RHR: Preventing and Reversing Alzheimer’s Disease, with Dr. Dale Bredesen

In this episode, we discuss:

• Common factors for neurodegenerative diseases
• What a cognoscopy is
• The subtypes of Alzheimer’s disease
• How your oral health impacts your Alzheimer’s disease risk
• The KetoFLEX 12/3 diet
• Positive outcomes for people with Alzheimer’s disease

Show notes:

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Hey, everybody, Chris Kresser here. This week, I’m really excited to welcome back Dr. Dale Bredesen as my guest.

Dr. Bredesen is an internationally recognized expert in the mechanisms of neurodegenerative diseases like Alzheimer’s disease and the author of The New York Times bestseller The End of Alzheimer’s, which we talked about on the former show. He held faculty positions at [the University of California, San Francisco] (UCSF), [the University of California, Los Angeles] (UCLA), and the University of California, San Diego, and directed the program on aging at the [Sanford Burnham Prebys Medical Discovery Institute] before coming to the Buck Institute [for Research on Aging] in 1998 as its founding president and CEO. He’s currently a professor at UCLA.

I’m really excited to talk to Dr. Bredesen again about Alzheimer’s disease. He has a new book out called The End of Alzheimer’s Program, the first protocol to enhance cognition and reverse decline at any age. So this is a sequel to his original book, and I know from being in pretty regular contact with Dr. Bredesen over the last few years that he has learned a lot in the course of treating hundreds more [patients with] Alzheimer’s [disease] since he wrote that first book, and has updated this protocol with all the lessons learned in treating these patients.

So I’m looking forward to learning more about what those new insights are and sharing them with you. So, without further delay, I bring you Dr. Dale Bredesen.

Chris Kresser:  Dale, it’s such a pleasure to have you back on the show. I’ve been really looking forward to this conversation.

Dale Bredesen:  Great to be back, Chris. Thanks very much.

Common Factors for Neurodegenerative Diseases

Chris Kresser:  So you really pioneered an entirely new approach to treating Alzheimer’s [disease] and other cognitive disorders, one that is really focused more on addressing the root cause and I think gave people with these conditions hope perhaps for the first time. And I’ve been so grateful and appreciative of your work in this area, and so many of our patients have benefited from it. And I know that since we first spoke, and since you first developed The ReCODE Protocol eight years ago, a lot has changed and you’ve learned a lot during that time.

So I’d love to spend some time today talking more about those new insights that you’ve developed from treating, I’m sure, thousands of patients with these disorders since you first developed The ReCODE Protocol and published your first book, The End of Alzheimer’s.

Dale Bredesen:  Thanks so much, Chris. And as you know, the things that we studied in the laboratory over 30 years and all the test tube research and transgenic mouse research and cell culture research and all that really brought us to a place that fits very, very well with the things you’ve been talking about for years. And we’re running into very many of the same things, which really convinces me that we’re on the right track because we’ve come from such different pathways and ended up at very much the same place. And as you said, it really is getting at [the] root cause. And it’s been so surprising to me that in the history of trying to treat cognitive decline, Alzheimer’s disease and frontotemporal dementia and Lewy body [dementia] and things like this, all the trials, for example, have predetermined the treatment. So you say, okay, we’re going to treat it with X, Y, or Z, this drug or this lifestyle change or what have you. And none of the trials has been a trial in which you say, we’re not going to predetermine a treatment; we’re actually going to look at all the underlying contributors. And so that’s where the science has helped to identify these contributors.

And so one of the things we’ve learned over the last eight years has been that this sort of approach should be valuable for all the different neurodegenerative diseases. In other words, they have one thing in common, which is that there seems to be a mismatch between the specific neural subsystems requirement, which is different for your macula than it is for your plasticity, and then Alzheimer’s disease, which is different than it is for motor modulation in Parkinson’s disease, and on and on. Each of these neural subsystems has a set of Achilles’ heels, and here’s an example. If you’ve got, if you’re inhibiting your complex I, for example, from your mitochondria because you’re exposed to specific toxins that you’re not aware of, for example, then, in fact, you’re going to end up having to downsize your ability to control your movements. Literally, you’re going to now have a tremor; you can’t keep still. You’re now going to walk more slowly; you’re going to be stooped over. We call that Parkinson’s disease. But it’s really because the subsystem, that particular one, the Achilles’ heel is complex I of the mitochondria.

On the other hand, in Alzheimer’s disease, of course, it’s the neuroplasticity signaling the synapto blastic signaling, which is making and keeping your synapses, versus the synapto clastic signaling, which is pulling them apart. And then in macular degeneration, [it’s a] different story again. It’s a very highly metabolically active region of your body, and, therefore, the way that you mess that up and get macular degeneration is that you don’t get enough oxygen to that region, you don’t get enough blood flow [and] you don’t get enough mitochondrial support. So although there are certainly overlaps in these different ones, each one has its own specific chemistry. And we should be able to now address this for everybody. So we call that the UARK project. We’re looking at small numbers of people with each of several different neurodegenerative diseases.

