. How do you see that dialogue evolving?

Dale Bredesen:
It’s a really good point, and I’ve really … I have to say, I’ve really been surprised. I went into academic neurology because I really thought this is where the truth is. This is where we’re going to find new things, we’re going to find new information, and we’re going to ultimately have something that will help these various patients. And I’ve really been surprised to see how much pushback there is, how much just dogged determination that we’re going to stick with a one-drug approach, and this is the way it’s always going to be, and we’re not going to allow any other consideration. I’ve been very surprised at the close-mindedness. So, fortunately, the whole functional medicine community, Jeffery, and you, and David, and Mark Hyman and all the various people who embrace functional medicine, have really understood that the science, if you just go … You know, we’ve been completely agnostic. I didn’t have any particular interest in functional medicine. So, we’re just looking at what actually helps these people, and if you just go straight from the test tube to the bedside, what you end up with is a functional medicine approach.

Dale Bredesen:
You know, it makes a lot of sense. I do think that in the long run, it’s going to take showing that, in large trials, you can repeatedly make people better. So, you’re kind of working at two things at once. On the one hand, you want to continue to make the protocol better and better and better, so to some extent I think that these anecdotes are actually teaching us all a lot. Because you find out, oh, we really do have to look more at nocturnal oxygenation, or a specific level of ketosis, or specific pathogens that are coming up again and again and again. Or, you know, oral microbiome. There’s things that are coming out that are turning out to be critical. Or specific toxins that you didn’t realize before are major players in Alzheimer’s disease. And, at the same time, we’ve got to think about large trials. All the trials are set up to evaluate single variables, and that’s a real problem. The fundamental nature of the way clinical trials in medicine are set up is against a functional medicine sort of approach. So, we really have to have more understanding of this form of medicine if we’re going to get optimal outcomes.

Craig Tanio:
One of the things that we’ve been trying to work on and we actually got IRB approved the last couple of months, is to set up a registry, and to at least kind of … If you can’t do it against a control, at least be prepared, as a practice who’s trying to follow a lot of these root causes principles, to capture all the data. One of my thoughts would be is if we could accelerate the number of people who are capturing all of the data, at least that can get us a sense of what the upside really is for patients, because there’s a big move in conventional medicine to just understand real-world data. Because we all know that the data doesn’t always apply from research as it gets translated into clinical practice. But, you know, my hypothesis is when you do root cause medicine, it may actually be the opposite, that the real-world data may look better than what actually is happening in these single intervention studies because no one’s looking at how they all add up together.

Dale Bredesen:
Absolutely. And you can see this, even in the molecular biology of this, you can see that as an example when you add estradiol, for example, estradiol binds to its receptor, enters the nucleus, alters the transcription of hundreds of genes and one of the genes that has increased in its protein is the alpha-secretase. So, now you’re pushing that APP toward a synapto-blastic type of signal. And on the opposite side, you have inflammation. NF-kappa B gets activated. It also affects hundreds of genes, and it affects the genes that are actually cutting to give you the four that are on the protective side, because you’ve got something invading, you’ve got an ongoing inflammatory state, and there are many parallels between what’s happening with COVID-19 and what’s happening with Alzheimer’s disease, including this cytokine, ‘course it’s cytokine storm in COVID 19, and in Alzheimer’s it’s cytokine drizzle. You’re drizzling these cytokines for dozens of years that are ultimately giving you this pullback. So absolutely I agree with you. I think a registry is a fantastic way to go and, as we start to get all these data, we’re going to be able to see what’s actually critical and this is where artificial intelligence is going to be so helpful because you’re no longer looking at yes variable, no variable. Now you’re looking at hundreds of things that are changing. And so you need to see thousands of people to see, okay, what are the patterns here? You know, one of the things that’s been interesting is people have assumed that this is a linear system. That is to say, if you’re going to use 3 or 5 or 10 or 20 interventions, then you have to show that each one by itself has a statistically significant effect. Well, that’s not the way biology works.

Dale Bredesen:
So there are going to be many of these things that by themselves don’t have a statistically significant effect. But when you put them together as a protocol that is targeting the problem of that particular person, it’ll have a striking effect. So if you want to study how one thing works, you’re going to have to probably take it away from an overall protocol, or you’re going to have to use AI to study many, many different people and to see patterns that look critical and I think we’ll all begin to learn more and more about what are the most critical pieces of this.

Craig Tanio:
Well, it definitely feels like clinically that people hit their tipping point where it becomes very clear that something positive is happening, but that tipping point isn’t always the same to different individuals. And so that’s, I think one of the big challenges.

Dale Bredesen:
Absolutely. And you know, this is the same thing that Dean Ornish found with cardiovascular disease 30 years ago, that you have to get to a threshold. So again, in his case you have atherogenic and erythroclastic effects. And so, as he found, when you get to that tipping point, you actually start picking up the plaque again, instead of actually putting it down and we’re seeing, as you said, the same thing with cognition. You have essentially imagined, theoretically, that change in APP, you’re going from predominantly synaptoclastic signaling, losing synapses, shutting down the brain, atrophy, Alzheimer’s disease to a predominantly synaptoblastic form of signaling where people are now saying, wait a minute, I can remember things again. I can learn new things again. And it is striking to see these people as they come back and say, oh my gosh, you know, I’ve got my ability to form new memories back once again. And so what’s interesting is there is clearly a chemical effect here. We know that Alzheimer’s has chemical effects but also has anatomical effects. So we really need to think in terms of removing the problems that are causing this, whether it’s micro toxins or the insulin resistance or the vascular supply, et cetera. Then a resilience, getting all the trophic factors lined up and getting all the different pieces, but then ultimately a rebuilding as well, because you’ve lost a number of synapses, even relatively early in this disease, as you know, the diagnosis of Alzheimer’s doesn’t come typically until 20 years after the path of physiology begins. So one of the things that we all have to do is encourage people to get in as early as possible, preferably on prevention when they turn 45. But if you don’t do that, that at least get in as early as possible, because we’re really realized now that we can make Alzheimer’s a rare disease, this should be a very rare problem.

Craig Tanio:
Yeah. I think that’s such an important point that so much of this can be prevented. And the downside of following some of these programs, as you have said before is to lose weight and feel better. But in your first book, you talk about the five or six different types of Alzheimer’s. Just curious how you kind of settled on those and how that’s kind of helped to implement the protocol.

Dale Bredesen:
Yeah, that’s a really good point. So what happened, we were looking at, okay, what are the things that drive APP toward Alzheimer’s type signaling, synaptoclastic signaling, versus the other direction. And again, as I said, you could follow things like estradiol, you can follow the molecular species directly to changing APP. And so as we started to get these larger data sets on people, we said, okay, well, we got to look at their inflammation, we got to look at their insulin resistance, got to look at the pathogens and the toxins and the vasculature. We started realizing, ah, we’re seeing profiles where the main problem is inflammatory. So we called that Type One Inflammatory, again it makes sense. So much of age-related problem, so is so-called “inflamaging”. But again, it’s not all of it. There are so many people that will ever want to grab onto one thing.