The second thing that when you and I talked last time, we weren’t quite, I wasn’t quite aware of at the time, and you may have known this at the time, but I didn’t realize how important it was. And that is that so many of us as we sleep at night are dropping our oxygen saturation. And, of course, we’d like that to be 96, 98 percent, something like that. There’s some very interesting research showing that just looking at the average of your oxygen concentration as you’re sleeping is directly proportional to the volume metrics of multiple, of the different nuclei within your brain, including critical ones for Alzheimer’s disease.

So for all of us who are sleeping and dropping down into the upper 80s, and we’ve had people even in the low 70s, often without knowing it without having full-blown obstructive sleep apnea, we are really impacting our brains over time. And so we found that it’s absolutely critical for these people to get that oxygen tension up, not only while they sleep, but also while they’re awake. And, in fact, many people turn out to do better with things like EWOT, with things like exercise with oxygen therapy. And so we’re beginning to understand that these are critical. The brains that we have are kind of like Maseratis. They’re going a million miles a minute here and they’ve really got to be supported optimally. And this old idea that they’re pretty strong and you can get knocked around a lot and you’re probably going to be just fine, and you can probably, you can damage it with lots of alcohol here and there, and it’s probably going to be just fine. That just turns out to be wrong. And we’re all putting ourselves at risk with everything from the diets we have and all the things that you’ve talked about. And I think we’ve come to very many of the same conclusions that you have about the importance of health coaches, for example, and the importance of mycotoxins and making sure that you’re living in the right place and things like this. These are all turning out to be critical for optimal cognition.

Chris Kresser:  Yeah, I mean, what’s so encouraging about this, I think, is that you’re developing these, as you said, unique signatures, if you will, for different issues in the brain. Motor problems like Parkinson’s [disease] and cognitive issues like Alzheimer’s [disease]. And not only that, also identifying more common contributing factors to each and correlating those with each signature. So the example you used for Parkinson’s [disease] with toxins was really interesting because I imagine you might be familiar with Dr. Ray Dorsey’s book that was recently published [called] Ending Parkinson’s: A Prescription for Action in which he talks about the huge body of evidence linking exposure to pesticides, solvents like [trichloroethylene] (TCE) and then heavy metals like lead and mercury and numerous other chemicals to Parkinson’s. And this was something that I think a lot of people in the Functional and integrative medicine community have been talking about for a long time, but it’s now really quite mainstream, in terms of the recognition of the role of toxins in Parkinson’s. And I think that that’s happening now in large part because of your work with Alzheimer’s. Whereas before, the idea was gee, shucks, bad luck, right? This just must be your genes that predispose you to getting these diseases. We don’t really know why they occur. And, therefore, we don’t really have much to offer other than a drug to try to slow the progression. Although, as you pointed out before, no such drug has really ever even been developed in the case of Alzheimer’s despite 25 years of effort.

Dale Bredesen:  Right.

Dr. Dale Bredesen is a pioneer on the Functional Medicine approach to Alzheimer’s disease and, in this episode of RHR, we discuss his newest book on the subject. Check it out for more on his updated approach to treating Alzheimer’s. #functionalmedicine #chriskresser

What Is a Cognoscopy?

Chris Kresser:  So this really gives people the possibility of not only preventing these conditions by addressing these factors in advance but also sometimes possibly slowing the progression and even reversing the progression of some of these conditions. One of my favorite sayings of yours is we don’t need a silver bullet, which is the drug that’s going to cure Alzheimer’s, but we need silver buckshot. So what you’re talking about here is that there are multiple contributing factors, the buckshot. And that’s what we need to be testing for and addressing. And you do this with what you call a cognoscopy, which is, of course, a play on colonoscopy and endoscopy and other procedures that we use to assess the health of the digestive tract. So tell us what a cognoscopy is and what you’ve learned. How [has] the cognoscopy evolved over time based on what you’ve learned?

Dale Bredesen:  Yeah, that’s a great point, Chris. And I did read Ray’s book and thought it was excellent about Parkinson’s. And part of the issue then is if, this has been an area where, as you said, we haven’t had an understanding of what causes these neurodegenerative diseases, nor have we had anything to offer. In fact, Parkinson’s was, “the good one,” because we could actually give Sinemet, which, again, doesn’t change at all the degeneration itself. So what we want to do then is increase our data set size, and just as you do when you’re evaluating your patients, we want to understand. And the good news is, the research guides us to say, here are the things that actually affect the signaling. In this case, as you said, neuroplasticity signaling, what is actually impacting amyloid precursor protein driving it toward synapto plastic versus synapto clastic signaling. And we can literally trace the pathways.

So, of course, we want to know if you have ongoing inflammation. In fact, [nuclear factor kappa B] (NF-ᴋB) actually enters the nucleus and activates hundreds of genes. And among them are the proteins. In fact, the genes for the proteins that cleave [amyloid precursor protein] (APP) on the synapto clastic side at the beta and the gamma site. So you can trace a direct pathway from inflammation to the production of a beta, which collects in the plaques in Alzheimer’s disease. And why would that be? Well, it actually makes complete sense because amyloid beta has turned out to be a part of your innate immune system. So it is actually an antimicrobial and interestingly also toxin binding peptide, which you are activating when you have these various insults. So anything that leads to inflammation is putting you at greater risk for Alzheimer’s disease. And that can be local inflammation from things like molds that are actually in your brain, and looking at the Alzheimer’s brain you find everything from oral bacteria, to molds from your sinuses, to Borrelia to Candida. It’s actually amazing what you find in the brains of patients with Alzheimer’s disease. So anything that triggers that inflammation.