Dale Bredesen:
Okay, it’s all about inflammation. Okay, it’s all about A, B or C. It’s not, as you said earlier, this is like an orchestra that’s got to be playing together. It’s like a whole group of things that has to be coordinated. So there are people that have mostly this Inflammatory Type One. There are people that have mostly Type Two, they’re very different. They’re atrophic, they’re dried up. They don’t have nutritional, hormonal, and trophic factor support and getting that optimized is helpful to them. They’re often the kind of older people in their 70s or 80s, and they have low levels of these various things that need to be replaced. So that’s Type Two or Atrophic Alzheimer’s. And then interestingly, the glyco toxics, the people who have insulin resistance, we call them Type 1.5 or glyco toxic because they have both. They have the inflammation of the glycation, the glycation of the proteins.

Dale Bredesen:
And of course, we measure this as hemoglobin A1C, but there are hundreds and hundreds of proteins that are glycated. It changes their shape, it changes their immunogenicity. So you have that inflammatory piece, but you also have the insulin resistance. So insulin is such a critical factor. When we used to grow brain cells in dishes, you always had to include insulin, transferrin, and selenium. Those were the big three that make these neurons survive. And so insulin is a critical trophic factor and when you lose your sensitivity to it, you really are putting yourself at risk. And as you know, this is so common in Alzheimer’s. So that’s Type 1.5. And then Type Three, we didn’t know about at the beginning until we saw people who were failing. When we would get the other three effects, we thought, wait a minute, what’s going on here? And these turned out to be very toxic people who have as you know, toxins, and it’s typically one of three groups, it’s the metals or other inorganics. And of course, a lot written about air pollution lately, really worrisome with the California fires, really worrisome with the air pollution in various cities. This clearly increases your risk for cognitive decline. Then there’s the organics, you know, all of the things like formaldehyde and glyphosate and benzene and talumine; people who are around the World Trade Center; people who have a candle burning for years, paraffin candles and have high levels; people who are around car exhaust and things like that; acrolein and stuff like that, all at increased risk for cognitive decline. And then the third group, of course, is the biotoxins, especially the mycotoxins, the trichothecenes and the ochratoxins and all these sorts of things that are critical, that turn out to be so common in their contributions to cognitive decline. And again, it’s as I wrote about a few years ago, this is a treatable, yet unrecognized really epidemic.

Dale Bredesen:
There are just so many people who have this. So that’s Type Three, Toxic. Then of course, Type Four is energetic, it’s a vascular. These are people who have a vascular contribution. When I was a resident, we learned to perform what was called a Hachinski Score that tells you whether you have vascular dementia or Alzheimer’s. And of course that turned out to be wrong, there’s a lot of vascular component to Alzheimer’s and so vascular support. And again, it boils down to an insufficiency. You need oxygen, you need the ketones to burn or something to burn, and you need the blood flow. And if you’re missing any of those, and of course you need the mitochondria to do the burning, any of those four that are not working optimally and you are at increased risk for cognitive decline. So you’ve got to look at that and optimize that. And many people, their blood flow is just not what it should be. So that’s Type Four, which is Vascular. And then of course, Type Five is traumatic. So people who’ve had head trauma have increased risk for cognitive decline from Alzheimer’s, of course also CTE which is very common. But when you get head trauma, beautiful work years ago, showing that when you have head trauma, what happens? You make a lot of amyloid for the next week or 10 days at least, when you have had head trauma. So again, this is part of this protective response when you’ve lost those synapses. So those are the six types of Alzheimer’s. And again, as you know, people often have multiple. They’ve got some vascular component, they’ve got some inflammatory component, but often what you’ll find is that there will be a predominant one that people will have mostly metabolic syndrome, for example, and have kind of a combination of one and 1.5 or they’ll have mostly a vascular presentation, and so many have a toxic presentation.

Dale Bredesen:
And until you get that toxicity dealt with, you aren’t going to get a lot of improvement. The good news is you can begin by treating some of these other pieces and then tweaking, tweaking, tweaking. And as you know, these people often look different. The typical, your typical apoe4 associated inflammatory or glycotoxic Alzheimer’s, these are people who typically show up in their 60s, for example, and they often have a kind of, an American lifestyle. They’ve got a high HS CRP, they’ve got some glyco toxicity, they have a poor lipid profile. But then you’ve got the ones who are Mycotoxic. They often show up in their early fifties. And they’ve got, in there, they have a non-amnestic presentation. They look different. People often think initially, oh, this isn’t an Alzheimer’s patient. It may be more like Frontotemporal Dementia. And it turns out that they do have Alzheimer’s either by PET Scan or by CSF. And it turns out that they have these microtoxicity that you have to identify and detox, and they often of course do better if you optimize their hormones as well. So these groups tend to look different as well. And you can of course, figure this out with their biochemical profiles and then of course respond differently. They need, obviously, targeted to their problems to get best outcomes.

Jacob Gordon:
For someone with CIRS or other mold-related Alzheimer’s, would that fall moreover into the biotoxin or the inflammatory type of Alzheimer’s or the glyco toxic?

Dale Bredesen:
You’re right. So they really have Type Three. It’s mostly a toxin-related problem. And these other toxins, it’s a really good point you make, because the other toxins don’t tend to give you as much of an inflammatory response. Whereas someone with a biotoxin has that combination of some degree of inflammation, as you know, their HS CRPs are typically not off the charts, but they might be one and a half or two. So absolutely you’re getting some inflammatory response. And interestingly, for these, just as with COVID-19 and patients with Alzheimer’s, they tend to have this mismatch between their innate immune system. So you’ve got this inflammation ongoing, but their adaptive system is not keeping up. So the adaptive system should be coming on, clearing things, and then resetting the innate system but that’s not happening. So you have a chronic insufficiency of the adaptive system, whereas therefore you have this just continued, the a-beta that the amyloid itself is actually a part of the innate immune system’s response.

Dale Bredesen:
So again, your immune system thinks it’s doing its job. Yes, you’ve got a problem. I’m helping you with that by turning this on, but now wait, what’s happening to my adaptive system that should be coming in, cleaning things up and then resetting me. So it’s just in this long-term mode of saying I’m waiting, I’m waiting, I’m waiting, and while I’m waiting, I’m making a-beta, I’m making cytokines. And so you’re right. For people who have this kind of the Type Three, the biotoxin type, they have some degree of inflammation as Ritchie Shoemaker and others have pointed out over the years, in addition to their significant toxicity, as you know this is affecting all sorts of structures. There’s nefro toxicity, there’s immunotoxicity, there’s neurotoxicity. You can even have carcinogenicity from some of these things. So these molds are fighting us to stay alive, right?

Jacob Gordon:
Yeah, it’s like a battle. What I find really interesting about your work is showing how amyloid-beta or beta-amyloid is actually a protective mechanism and not what we’re trying to treat.

Dale Bredesen:
We’re trying to treat what’s causing the beta-amyloid. So, yeah, great biomarker to tell you something bad is going on. But I think it’s really led to, unfortunately, the spending of billions of dollars to try to get rid. This is like trying to get rid of your mother-in-law or something. It’s like, wait a minute, she’s telling you to eat your vegetables. Maybe you should listen to her. She’s really telling you something important and telling you it’d be healthy, and groom appropriately, and eat appropriately, and exercise. And you’re saying, if I could just get rid of her, then I’ll be fine. Well, no, you’re just going to be in bad shape. You’re going to eat the wrong things. And you’re going to, you’re going to get sick when you’re younger.

Dale Bredesen:
So getting rid of the amyloid is going to be great one day when you’ve gotten rid of all the things that are causing it. Then I do think, absolutely. I actually think that these drugs are going to be helpful in the future once you target all the insults and you get people better. Now what’s happened is the amyloid has a very long half-life, and so it will stay in your brain. It’s a little bit like you get the soldiers out to try to fight the bad guys, and then you put them in a fort.

Dale Bredesen:
So you put the amyloid in these lakes that are actually not very toxic because you’re saying, I might need this again someday. So I want to be able to rapidly depolymerize it and make those oligomers that are fighting the bugs, but also downsizing the brain. But as long as you’ve got the insults, you just keep downsizing, downsizing, downsizing until ultimately you get Alzheimer’s and die. So what we want to do is get rid of all these insults. Identify them, get rid of them, get all the resilience back, and then we want to add the drug. And now slowly get rid of that amyloid over time.

Jacob Gordon:
So it’s the reverse approach of which most clinical trials are doing right now?

Dale Bredesen:
That’s exactly right.

Jacob Gordon:
So in your book, you talk about there’s 33 or 36 different holes that are leaking in your roof and you call them the biomarkers that we should be looking at. You recently just said that there’s 150 now, or what’s the number currently?

Dale Bredesen:
Yeah, yeah. So I was the only, the reason that I came up was this original idea of 36. So I sat down one day and said, okay, my gosh, there are all these things that are driving APP in the wrong direction. Like wow, many of these things. So we looked at okay, if anything’s activating beta-secretase, gamma-secretase, reducing your alpha-secretase, all these sorts of things. So I listed all the things that we knew about, and there were 36. So I said to the patients, look, imagine you’ve got a roof with 36 holes. The drug is only going to cover one hole. It’s really not going to be. And it’s an easy way for people to think about, oh okay, wait a minute, this is how functional medicine works. Now, obviously, it’s relatively crude because it doesn’t tell you how they all work together, but it’s just easy for people to see.

Dale Bredesen:
Yeah, okay. Wait a minute. I really have to do more than one thing. Now, what I’ve mentioned about the 150 variables is we want to collect data. So that doesn’t, not all of these variables are mechanistically driven. So we want to know, for example, if you have things that are related to other neurodegenerative diseases. One of the interesting things that’s come out from the neuropathologists recently is that we used to think of these diseases as being very quantile, okay. You either have Alzheimer’s or you have Lewy body, or you have frontotemporal. And the neuropathologists have now said, wait a minute, when you look at the brain of an Alzheimer’s patient, guess what you see virtually every time? You see beta-amyloid, you see phospho tau. Those are kind of well-known. Guess what almost all of them have? Alphas to nucleon as well, which is what we used to think, well wait a minute. That’s Parkinson’s. And they almost all have TDP 43, which again, we associate with frontotemporal dementia and ALS. So these are not as perfect as we thought they were. This is, again, this goes along very much with what Craig and what we’re all practicing now, to say yes. There are many things that are driving it. Guess what? Alpha-synuclein is anti-microbial just like amyloid-beta is. This is your body trying to fight these different insults. And so that’s why we want to gather data to say, does the historical data suggest that we need to be thinking about the dopaminergic system as well? Do we need to be thinking more about the glutamatergic system? Is it mostly the cholinergic system? Do we need to be thinking more about NGF, BDNF, because we’re now of course the arsenal to be able to making a difference in these different neurochemistries is building.

Dale Bredesen:
So again, this is another thing that’s completely backwards. We’ve all been taught there’s nothing you can do about this illness. There’s just nothing out there. It’s the opposite. The bottom line is there’s a huge arsenal and you have to know how to use it optimally and what’s important for each person. So we now have things that can increase your BDNF, things like whole coffee fruit extract, and of course exercise is the classic one. We now have things that can increase your NGF. Things like ALCAR and Hericium erinaceus or the lion’s mane mushroom and things like that. So there are different things that give you the ability to manipulate different parts of the neurochemistry for the benefit of the patient.

Jacob Gordon:
That’s really interesting. So speaking of some of those alternative therapies or new things that can promote BDNF for NGF, what’s your opinion on things like 7,8-DHF or TrkB?

Dale Bredesen:
Yeah, yeah. So of course, Dr. Keqiang, fantastic professor at Emory, I’ve known Kitchein for many years. He’s doing some absolutely brilliant work on how Alzheimer’s develops and specifically around a specific cleavage. So a different cleavage event that’s different from the alpha and beta and gamma cleavage. And he’s shown that this is very important. And interestingly, effects on all, again on this whole system related to dealing with insults and related to trophic factors and things like that. And so they are actually developing various things that will, small molecules that will increase track B signaling, will increase your BDNF related signaling and 7,8 Dihydroxyflavone which was one of the early things. And so I think that these are going to be valuable and they’re developing ones that are more potent than. So I think that these are going to be helpful and of course the whole coffee fruit extract that I mentioned, a lot of people been using that. Increases your BDNF very nicely.

Craig Tanio:
Yeah. You had mentioned sort of Lewy body and frontotemporal and Alzheimer’s overlapping. Are you seeing that there are any different root causes for Lewy body and frontotemporal that are different than for Alzheimer’s?