And it’s a little bit like, we’ve learned so much in COVID-19 about comorbidities, and Alzheimer’s and COVID-19 have some really interesting parallels. With Alzheimer’s, of course, it’s over decades that you have things like insulin resistance and ongoing inflammation. COVID-19 has compressed these various comorbidities, including things like obesity and type 2 diabetes and hypertension, all these down into a couple of weeks. But it’s the same idea that you have a mismatch between the innate immune system where you’ve got the ongoing inflammation and the adaptive system, which is not keeping up, unfortunately. And so you get the cytokine storm, of course, in COVID-19. And with Alzheimer’s, you get this, what we call innate system immune stimulation, which just goes on for years, and keeps you producing this amyloid, unfortunately. Because you’ve never managed to get the adaptive system to clear this. And that can be because you’ve got continued exposure to these various molds or various oral pathogens or what have you. Or it could be because you’re not particularly good at clearing it. People who have, for example, poor phagocytosis. And how do you get poor phagocytosis? Lower your vitamin D, lower your omega-3s, things like that will give you a poor ability to phagocytose these and to present them appropriately.

So for the cognoscopy, what we really want to do is understand that. So number one, [we] want to know if you have ongoing inflammation. Number two, we want to know if you have insulin resistance or glucotoxicity. What’s your hemoglobin A1c? What is your fasting glucose? And what is your fasting insulin? And then we want to know what about the support side? It’s a mismatch between the demand and the support. So you need to know the support and that includes the various hormones, estradiol closely linked, as you know, to Alzheimer’s disease. Testosterone, critical progesterone, pregnenolone, [dehydroepiandrosterone] (DHEA), free T3, free T4, reverse T3. All these sorts of things. So we want to know your support. We’d like to know your [brain-derived neurotrophic factor] and your [nerve growth factor]. There’s not a simple way to measure that directly in the brain right now. I hope that that will be available at some point with things like neural exosomes, but the exosomes, I have to say, have come along very slowly as ways to evaluate these things. They look very promising. But the realization of that promise has been very, very slow.

And then we want to know, just as you indicated, about the various toxins. Absolutely critical and that’s been another thing over the last eight years that has really shocked me. Because I was never taught in neurology residency that Alzheimer’s disease was going to be often due to biotoxins. But it’s turned out, as you know, that this has been a huge problem. So the toxins are basically three different groups. We want to know about metals and especially mercury, which is the most important one for Alzheimer’s disease. And then other ones that can contribute. Things like copper load and iron load. Things like that. Lead and arsenic and all these sorts of things. And then we want to know about other inorganics because air pollution has emerged just over the last few years as being a very clear player in [the] risk for Alzheimer’s disease.

And then the second group, we want to know with the organics, of course. So we’d like to know, propylene oxide, we’d like to know acrolein. Acrolein is coming out repeatedly as something that is putting people at risk, which has been a bit of a surprise. And, of course, this is something that’s in various pesticides and herbicides and things like that. But it’s also incomplete combustion. So if you’re hanging around car exhaust, or if you don’t have good ventilation in your car, you are at risk for having [an] increased load of acrolein, as an example. And then the third group, as I mentioned earlier, the biotoxins, of course. Things like the trichothecenes and gliotoxin and ochratoxin A and things like that. And, of course, so many of us are living in mold. We often live in mold food, our homes, the way they are designed and built. And we don’t know it until we have a problem, be it asthma or rashes, or cognitive decline. And it’s been surprising how commonly these things affect us. And especially, of course, the ones who end up having nulls in their various detox pathways, [glutathione S-transferase] (GST) and [glutathione peroxidase] (GPX) and things like that, and poor methylation pathways and some of the things I’m sure you’ve heard about. You’ve talked to Sharon Hausman-Cohen about her Intellexx[DNA] approach, and others have done similar things with looking at what actually allows you to detox.

So if you are a poor detoxer, and you’re living in a place that happens to have these toxins, and often people don’t recognize that. We had one person who was going to work and they were doing a lot of candle burning. And over time, this actually led to her, and you can see the signature in her blood, of specific candle-related toxins such as toluene. This led to her cognitive decline. Another person who was in the World Trade Center cloud ended up [with the] same story. And again, you could see the signature of that cloud in her evaluation. So these sorts of things we often are unaware of. So for a cognoscopy, we’re basically practically speaking doing this with three things. Number one, blood and urine tests. Pretty straightforward with the things that we just talked about. Number two, looking at an online cognitive assessment, which is pretty quick. You can do it in about 30 minutes or so and save all the hours and hours that the classical neuropsychological testing took and save a lot of that stress, as well. But you want to know where you stand. Many people who are coming for prevention have already started down the path. And so it’s very fortunate that they’re coming in early on because it’s very easy to see improvements with people who aren’t too far along.

Chris Kresser:  Yeah.

Dale Bredesen:  We see it later, but [it’s] not always as easy. Then the third thing is, if you’ve got symptoms, you also want to make sure to have [a magnetic resonance imaging] (MRI) [scan] and include the volumetrics so that you can see if you have any shrinkage, any atrophy in your hippocampal region especially.