Dale Bredesen:
Yeah, this is a great point. And so again, what we’re finding is that each of these things has, each of these neural subsystems that’s affected has a different Achilles heel. So each thing is it’s kind of like you have a Maserati in the garage, which is running at 200 miles an hour, and that has certain ways. As they always say, certain cars tend to have certain things go wrong with them, but then you’ve also got a motorcycle that tend, they can go very fast. That has its own set of problems that typically fail. And that’s the way we’re seeing these neural subsystems. And so what’s happening is because of evolution, you are driving these systems because yeah, let’s face it, evolution is driving you to be able to out-compete other species and other species and other members of your group. That’s the way evolution drives you. And so to do that, you are at risk for things failing over time. And so they tend to fail in different ways. So the motor modulation system, which is what’s affected in Parkinson’s, tends to fail because you need that mitochondrial complex one function. As we talked about with Alzheimer’s, it tends to fail because you’ve got insulin resistance and because you’ve got toxin exposure and things like that.

Dale Bredesen:
It is very much like an aging phenomenon, it’s almost like an aging of the brain. You’re failing in multiple ways and you’ve got to deal with all of them. When you look at ALS and frontotemporal dementia, which are essentially cousins, as Bruce Miller has pointed out years ago, most people with frontotemporal dementia will have some degree of ALS, and most people with ALS will have some degree of frontotemporal dementia, even though it may be modest. At least in some of their subtypes.

Dale Bredesen:
And so in that case, that seems to be a failure that’s common with glutamatergic failure of clearance. So you have this phenomenon of excitotoxicity. If you look at the motor system, what’s striking about that, and each of these systems has their own things, what’s striking about that is that you have the integration of more signals than you typically have from other systems. This motor system is having thousands of inputs that are all impinging on it. And, of course, the problem is you’ve got all this glutamate that’s being spritzed onto here, and as long as you can keep up with the clearance of that, you’re in good shape. But there are many things that either reduce the clearance of it, or increase the amount that’s actually coming in. And, of course, one of the things that’s been pointed out is L-BMAA, which is an excitotoxin, which is unfortunately present in things like cyanobacteria.

Dale Bredesen:
And this was discovered, of course, by people eating fruit bats, where they have a lot of this stuff. And so you’re essentially giving more than the system can handle. And ultimately the system fails, because it’s got this excitotoxicity again and again. So, again, each of these things has a different way. Now, what we’re seeing good results with Lewy body. And Lewy body turns out to be very much related to type three. Virtually everybody with Lewy body has some toxic exposure. And we’ve seen metals, and we’ve seen the biotoxins, and we’ve seen organic toxins, and I’m sure you’ve had this same experience that these people typically have toxins exposures.

Dale Bredesen:
And again, very much like Parkinson’s. There’s a wonderful book that came out in Parkinson’s a few months ago called A Prescription For Ending Parkinson’s. And they pointed out that Parkinson’s is more rapidly increasing than any other neurological degenerative disease. It’s really strikingly increasing right now. And they believe it is related to more exposure to toxins. And there are these multiple things like trichloroethylene and perchloroethylene. And of course, although they didn’t mention in the book, some practitioners are pointing out that people often have high glyphosate levels when they come in with, especially young, otherwise healthy people who are showing up with just Parkinson’s or just ALS.

Dale Bredesen:
And that’s like, “Wait a minute, you’re in your early forties and you’re doing well, what are you doing getting this disease?” And they’re turning out to have very high glyphosate levels. Whether that’s the key driver, we don’t know yet, but as you know, nice work from Stephanie Seneff suggesting that yes, there’s every reason in a molecular sense for glyphosate to drive ALS and potentially other forms of neurodegeneration. I tend to think that she’s on the right track here. And so I think this is one of the contributors. So, yes, I think that we see different patterns. And as I said, Lewy body disease, to a first-order approximation, Lewy body means you have Parkinson’s drivers and Alzheimer’s drivers. And so you need to look at both of those. You need to look very carefully at the toxins.

Dale Bredesen:
If you’ve got ALS or frontotemporal dementia, you need to look very carefully at excitotoxic signaling, because that appears to be what’s driving this. I have to say, frontotemporal has been the tough one as you know. People who get frontotemporal dementia, much less common than Alzheimer’s, much less common than Parkinson’s or Lewy body, but they are people that have been tough to treat and have failed. There is no effective treatment right now, a standard treatment for frontotemporal. There are a few examples of people who improve with integrative and functional medicine sort of approach.

Dale Bredesen:
And I think that this is where we’re really interested in, what we’re calling the arc project. Which is, the arc was two by two, by two, to just get small numbers of people who are very early on in these various conditions and look at them very deeply to look at as many different characteristics to determine, what are the drivers of each of these diseases? And, of course, genetics represents a part of it, but as you know in Alzheimer’s, 95% of the cases are sporadic, only 5% are truly familial Alzheimer’s disease, with APP or PS1, or PS2 mutations. And for most of these diseases, genetics, that’s the background, but they’re not your fate, they’re just giving you your risk.

Jacob Gordon:
So, what can you do with someone with ALS or someone who has excitotoxicity with glutamate? How do you increase glutamate and improve long-term potentiation, but without getting the excitotoxicity?

Dale Bredesen:
Yeah. I mean, that’s a very, very good point. There’s some nice work that came out of Duke, looking at people who spontaneously improves, “spontaneously.” And I think, again, these anecdotes can be very teachable moments for all of us with ALS has been so tough, not only because it has not responded well to standard treatment, but also because it marches forward more rapidly than someone with Alzheimer’s. So Alzheimer’s, it goes year to year, and ALS is going month to month, and people typically are living between one and three years, is typical. So, unfortunately, it is progressing more rapidly and you really have to jump on it. But they showed a number of things that were associated with either slower decline or with some degree of improvement.

Dale Bredesen:
And interestingly, it goes back to some of the trophic support. Things like IGF-1, which turned out to be important for motor neurons. BDNF turns out to be important for motor neurons. There does seem to be a difference in the metabolic status. So, it’s not so much about insulin resistance. If anything, the people who had type two diabetes progressed more slowly. So, again, we have to look at each of these a little bit differently. You’ve probably seen, there’s an interesting site called healingals.com, and Coco Newton, for example, and others have worked on this. And they’ve pointed out that getting the appropriate dietary input turns out to be important for giving these people best outcomes.

Dale Bredesen:
There was a whole set of things about metals. Interestingly with Alzheimer’s, as you know, copper-zinc ratios tend to be high. This is a characteristic of many of these people with toxicity. In ALS, it’s the opposite, the zinc to copper ratio tends to be high. So, there are trophic influences, there are metabolic and dietary influences, there are inflammatory influences, there are glutamatergic influences. As you indicated, you’ve got to have glutamate signaling, but unfortunately the inability to keep up with it, which again, is why these tremendous athletes like Lou Gehrig that are just driving, driving, driving, hyper driving the system every day for years ultimately have trouble keeping up with the glutamatergic signaling.

Dale Bredesen:
So, the answer is, this is what the Ark Project is all about. We want to look and address each of the potential contributors for each of these people. Macular degeneration, another great example, and all of these things that are critical for getting best outcomes.

Jacob Gordon:
What have you found with macular degeneration?

Dale Bredesen:
So, macular degeneration, I actually think is one of the most intriguing of these neurodegenerative conditions. And you can argue, “Well, yeah, it’s really about the retinal pigment epithelial cells. It’s not a primary neurodegeneration,” but it is closely related and it fits this model, and in fact it is an important support for the model I’ve been talking about, this mismatch between the support and the demand. So what happens with macular degeneration, which is about twice as common as Alzheimer’s. About 11 million Americans have a macular degeneration. This is a major, major global cause of poor vision. Whether the people become all the way blind or not, it’s a major cause of visual reduction as we age.

Dale Bredesen:
And what happens there is, as long as there’s any light, you are driving this system, you are driving your photoreceptor cells 24/7. So, again, when it’s dark, fine they’re off, but otherwise the whole time, just imagine driving these same neurons all day. And so this is, again, like a Maserati going 200 miles an hour. This is a supply and demand issue. And you are right at the limit of supporting these with blood flow, with oxygenation, and with the drivers themselves, blue light. So if you’re overdriving them, or if you’re undersupplying them, then you’re right at that edge and you have a chance and of course, inflammation plays into this as well. So it’s a slightly different formula than Alzheimer’s, but it’s a similar idea.

Dale Bredesen:
And so all of these different things, you can now see immediately all the things that increase and decrease your likelihood of getting this. So if you live at high altitude where you’re getting less oxygenation, guess what? You have an increased risk for macular degeneration. If you live near the equator, you’re getting more direct light. Guess what? You have an increased risk. If you smoke, if you have reduced blood flow, any vascular disease, the big one of course in the past was people who smoked. They have all these toxins they’ve added to the system, plus the reduction in blood flow, and they would dramatically increase their risk for having macular degeneration.

Dale Bredesen:
On the other hand, on the positive side, if you’re doing things like hyperbaric or like EWA, like exercise with oxygen training, you’re helping these people. If you are giving them better blood flow, more oxygenation, reduction in inflammation, all of these things are very helpful to these people. Now, some people, it does look like CIRS can be one example of a patient who’s clearly got biotoxins as part of the overall problem and doing well by addressing those in herself, as well as her oxygenation. Insulin resistance also plays a role in this particular illness. So this is, again, something where you’ve got to get the supply and the demand lined up.

Dale Bredesen:
One interesting point about this is, people with APOE4 are at reduced risk for macular degeneration. People with APOE2, the thing that protects against Alzheimer’s are at increased risk for macular degeneration. And it’s fairly clear effect. And so we need to understand more about why that is.

Craig Tanio:
But it’s interesting with macular degeneration, that is one of those areas where at least the conventional medicine organizations have embraced that there’s nutritional issues that exist, and that additional supplementation is effective at improving outcomes. And I might try it a little bit of an artificial exercising question on you around the actual protocol itself, but it might come up in an IRB. If you had to, obviously in clinical care you’d want to address as many of the root causes as possible, but if you had to constrain the protocol to let’s say your top four or five interventions, I mean, is there any type of prioritization on the protocol, especially, for example, if people may not have the resources to afford all of the interventions. Is there a hierarchy at this point?

Dale Bredesen:
Yeah. Absolutely. Now the problem is the hierarchy is different-

Craig Tanio:
For each one.

Dale Bredesen:
… for each person.

Craig Tanio:
Sure. Yes.

Dale Bredesen:
That’s the tricky part. And one of the things I’m very interested in doing with the computer software is to be able to take each person and say, “What is the number one thing for this person, number two, based on their profile?” Because it’s going to be different from person to person, it’s not always obvious. Well, let me just comment on one thing you said earlier about nutrition for macular degeneration. So as you know, AREDS2 is the current standard. You have some zinc and some lutein and that sort of thing. With AREDS2 which is the standard of care for macular degeneration, what they’ve shown is, instead of losing 13 lines of vision, you lose 12 lines of vision.

Dale Bredesen:
So, again, this is something where, they’re not embracing all the different things that are actually driving this and therefore the outcomes are very poor. So, again, as you said, you got to exceed that threshold. Now, you mentioned prioritization. Are you talking about for cognitive decline or are you talking about for visual decline or for motor decline?

Craig Tanio:
Well, let’s keep it at cognitive.

Dale Bredesen:
Yeah. Okay. Good. So, for cognitive decline, this is where the subtyping is helpful. It’s going to be different for each person. The top things are going to be either inflammation and addressing that and identifying pathogens. For many people, pathogens are critical, whether it’s herpes simplex, HHV-6A, P. gingivalis, as you know, from your oral microbiome, or F. nucleatum, or T. denticola, or other things. Or whether it’s more tick-borne illnesses. A lot of people end up having a babesia or, borrelia, or bartonella, or things like that that are critical. Ehrlichia, all these tick-borne illnesses.

Dale Bredesen:
So for them, that’s the highest priority. For other people, I’d say for the most common is probably going to be insulin resistance, and it’s associated, metabolic syndrome where metabolic syndrome increases your risk for Alzheimer’s by more than double. So, several fold increase in your risk for Alzheimer’s. And for people who do have metabolic syndrome improving on that, of course, that is associated with inflammation, it’s associated with gut abnormalities. It’s associated with signaling changes. So, that’s going to be the highest priority for those people. And, again, you can do a tremendous amount with just diet, exercise, optimal sleep, stress reduction, and some brain training.

Dale Bredesen:
All of those are inexpensive. You can do a lot of, again, the earlier the better. But unfortunately, there’s no one size fits all. That’s the thing. Unfortunately this is not a procrustean, the prescription, because it is different for each person. And I see sometimes people will get lost in one detail and not realize that, “Okay, wait for you, it’s this area, and for that person, it’s that area.” So it does differ. And in some people it’s going to be getting best vascular performance and energetics.

Craig Tanio:
But if I hear you right, it does seem, in a little bit my experience is that there’s thematically lifestyle changes can be applied pretty consistently across the types, even though certainly with, if you’re APOE4, there may be some limits on dietary changes, et cetera. But that there is some prioritization that can happen in the protocol, but that priority is uniquely determined by where each individual is. It cannot be one size fits all.

Dale Bredesen:
Exactly. And this is exactly why we worked on the software. And again, you start out with something like this and at the beginning, it doesn’t add much. You can do a lot on your own. So the next version, what we call re-code, actually will now make it so that it will do things that you can’t do as a practitioner. So in other words, it’ll be putting genomics together with imaging changes, with all these different pieces, you’re exposome, et cetera. Because ultimately we all should be helped. This is like having an assistant. You should be helped by having all these different pieces of data. It’s funny that all this beautiful logic has gone into Google knowing where you shop each day. There’s all this high-level mathematical logic to sell you stuff, but we haven’t been using the same sort of wonderful logic for getting better outcomes in our patients. It’s backwards, shopping is great, but patient outcome’s much, much more important.