Chris Kresser:  So this is, of course, one of the biggest differences between the conventional approach and the approach that you take, is the amount of testing that’s done up front. And I think for people who are not familiar with this kind of Functional approach, that can be off-putting and intimidating because it can be costly and time-consuming and all that. But if we proceed from the premise that this approach is all about identifying and then addressing the underlying causes of cognitive decline, there’s no way of knowing what those causes are without doing the testing. So even though you may need to spend more money and time doing that testing up front, if it can lead to slowing the progression or even reversing the progression of this disease, there are very few people, I think, that would say that that’s not worth the effort and time up front. I think it’s just such a different approach, and so different from what is offered in the conventional paradigm, that people may be surprised or unfamiliar with that.

So what has your experience been with that? And, of course, one of the challenges that we both face is that a lot of this testing isn’t currently covered by insurance. And so this kind of approach is not accessible to people who aren’t able to afford this testing up front. So what have you seen in regards to this and what do you think is possible going forward?

Dale Bredesen:  Yeah, that’s absolutely true. And so, unfortunately, the standard approach to cognitive decline has been completely upside down. So it says, don’t come in until you’re really late because there’s nothing we can do anyway. And then we’re going to check a small number of things because nobody knows what causes this, [and] there’s nothing we can do about it. Then we’re going to give you a drug that doesn’t work. And then you’re going to spend the vast majority of your money on a nursing home. That’s just the opposite of what should be done. And so what we’re doing is saying, okay, please come in as early as possible. If everybody would get on prevention or earliest reversal, we could truly make dementia a rare condition in the world. And that’s the goal, to reduce the global burden of dementia. And figure that instead of spending, what is the average? So how much does it cost the average person to go through Alzheimer’s disease? The number is actually $384,000, what it actually costs to have this disease from when you get it to when you die. And a lot of that, of course, is spent in [a] nursing home.

And, of course, some people, it’s two or three times that. Now if you come in and get evaluated, then it’s going to cost you on the order of 2 percent of that, 3 percent of that, something like that. And so yes, it’s going to cost you something, but what better investment could there be than an investment in your brain where you’re going to prevent these nursing home bills, keep yourself out of the nursing home, and, hopefully, keep yourself sharp for decades to come?

Chris Kresser:  Right, and I mean, what price can you put, [what] value can you put on maintaining your mental clarity and cognitive function as you age so that you can continue to contribute and interact with your family members and be cognizant of what’s happening around you? I mean, it’s almost impossible to put a value on that. And I’ve used a similar example of diabetes costing $15,000 a year and someone being diagnosed at age 40 and dying at age 80. That’s $600,000. And if you spend even just a few thousand dollars up front, you can prevent diabetes from ever happening and save the healthcare system and the person that money. But [it’s] not just the money. It’s the quality of life, which is really priceless. So first …

Dale Bredesen:  I’m just going to mention I’m just finishing a book called The Gene Guillotine written by just a courageous woman, Kate Preskenis. And boy, if anybody questions putting money up front to keep themselves out of a nursing home, please read The Gene Guillotine by Kate Preskenis because she talks about what her mother went through, and just how difficult this is. Their family has a specific mutation that makes it so that many of the members of the family, unfortunately, develop Alzheimer’s. And it’s just really tough to read about and from someone who’s just experienced that firsthand, and it really shows you why if [there’s] anything possible to prevent or reverse this problem, you want to do it.

The Subtypes of Alzheimer’s Disease

Chris Kresser:  Absolutely. So in your first book and in the first version of the ReCODE Protocol, you identified three distinct subtypes of Alzheimer’s disease. And it was inflammatory, which is pretty self-explanatory, toxic, which is again self-explanatory, and then atrophic, which is a term listeners might not be aware of, which basically referred to deficiency of hormones that are important for maintaining various body systems like estrogen in women and testosterone in men. And now you have added three new subtypes, it looks like, based on the clinical experience you’ve had over the past several years. So tell us a little bit about what those subtypes are.

Dale Bredesen:  Yes. So what we found is as we, again, as we look through various people and find out what’s driving the disease, which is the whole goal of the evaluation, so that we can target those things, we found that there are three additional ones. And so one of them is glycol toxic or sweet. We call this type 1.5. Because having high insulin and having sugars over the years, not only, of course, [increases your risk for] type 2 diabetes, but it also increases your risk for Alzheimer’s rather dramatically. And it does this both through the inflammatory side, you’ve got the glycation of the proteins a little bit like remoras on the shark so that you alter the function and the structure of these proteins and your body can recognize them as foreign. And then that gives you some of the type 1 inflammatory part. But you also develop this clear insulin resistance, where you have specific phosphorylations on serines and threonines in [insulin receptor substrate 1], and as Professor Ed Goetzl has shown, virtually everybody with Alzheimer’s disease has some degree of central insulin resistance whether or not they have it peripherally. But because you’re actually altering the phosphorylation on this signaling protein. So, therefore, you don’t get that nice trophic response. When we used to grow neurons in the lab, we would always have to include insulin, transferrin, and selenium in the bathing medium to keep them alive because insulin is a wonderful neurotrophic factor, just as brain-derived neurotrophic factor is, just as nerve growth factor is. These things are all critical for [the] best outcomes.