Jacob Gordon:
Yeah. We need to focus our technical resources in the right places now.

Dale Bredesen:
Exactly.

Jacob Gordon:
In terms of the diet, what kind of diet is it that you advocate?

Dale Bredesen:
Yeah. This is a really good point because there’s so much now around, what are the critical features of different diets? There are people who are just saying carnivory is the only way to go. It seems to be helpful to some people who have auto-immune conditions. So, great. Again, we’re agnostic. Whatever works. But what’s turned out to work the best is what we call KetoFLEX 12/3. And people use different variations. People like Mediterranean diet and is like … Well, we just go back to the biochemistry. I have to say, I’m not a nutritionist, so I’m just interested in the biochemistry that drives your synaptic formation and maintenance. And what works best for driving that is a combination, which is, number one, getting you into ketosis, somewhere between one and four millimolar beta-hydroxybutyrate, or if you like to look at your acetone so it’s nice not to have to prick your finger.

Dale Bredesen:
Then if you use, for example, Biosense, you want to get above seven on the ACEs. You want to be blowing a 10 or a 15 ultimately, which again, corresponds to about the same amount of VHB. And then secondly, you want to have some fasting, because it has so many helpful things, helpful pieces to that of 12 to 16 hours, and typically at night, because again, it helps increase your BDNF. It helps drive your ketosis. It helps drive your autophagy. So we’re, again, just focusing on the molecular mechanisms that make the phenomenon of Alzheimer’s better.

Jacob Gordon:
With fasting, is it just water fasting or would tea and coffee break this type of fast that you’re trying to improve autophagy and BDNF?

Dale Bredesen:

Yeah. Tea and coffee don’t break it as long as you don’t have calories with them.

Jacob Gordon:
Okay.

Dale Bredesen:
And, again, you can also think of a variation on this. You can still keep yourself in ketosis, by throwing in some MCT oil or something. Now that does break your fast, so you’re losing part of it, but you’re keeping a critical part of it, which is the ketosis part. The general, as you know, rule of thumb is, as long as it’s less than 50 calories, you’re probably still going to keep yourself in a fasting mode. So that’s the critical thing there. Then you want it to be high fiber because high fiber helps your microbiome, it helps your detoxification. Most of us are getting way too little on the overall fiber. So we pushed people to get at least 30 grams a day. Please get up there. Our forebears probably were more like 100 grams a day, but so many of us are walking around with five grams of fiber a day. It’s horrible. It’s horrible for our glycemic load. It’s horrible for our lipids. It’s horrible for our gut microbiome, for our detox, all of those.

Jacob Gordon:
Tell that to the carnivorous people.

Dale Bredesen:
Yeah. Exactly. So these things are critical. So ketonic, so fasting, so getting fiber, and then, of course, all the phytonutrients that are critical. So this is a plant-rich, and if you want to be a vegetarian, no problem, you can do it, but you also can do it with fish and with some grass-fed beef and with some chicken. So you’ve got all sorts of workarounds here. There are all sorts of good things you can do, but you just don’t want to toxify yourself too much, and get appropriate protein levels.

Dale Bredesen:
I like to use Cronometer myself. I find it very helpful. And one of the things that popped out for my own Cronometer was that I wasn’t getting nearly enough choline per day. And so we should all be getting around 550 milligrams of choline or more per day. Most of us are coming in more like 300 milligrams per day. That is not good because acetylcholine is the critical neurotransmitter for Alzheimer’s disease. It’s the thing that is decreased, and it’s the thing that is critical for forming new memories. So, the last thing we want to be doing is walking around choline-deficient.

Jacob Gordon:
That’s an interesting point you make about choline and acetylcholine. I’ve noticed that when I take anything that is high in choline, whether it’s eggs, blueberries, or any cholinergics or anticholinesterase inhibitors, I noticed that it makes my cognition significantly worse. Have you seen that as a result in any of your research?

Dale Bredesen:
So you’re saying when you increase your choline levels, your cognition gets worse?

Jacob Gordon:
That’s correct.

Dale Bredesen:
So the one issue that has been pointed out with this is that when you increase choline levels, it has been associated in some people with depression. So if it’s changing your mood, that would make some sense. But if it’s just worse, then have you looked at how much? I mean, maybe you actually are. I have plenty of choline, I don’t know, but for most of us we tend to be too low and you do need enough acetylcholine to make new memories. So yeah, that would be my guess is that it’s actually impacting you because there is a ratio as you know, for acetylcholine to your to dopamine and to …..

Jacob Gordon:
Absolutely. I noticed dopaminergics definitely help with that, the brain fog that I get from acetylcholine. So I just find that interesting that it’s highly promoted. I know it’s really important for cognition, a few others and I have that problem with acetylcholine.

Dale Bredesen:
So your cognition does better when you’ve got enough dopamine?

Jacob Gordon:
Better with dopamine or things that reduce acetylcholine. So things just simply like taking Benadryl.

Dale Bredesen:
So they’re very interesting to deal with that? So did you ever have any Asperger’s when you were younger?

Jacob Gordon:
No, but I believe I’m slightly on the spectrum.

Dale Bredesen:
So that’s been pointed out before and then this, it goes along really well with what we’d talked before about this APP relationship. So what’s interesting is if you look at young people, obviously you’re still a very young guy, but where I go back to when you were growing up, people who have Asperger’s, who are on that spectrum are actually the opposite of Alzheimer’s. They have too much cholinergic, they actually have slightly larger brains than others, they have increase in BDNF, they have an increase in sAPPalpha. That entire system is on the opposite side. And so what’s been pointed out is they tend to do better with anticholinergics. And this has been suggested before as a treatment for people who are on that spectrum. On the other hand, the ADHD people are more on the Alzheimer’s side. They tend to have reduction. It’s interesting, we tried to make a fruit fly model so-called “Allsflymers” years ago in the lab.

Dale Bredesen:
And so we changed the APP till it was on the Alzheimer’s side. And guess what happened? The fruit flies get ADHD. It’s really interesting. It’s very much similar to what we see in humans. It’s males more than females, they move way too much, if you give them simple carbs they get much worse. You give them the treatments for ADHD, they get much better. So it’s interesting that APP, when it’s not degenerative associated with Alzheimer’s, when you’re looking at it, it develops mentally that pattern is on the one side of it is Asperger’s, and on the other side of it is ADHD. So my guess is if you’re doing better with these anticholinergics, you probably were a little bit on the effort, you got a great brain with lots of very tight synapsis. Whereas the ADHD side is essentially looseness of the synapsis based on your APP signaling.

Jacob Gordon:
Oh, wow. That’s fascinating, I just learned a little bit more about my health.

Craig Tanio:
So, Dale, I wanted to talk a little bit about implementation of the protocol. You’ve had two New York Times best sellers, you’ve had multiple training opportunities for the practitioner community through MPI then IFM and now currently through APOLLO, and I know you probably have had now at least hundreds, if not thousands of people who have trained. So I’d just be interested in your observation about, kind of translation of ReCODE into practice. How do you think that’s going?

Dale Bredesen:
This is such a good point because you’re right, it’s been the practical. And obviously, you’ve dealt with this yourself and bringing all of your experience with functional medicine to bear on this. And yes, what we found in there are we just had a new release of the new training through APOLLO, as you mentioned just recently. And so there another over 400 people that have now that are going through the training. And of course it’s evolving over time. And you’re absolutely right, the surprise here, in the past, the rate-limiting step was we didn’t know what was causing the problem, and we didn’t have a medicine for it. Now we know a lot about what’s causing it. We have the arsenal, it’s huge, and it’s knowing the prioritization as you said earlier, and it’s knowing how to use the various things for specific people.

Dale Bredesen:
But the problem now is the practical nature of it. So yes, we’ve had some people who said, “I’m now going to be claiming to be doing this and charge people a lot of money, but I’m not really going to do much of it, and I’m just going to see if I can make some money doing this”, which is really sad, I think. We’ve had other people who’ve embraced it, but said, you know what, it’s too hard to do the too many things. So this is unfortunate, your brain is complicated and there are lots of complications that go into this. So we’re evolving this as how do we do it best? And we’re learning as we go along to, okay, how much can we get done by starting people on the basics, as you said earlier on, things like the diet and the exercise and sleep and stress, and how much is it going to be that we have to look at specific pathogens?

Dale Bredesen:
How much are certain modalities? As you know, there’s been stuff published recently on plasmapheresis as helpful. And so for some of these people, that’s going to be really important and really helpful, but it’s expensive. We’ve had, what about STEM cells? For some people that’s really going to be helpful. It’s expensive. For other people, EWAT very helpful or H-BOT to hyperbaric. It’s expensive. So the question is, when are these just being used as business modalities, and they’re not really the critical pieces? And on the other hand, when should we encourage the patients? Look, this is really important. Look, if you can save 90% of what you are going to have to spend for nursing homes, it’s probably worth that 10% to keep yourself out of a nursing home. You’ll have a better life. And in the long run, you’ll save a lot.

Dale Bredesen:
So this has been such a huge problem with the tremendous amount of money that’s been spent on nursing homes. And it’s so sad to see these people. Just this last week, one of the people that started several years ago, who turned out to have very significant toxicity and kind of bounced around and tried a little of this and a little of that, and unfortunately ultimately just passed away last month. And it just hearing about anyone who’s passing away from this, it just kills me. It bothers me because this is what we’ve been focusing on for 30 years to try to make it so that this is a rare disease so that people respond, but we still do have some people who don’t. So you’re right, we’re having to look at how do you do this practically?

Dale Bredesen:
And I do think that what has worked best so far is very much of a functional medicine sort of practice where you get people started. And this is the sort of thing that we did for the trial. We have three absolutely fantastic functional medicine physicians, Dr. Kat Toups, you know all these people very well. Kat Toups and Dr. Anne Hathaway and Dr. Deborah Gordon, and they evaluated the people, looked at the various drivers and then worked with them in their offices with appropriate nutrition and with appropriate exercise. They looked at sleeping, turning out, getting your improvements in sleep and turning out to determine whether you have reduced oxygenation nocturnally, turned out to be huge. All these things are critical. Looking at oral microbiome and gut microbiome. They also use feedback stress as is so critical in this illness.

Dale Bredesen:
And people have argued that even you look at the neuroanatomy, the amygdala and this response to threat as your Dr. Clawson has pointed out repeatedly part of this disease is that response, not just response to pathogens, but response to threat. And we have a lot of people, as you know, that will go downhill when they are under stress and will improve when the stress is reduced. And so I think that the functional medicine approach and continuing to just work with these people over months and tweaking things has been the most successful way to go. The problem is, of course, people want a quick fix, they want that quick pill, and that simply has not worked in this illness.

Craig Tanio:
And what’s the time courses if you have a specialized clinician and the patient is committed, can you usually see some type of results or at least a stop and decline within six months? What’s the usual time course of response?

Dale Bredesen:
Yeah, it’s a really good point. Typically I always tell people, give yourself three to six months after you’ve gotten things optimized. So not from day one, but start with, get yourself insulin-sensitive so that you don’t have inflammation. Optimize your sleep when you’ve optimized these things, then add three to six months. And that’s when you should be seeing an effect. Now we do see people earlier. We’ve had people you’ll respond within a few days because they had a lot of toxic exposure and just getting out of that, helped them. And we’ve had people that, after a year or two, they’re still tweaking and still improving. One of the things that I’m sure you’ve seen as well, people will get to a plateau, they’ll improve, and then there’ll be stuck there and you have to find the rate-limiting problem then.

Dale Bredesen:
You find out, Oh, wait a minute. They had a pathogen I wasn’t aware of, or, Oh, they had a toxicity that I wasn’t aware of. And now they’ll get in continued improvement. One of the exciting things to be is as we’re able to look at more and more of these variables, we’re able to see better and better why each person got this. And Sharon Hausman-Cohen, who’s got IntellxxDNA, which I think has been helpful looking at who are the people who have NOLs in some of their glutathione pathway. These are people that are going to be hypersensitive to toxins. So we have to go the extra step for those people who are the people that are, have increased clotting, who therefore we have to go the extra step up, maybe using things like pycnogenol or nattokinase because they’re having problems with micro clots and microthrombi that we’re not aware of all of these things are contributing.

Dale Bredesen:
And so again, I always tell people, give it three to six months after you’ve optimized these things. And then if things haven’t turned around, we need to dig deeper. And I’m working with a, for example, a family right now where the woman clearly responded. She has very significant toxicity. She’s clearly improved, but she’s on a plateau now. And we need to understand why is it that she really hasn’t gone farther? And what there’s something out there that is still contributing to her. Now, the good news she’s stable, but we want to now get over that threshold. As you said earlier, that threshold is a key piece and we need to understand what is it about that threshold that’s being missed?

Craig Tanio:
Sure. So tell us about the new book that came out recently.