You’re unfortunately dismantling this wonderful neural network that you have when you have Alzheimer’s disease. So part of the way to dismantle that is to give yourself insulin resistance. So that’s type 1.5. Type four is vascular. And it has been striking. It used to be said that you either had vascular dementia or you had Alzheimer’s disease. As you know, it’s turned out that these things are much more intimately related than we realized initially. And, in fact, just the vascular support of brain tissue turns out to be critical for cognitive support. And very commonly, as you’re getting Alzheimer’s, unfortunately, it’s a little bit of a vicious circle. You’re decreasing your blood flow, [and] you’re now lining these vessels with amyloid, which further decreases the blood flow, which further gives you more amyloid. So you just go around and around, unfortunately. And you can get things like micro-strokes as part of this.

As you know, you also have a leakiness of the blood–brain barrier. And, of course, Professor Fasano has written so nicely about this and its relationship to leakiness of the gut. So all these things are contributing. So we call this a type four or vascular Alzheimer’s and it’s a very common contributor. And part of the treatment to reverse that is to optimize the flow, the oxygenation, and, of course, what it’s actually delivering to these regions of the brain. And then type five is traumatic. Of course, there are many people who do have [an] increased risk for cognitive decline being related to head trauma. We think often about chronic traumatic encephalopathy (CTE), which was so nicely shown in the film Concussion with Will Smith. But, in fact, there are a lot of people who do have Alzheimer’s also related to this. And basically, CTE is a little bit like Alzheimer’s, but you’ve just been effective enough at clearing out the amyloids. So what you’re left with is a tauopathy that we call CTE. And that you can actually pick up because they tend to have the triad of aggression, depression, and dementia. So if you see that triad, then you really have to think about a component of trauma.

So these are the things that we’re running into again and again and again, and addressing these and understanding where they came from, as you said earlier, the root cause analysis, I think, is really linking basic science very nicely with Functional Medicine.

How Your Oral Health Impacts Your Alzheimer’s Risk

Chris Kresser:  Let’s talk a little bit more about oral health. We actually touched on it kind of indirectly when you were mentioning hypoxia and apnea. Not necessarily full-blown sleep apnea. I think this is a mistake that’s often made where somebody goes in, gets a sleep study, and the doctor says, “Hey, good news, you don’t have apnea. But you may have some transient low oxygen events.” And the implication there is there’s no risk. But you’ve shown there [are] lots of data that show, as you mentioned earlier, that there may actually be [a] risk even with mild hypoxia. And one of the potential causes of hypoxia is malocclusion of the jaw. The lower jaw recessed and when you’re lying down, that makes the airway narrower and makes it harder to breathe. So that’s one of the potential causes of apnea.

And there are dentists out there who are now doing what is sometimes called dental orthopedics where they use devices to bring the lower jaw forward and open the airway. And this can be done with mandibular advancement devices, which is kind of a temporary, non-permanent fix, or it can be done with devices like the [Advanced Lightwire Functionals] or Invisalign, [which] can more permanently change the structure of the jaw and open the airway. But there are other aspects of oral health I think that we know more about now as contributors to cognitive decline. Let’s talk a little bit about those.

Dale Bredesen:  Yeah, that’s absolutely right. And that’s been one of the common causes that we didn’t think was such an important cause six years ago with the first paper and has turned out to be very common. So, in fact, a lot of your risk for Alzheimer’s does come from the oral region. You can start with things like, as you said, reduced airway with obstructive sleep apnea. Then you look at the mercury that people have with their amalgams. And then you look at the oral microbiome. And you and I touched on this before talking about the rhinosinal microbiome a few years ago. Of course, we think a lot about the gut and the gut microbiome. But the oral microbiome turns out to be incredibly important. And just as we think about okay, it’s not about having the germs or not having the bugs, not having the bacteria, etc. It’s really more about what the distribution is.

So there are very specific pathogens and you can start with Porphyromonas gingivalis is one, [Treponema] denticola, [Fusobacterium] nucleatum, and Prevotella intermedia, all these. There are specific pathogens that really form the basis for very significant periodontitis and gingivitis. And these are the guys that you don’t want [to have] access to your brain. And so a good test is just to look at an oral DNA test to look at whether, in fact, you have a lot of these pathogens or whether, in fact, your oral microbiome is in good shape. And it turns out to be a very important thing. So one of the things that we suggest for many of these people is Dentalcidin toothpaste and Dentalcidin mouthwash. You’re trying to improve your microbiome. These things are found in the brains of patients with Alzheimer’s disease. It’s not 100 percent clear how it is that they’re getting from the mouth to the brain, but somehow they indeed are.

In addition to these various pathogens, of course, you’ve also got herpes simplex type 1 on [the] lip, which many of us have, as outbreaks again and again. And some very nice work out of Taiwan [shows] that people as they were aging, who actually dealt with this as they got the outbreaks, reduced their risk for dementia rather markedly. More than 50 percent reduction in their dementia. And, of course, Professor Ruth Itzhaki has spent her entire career showing the relationship between herpes simplex 1 and risk for Alzheimer’s disease. It is unlikely to be the only cause, and so many times we hear, well, so this is what it is or that is what it is. It doesn’t seem to be one thing. It is a pathology. The pathologist[s] say, this is what Alzheimer’s is and we’ve got to look, evaluating these patients we’ve got to look at what is driving that pathology. And certainly, recurrent [human] herpes[virus 6 variant A] (HHV-6A) is another important one. So all these things and HHV-6A probably coming in through the sinuses. So no question, as you indicated, many things from the oral and dental region [are] very important. Periodontitis, gingivitis, amalgams, the herpes simplex lip. Again and again and again, these things are critical in your risk. [They’re] all good things, too, to evaluate and take care of.

The KetoFLEX 12/3 Diet

Chris Kresser:  So I want to talk a little bit about diet because I know you have a relatively new program that wasn’t fully conceptualized the last time we talked and had you on the show, called The KetoFLEX 12/3 lifestyle approach and brain food pyramid. So tell us what this is and how you arrived at this approach for cognitive decline.

Dale Bredesen:  Yeah. And, of course, you know far more about diet than I do. We are just asking what is the way that we can drive a person’s biochemistry toward producing and maintaining synapses? How do we get there? And there are, of course, lots of ways to do that. And diet is an important part of it, perhaps the most important part of it. And so what’s come up again and again and again, I’m agnostic of things, this may change over time. But what has worked so far and what has been published to be working so far is something that will drive you, as you know, into mild ketosis. You want to be in that 1.0 to 4.0 millimolar beta-hydroxybutyrate range. Something that has high fiber, something that has a number of colorful plant things like anthocyanins and all the various colorful things that we’re looking at. Polyphenols and so forth, so on, that have, again, been shown to inhibit cognitive decline. And you want to have appropriate fasting.

And then, of course, the fiber critical for your glycemic index, for your lipid profile, for detox. It’s amazing how important that is. So if you put all these things together and ask what is a diet that actually works, we call this KetoFLEX 12/3. And the idea is it’s mildly ketotic, it’s plant-rich, and sure, fish, wonderful. Make sure they’re not high-mercury fish. But [salmon, mackerel, anchovies, sardines, and herring], things like that, and getting appropriate omega-3s. Very, very important. And obviously high choline. One of the things that’s been striking to me in the last few years is how many of us are deficient in choline.

Chris Kresser:  Yeah, I’ve seen 97 percent is one estimate that I’ve seen.

Dale Bredesen:  Really?

Chris Kresser:  Yeah.

Dale Bredesen:  Incredible.

Chris Kresser:  Don’t get enough. Yeah.

Dale Bredesen:  Yeah. Incredible. So we should be getting about 550 milligrams of choline per day. And one of the things I’ve been doing during COVID-19 is going through my own Cronometer each day and just see where I stand. And I find, just like the vast majority of Americans, I do not typically get enough choline unless I make sure to add some to my diet. And, my gosh, that’s one of the last things you want to be low on because acetylcholine made from the choline is the most critical transmitter for memory. So, again, if you want to give yourself Alzheimer’s disease, make sure you’re low in choline as well as these other things.

And so that’s the sort of diet you want to have. KetoFLEX, it’s ketotic; it’s flexitarian. Yeah, you can have meat if you want to have the right kind of meat. We typically go for one gram per kilogram per day. But I know there [are] all sorts of, people keep saying this diet’s better, that diet. A lot of recently on pure meat diets. Nothing has been, and for some people with autoimmune disease, it seems to be helpful. Hallelujah, whatever works. But so far, nothing has been published to suggest that a pure meat diet is the best thing for your cognition. So [in] the KetoFLEX 12/3, you want a minimum of 12 hours of fasting and a minimum of three hours between finishing the last meal and going to bed. So when you put those things together, you seem to get the best outcomes. And we, again, we see people get more, become more insulin sensitive. We see them drive themselves into mild ketosis, we see them improve their cognition, and, most importantly, we see them sustain their improvements. And that’s probably the single most important thing of all. We have people who are now over eight years on this protocol because the first person started [in] April 2012, and [they are] still sustaining their cognition really well. So that’s the most important piece. We’d like to target the things that are causing it so that we can get you better and keep you better for years to come.

Chris Kresser:  Yeah, we use a similar approach that’s a combination of [the] ketogenic diet, intermittent fasting, and also some longer periods of fasting with refeeds and have just incredible results with that. And I, we use lots and lots of different elements of your protocol and I still see diet often making the biggest difference, especially in terms of the longer-term result. And as you said, people being able to maintain the changes over a sustained period of time.

On that note, I’d love to step back a little bit and talk about just what you’ve seen in the past decade of using this protocol and refining and tweaking it. Because still, I think in most people’s minds, the diagnosis of Alzheimer’s is just a death sentence. And it’s also kind of assumed that it will just progress and get worse. That’s the only direction that it’s going to go. And so I’m curious to know what you have witnessed over this past decade in terms of the range of possible outcomes. I know, of course, it varies based on so many different factors, many of which we’ve already covered. People’s genetics, their epigenetics, their contributing triggers, and factors that you’re addressing and how successful you can be in doing that, their compliance with the protocol, where they live, whether they’re able to get out of their exposure to biotoxins if they’re living in mold, all these factors, of course, determine the outcomes. But is there anything general that you can tell us about the types of outcomes that you’re seeing and what people could expect if they themselves have a cognitive issue, or maybe a family member does, and they’re thinking about going down this road?