Dale Bredesen:
What happened was in 2017 I published The End of Alzheimer’s. Actually that title, The End of Alzheimer’s, that was a title that Random House I’d have been criticized for that title. The title that I wrote that under was called Wits End. It was the idea was I’ts the Wit’s End” is the disease, and wit’s end is the research. They said, nobody is going to buy a book called Wit’s End. So forget it, we’re not selling this book called Wit’s End. So they said we are calling this The End of Alzheimer’s. And of course, as a new author, they were right, I was wrong. But I recognize that it does sound like it’s pushing it a little to some people, but again, I had real fights with them about this at the time. When that came out, it was about, Hey, we can do this, here are the things we have to look at. It was about the 36 holes and all that. And a lot of people said, you haven’t given us enough details. We want to know day to day. Get someone who’s doing this day-to-day, and we want to know what to buy, where to go, what websites, what workarounds, all those sorts of things. And the second one is the program, The End of Alzheimer’s program. And it’s about the details that weren’t in the first book. And I worked with Julie G, who’s doing this every day on herself and doing very, very well. She’s now been on this for more than eight years, and she’s gone from 35th percentile to 98 percentile on her cognitive testing, just doing beautifully, and also work with my wife, Aida, who’s an integrative physician. And so we have the science side, we have the clinical side, we have the day-to-day use side, and that whole idea was to make it practical.

Craig Tanio:
We love the book. We advise all patients on the program to read it ahead of time. And I think the second book has really been very practical, very pragmatic, helping patients implement this. And I hear there’s an upcoming book?

Dale Bredesen:
Oh yeah. That’s a good point. So in August, there’s another one coming out, which is called The First Survivors of Alzheimer’s. So when we put out the first one, the other thing I wanted to do, I wanted to hear from the patient, wanted the patients to describe in their own words, this is what it feels like to start having cognitive change. This is what it feels like to go downhill and have your doctor tell you you’re going to die of Alzheimer’s. And then to be told that no, there’s something to do and then to get better and go back to work and be back to your family. This is really an emotional thing. We had one of the doctors who was crying when the patient came back and was doing so much better. As you know, to see people turn, which I never saw during my neurology practice, my neurology residency, or when I was in the lab, I didn’t see the mice get better in the lab.

Dale Bredesen:
This is an emotional, emotional issue. And so I have seven people who each tells his or her own story in their own words. This is what it was like, this is what it was like talking to my children and stuff. And they’re just such beautiful stories. And originally I had tried to include that in this second book, the program book, but there just wasn’t enough room. So this was broken off now as a separate thing, along with your updates, and this is what we’re thinking about with these different illnesses. But I have to say, it’s wonderful to read these stories from these different people and to hear about, Hey, it is, it’s not hopeless.

Craig Tanio:
I think hope is really the key piece, because I think so many patients have really get scared of the label and worry that there really is no hope. And I think the new book will probably be really powerful in terms of its impact on people, because it shows that there is hope, and you can hear about it in the program, but hearing individual stories are always the way that touches us.

Dale Bredesen:
Absolutely.

Jacob Gordon:
What’s your opinion on ISRIB?

Dale Bredesen:
Yeah, so, ISRIB is another great example of something where you’re trying to use a monotherapy. What ISRIB does is it prevents your brain from doing a one of its protective responses. And so ISRIB is a little bit like firing your CFO. You will let me spend, I know I’m in the red, but you will let me spend, and yeah, you’ll be able to spend a little more for a little time, but unfortunately,… If it works, I’m agnostic, anything that works will be great. So far it’s worked in animals, you’re driving the system to shut down its own protective mechanism and make protein when it otherwise is telling itself, I can’t afford to make protein right now. And yeah, maybe that’ll work, but I’m waiting to see what happens with human clinical trials, because my worry is again, you’re circumventing something, which is a natural protection.

Dale Bredesen:
So I’m concerned that it may be a short-term solution. Now, having said that all of these things, as part of the overall arsenal, when you’re doing the right things may be helpful. So for example, you may need to kickstart things into making the proteins again, into getting rid of that protective mechanism when you’ve now done everything else right. Hallelujah, it will be great to have a drug that helps you do that. So again, I think the long-term is, these drugs that are being discovered are going to be fantastic when used appropriately with appropriate understand it. I do think the future is all of us as physicians have to be good at strategizing biochemistry. So to think it’s not just anymore about, I give this drug because it worked in a double-blind trial. I’m giving this drug, knowing what all the changes in the system that it’s doing. So I am saying this system is out of whack because of a set of things. And I’m impacting that set of things. And part of that is going to be this drug.

Jacob Gordon:
That’s awesome. What should people be doing for prevention? I know you mentioned in your book pre-code and people should be getting a cognoscopy at the age of 50.

Dale Bredesen:
Yeah. You said 45 because we see people as you know, we’re seeing people late 40s, early 50s who clearly have cognitive changes. So we recommend anyone who’s 45 or over get checked, get a cognoscopy. It’s simple, it’s three things. It’s a set of blood tests, it is online cognitive assessment, very simple, and then the third piece, which is an MRI with volumetrics. If you’re asymptomatic, don’t worry about the MRI, just get the first two. If you’re symptomatic, you want to include an MRI. And then we develop this pre-code simply as a way to say, okay, here’s a set of things that you need to look at. Here are the blood tests and the urine tests that are critical for knowing what your risk. So again, just like knowing your cholesterol, people have done for years and knowing your lipid profile, you want to know whether you’re at risk for cognitive decline, because it’s always easier to prevent it than it is to reverse it.

Jacob Gordon:
Absolutely. I totally agree to that.

Craig Tanio:
If people want to know more and learn more, how can they find out more about you?

Dale Bredesen:
Yeah. Thanks so much, Craig and Jacob, appreciated the discussion. Lots to do so, yeah, you mentioned the books, you can go on drbredesen.com. If you’re interested in retraining or recode or pre-code, you can go on apollohealth.com. So any of those things to look at and, there’s Facebook Dr. Dale Bredesen as well and Twitter. So you can follow those as well. So any of those, there’s lots of ways to find out, and I do think again, we want to get the whole world to know that dementia should be rare and let’s get prevention or the earliest possible reversal, and really see a decrease in the global burden of dementia.

Jacob Gordon:
Thank you so much for coming on the show.

Dale Bredesen:
Yeah. Thanks Craig, thanks Jacob. Great to talk to you guys. Happy New Year, stay safe and stay and look forward to talking to you next time.

Jacob Gordon:
Okay, appreciate it. What a time to be alive with this type of technology, I’m really excited about our future. So thanks guys for listening, and I hope you enjoyed this episode of the Rezilir Way. If you want to find out more information about the Bredesen Protocol or how to prevent cognitive decline, I encourage you to head over to rezilirhealth.com or my biohack.com. As we’ve written up a few different articles describing Dr. Bredesen’s research. We also encourage all of our patients to read Dr. Bredesen’s The End of Alzheimer’s. Thanks guys. And I’ll catch you in the next episode.

 

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