Positive Outcomes for People with Alzheimer’s Disease

Dale Bredesen:  Absolutely. So we published a paper in 2018, documenting 100 cases in which all [100] had improvements so that we could see improvements in electrophysiology, improvements in volumetrics. And so we’ve been able to gather some more data. For many people, as you know, people are out there practicing and they don’t always get a baseline. They don’t always get the follow-up data. But where we do have it in those 100 patients, all of them improved. Now, of course, that wasn’t the denominator. There were others who didn’t. But those were the ones that we wrote up as here are 100 people; it’s not just 10. Here are 100 who we have clear evidence of improvement. And now we’re actually writing up one person who had because we’ve got [positron emission tomography] (PET) scan data before and after showing an improvement in the PET scan data. Volumetrics before and after showing an improvement in hippocampal volume. And then, of course, the cognitive assessments. Quantitative cognitive assessments showing improvement and showing us sustained improvement in someone who clearly had a diagnosis of Alzheimer’s disease.

So we’ve seen some remarkable stories like this when we are, although 95 percent, as you know, of Alzheimer’s is the sporadic kind. You have a risk, for example, from APOE4, but you’re not destined to get it. [In] less than 5 percent, you actually have mutations in APP, [presenilin 1] (PS1), or [presenilin 2] (PS2). And in those cases, it’s been in the past 100 percent penetrance. Now we’re just starting to see it. In fact, can we get a program that will actually stop that, as well? And that’s going to be very interesting to see. I think there’s a good chance starting early enough and doing the right things, we may be able to impact that, as well. But time will tell. We’ve had people, just a couple quick examples, someone who came in saying I’m here for prevention ended up having a [Montreal Cognitive Assessment] (MoCA) score of 23. So it was well into [mild cognitive impairment] already, now has a MoCA score of 30 doing absolutely beautifully. And that’s a kind of typical good story where we get people to recognize it early. Come in before things are too far along. Virtually all the people who come in early and do the right things will improve and sustain their improvement.

On the other hand, I had a note recently from a guy who was angry because we had said, “Look, if it’s late, you might want to think twice.” He said, “My wife had a MoCA score of zero. She’s clearly better.” He said, “Her MoCA score is not much better, but she interacts with us. She can dress herself again; she can do many things she couldn’t do before. She’s talking to us again. So how dare you tell people that it’s not a good idea to get going late.” So there’s an example where someone who was late on, although, of course, the later it is, the tougher it is.

Chris Kresser:  Sure.

Dale Bredesen:  There was one with. What’s that?

Chris Kresser:  I said sure, yeah, that’s true with just about any condition we know of, right?

Dale Bredesen:  Exactly.

Chris Kresser:  An ounce of prevention is worth a pound of cure has been frequently.

Dale Bredesen:  Absolutely. And then you probably know Dr. Heather Sandison from San Diego who’s opened what she calls Marama, which is the first assisted living facility that focuses on this protocol. And the whole idea is here’s an assisted living facility where you don’t come and stay; you come, you get treated, [and] you leave. And it was just so wonderful to hear the stories. The first woman who’s come in is sitting there saying, “Okay, I’m making plans for what I’m going to do when I’m leaving here and go back to my grandchildren” and all this. So just, things that you’ve never heard before. Really exciting. And more and more people, thankfully, and I’m sure you’re seeing the same thing, Chris, more and more people are coming in and saying, “I’ve got this in my family. I want to make sure I don’t get it. And now I realize there actually is something that I can do about it.” They’ll get on appropriate treatment.

Well, I just heard of one a few days ago, surprising, who actually started having some problems at the age of 28. Really surprising and then finally came in. And her doctors kept telling her, forget it, you’re just nervous. But we don’t know what it is, etc. [They] finally checked when she was 34 and [it] turned out to be APOE4 homozygote. And so [she’s] just starting up, and she should do very, very well. And so we’re seeing these sorts of things again and again. And on the other side, we are seeing people where they’ll write in and say, “I tried this for six months, [and] it’s just not helping.” And we look into it and so we have a whole troubleshooting algorithm. And we look at it and say, “Okay, let’s start with the beginning. What’s your ketone level?” “Oh, I don’t check that.” “And where’s the status with detox?” “Well, I didn’t do that part.” So yes, if you wait until very late, and you don’t do the right things, you don’t get better.

So I think the thing to emphasize is this is not easy. I think a lot of people felt that oh, okay, good. Now there’s something to do. I’ll just do parts of it. I’ll take some supplements and that sort of thing. And I’ll be fine. And, unfortunately, this has [not] turned out, as you know, very well. This has turned out to be much more like surgery than old-fashioned medicine. You have people like yourself that are getting repeatedly good results. And others. Dr. Kathleen Tubes, Dr. Ann Hathaway here in the Bay Area, just repeatedly wonderful results. And you have other people who are just not getting good results repeatedly because they’re not doing things right or they’re not getting the people to change their behaviors. They’re literally not changing that biochemistry. This is all about changing the critical signaling in your brain so that you can turn around from pulling back on the synapses to now laying them down and sustaining them, and you just can’t do it partway.

Chris Kresser:  Right. And this is where we both arrived at the importance of health coaching because there are obviously a lot of moving parts with a protocol like this, and especially if someone is dealing with cognitive challenges, it’s going to be even more difficult for them to comply with it and stick with it. So this is where a health coach can be a huge asset.

Dale Bredesen:  Absolutely, I think the health coaches are some of the most important people because they are the ones that are determining whether the person who’s trying to get better is going to have their best chance or not. I know I should add, we’re just starting; we’re just coming out with PreCODE. We have ReCODE, as you said, which is for reversal of cognitive decline. So we’re just releasing PreCODE for prevention of cognitive decline, which is a simpler protocol, Fewer things you have to measure, fewer things you have to do, which we believe everybody should be on for prevention, and a specific group of people who are the caretakers. As you know, the caretakers for people with dementia are at high risk for stress-related conditions such as hypertension, cerebral hemorrhage, gastric ulcers, things like that. And so we hope that, in fact, everybody will ultimately be on prevention.

Chris Kresser:  Yeah. When they want to study the effects of stress, they go get a bunch of caretakers and enroll them in the study. That’s how bad it is.

Dale Bredesen:  Exactly.

Chris Kresser:  This has just been a fascinating conversation, Dale. And I’m, again, so grateful for all the work you’ve done in this area in giving people hope who didn’t have any cause for hope before. I mean, it’s just such important work, and I applaud you for it. And it’s made, it’s given me the ability to help these kinds of patients in a way that I wasn’t able to before. So I’m very appreciative of that.

So let’s talk a little bit about resources. So let’s say somebody’s listening to this, [and] they suspect they might be dealing with the early stages of cognitive impairment. Perhaps they have a family member that is or they’re dealing with later stages. How can they, if they’re interested in doing this protocol, where can they go to get help?

Dale Bredesen:  Yeah. And let me first say, Chris, I appreciate your leadership role over the years. You’ve trained so many people, so much teaching, so much clarification of where this is all going and always being on the leading edge. So thank you very much for all the things you’re doing. With respect to where people go, they can go to MyCognoscopy.com or DrBredesen.com to get more information. They also can get more information either in the book The End of Alzheimer’s, which is now in 32 languages, or they can get it from The End of Alzheimer’s Program, which will be out on August 18.

Chris Kresser:  Right. So tell us a little bit about this book versus the first book. If someone has not yet read the first book, should they start there? Or does this book contain much of that material as well as updates? What would you recommend there?

Dale Bredesen:  Great point. So the first book is conceptual. It’s all about okay, here’s what the research told us Alzheimer’s actually is. That’s been the big problem, as you know, people don’t know what it is. It’s called a name, Alzheimer’s. It’s like saying when you take your car into the mechanic, oh, we know what this is. This is called car not working syndrome. It’s just a name. It doesn’t mean anything. And so you really want to know what’s driving it.The first book was about the concept. And then it began with okay, well, then that means you probably want to do this, that, and the other. Everybody said after the first book, hey, but wait a minute, we want more specific[s]. We want details. What are the URLs? Where do we go? What are the workarounds? How do you troubleshoot? What if this is not working for me? All these sorts of things. When should I get on this? What brand should I buy? All that.

And so what I did was to link up with someone who is doing this daily and has done exceedingly well. And this is Julie G., who is the one who started ApoE4.Info, which is a wonderful place for many people to look at. Very helpful with respect to people who are APOE4 positive. And so Julie and I, and then along with my wife, Aida, who is a clinician. So we have a scientist, a clinician, and a daily user collaborating. So I think this is a unique combination where we can have different pieces of it as a handbook. So within this book, the major part of this new book is a handbook that gives you all the details. And then, in addition to that, we have the new science, the various pieces on dementigens that we didn’t know about before. The various pieces, as you mentioned, the new subtypes and things like that. And then can we apply this to other neurodegenerative conditions? And then, finally, what’s the future here?

So this book is about details. So I would say [for] anyone who wants the conceptual background, the first book would be [the] better one. [For] anyone who wants the details on how do I do this for myself or my loved one, then I would recommend this book.

Chris Kresser:  Great. And, as you know, we have a lot of listeners who are both clinicians and health coaches. So for those that would wish to pursue training as a practitioner, or a health coach, where can they find more information about that?

Dale Bredesen:  So they can actually do that at ApolloHealthco.com. You can also get it through DrBredesen.com. And there is a training program, and we actually have ReCODE 2.0 training that is just finishing up. [It] should be available in August. I am going through all the updates to the protocol and all those sorts of things. So the training will be out and there will be a coach training, as well, and Christine Coward is leading the health coaching at Apollo Health.

Chris Kresser:  Awesome. Thank you so much, Dale, for coming back on the show. It’s been a pleasure. And thanks, everybody, for listening. Keep sending your questions to ChrisKresser.com/podcastquestion. Make sure to pick up both of Dr. Bredesen’s books if you haven’t already. They will completely change your view on cognitive disorders, including Alzheimer’s and what the possibilities are. It’s liberating and hopeful, and I highly recommend them. So [I] look forward to our next conversation, Dr. Bredesen, and please let us know, keep us posted with any new developments.

Dale Bredesen:  Thanks so much, Chris. I really appreciate all the great work you’re doing.

Chris Kresser:  Take care, everybody. We’ll talk to you next time.