Rhonda: Hello everyone. I'm really excited to be sitting here with Dr. Dale Bredesen, who is internationally recognized for his understanding of the mechanisms of neurodegenerative disease, particularly Alzheimer's disease. He holds faculty positions at University of California Los Angeles and the Buck Institute for Research on Aging. In fact, he was the founding president and CEO of the Buck Institute back in 1998, so that's really kind of cool. And he also is an author of a "New York Times" best-selling book called "The End of Alzheimer's Disease," which I'm sure we're going to talk quite a bit about today. It's got a really interesting multi-pronged protocol for preventing and also helping treat mild cognitive dementia and Alzheimer's disease. So thank you so much, Dale, for having me here at your place.

Dale: Thanks very much, Rhonda.

Rhonda: So maybe we can start a little bit by just talking about some of the characteristics and pathological distinguishing features of Alzheimer's disease and maybe what your thoughts are on what can cause Alzheimer's disease or leads to it.

Dale: Right, so it's a good point because cognitive decline, very common, and Alzheimer's is the most common cause of cognitive decline, ultimately dementia. And by definition, this means that you have amyloid plaques in the brain and phosphorylated tau tangles. So those are the two main pathological hallmarks of Alzheimer's. But as you can see, that doesn't tell you why you got it, it just is something you look at the brain, and of course, you can get something that looks virtually identical without the amyloid and you can get amyloid without the cognitive decline. So, it's a marker but it's an imperfect one.

Rhonda: Yeah, that's a really good point you brought up. And do you have any thoughts on why there are some people that do have amyloid plaques in their brain that aren't demented and then some others that just don't seem to handle it?

Dale: Yeah, it's a great point. So, here's the thing, the whole world is turning upside down now when it comes to our understanding of Alzheimer's. It's been over 100 years, of course, going back to Alois Alzheimer's publications back in 1906 and 1907, and there hasn't been a good understanding of this disease. And of course, amyloid has been for years vilified and there's no question, it is a neurotoxin. It does have toxic effects. The surprise has been that this is also a protectant. It's actually something that is made by your brain when you have specific insults.

And for example, Professor Rudy Tanzi and Professor Robert Moir of Harvard a few years ago showed that it is an antimicrobial. It also, as Professor Ashley Bush showed a number of years ago, it's actually quite a good binder of divalent metals like copper and zinc, and things like that, iron. And we showed a number of years ago, it is also a response to a reduction in trophic support, so you actually get a change in signaling. So, there are multiple different insults and metabolic changes that lead the brain to produce this stuff.

And so I think there's been confusion because it's clear that when you produce it you're at this increased risk for having a degenerative process, but as you indicated, there are many people that produce it and they successfully are protecting themselves, they don't actually have the downsizing. What's often been stated is those who then have inflammation on top of that seem to be the ones that do worse, and that's a very general idea, but really it is a set of things. And we identified and published, a number of years ago, 36 different factors that all contribute to this, but they actually break down into just a couple of categories.

So, any sort of pathogens, anything that's giving you inflammation, whether you have it because you have a leaky gut or because you have P. gingivalis in your brain, or because you have Borrelia of Lyme disease, or you've been exposed to specific fungi, things like that, all of these things can engender that response. And in fact, we think more and more of amyloid as being like napalm. You got the bad guys coming across the border, so you're now going to put down stuff that kills the bad guys, the napalm but in so doing you're now going to reduce your arable soil. You're now living in a smaller country, and that's exactly what's going on in the brain, you are downsizing the overall network. So, that's what we call type 1 or inflammatory or hot Alzheimer's.

And I should mention, it turns out ayurvedic physicians from thousands of years ago who recognized dementia that was related to something that was hot, that was abnormal and ultimately inflammatory, as well as that was related to dryness, which is what we call type 2, where you have decreased trophic support. It can be nerve growth factor, brain-derived neurotrophic factor, estradiol, testosterone, pregnenolone, progesterone, thyroid, vitamin D, all of these things are critical to support of synaptogenesis. So we think of the signaling as being a ratio of synaptoblastic activity where you're actually sending signals to make and store synapses (just like you think of osteoblastic activity) versus synaptoclastic activity where you're actively pulling back and you're reorganizing.

And of course, this is going on all the time. You're actively forgetting the seventh song that played on the radio on the way to work yesterday and you're actively forgetting a lot but you're remembering the key things, like where your keys are and where your son is and all that sort of stuff. And so, there is a change in that ratio in Alzheimer's disease because of type 1 with inflammation or type 2, which we call atrophic or cold, because you don't have the support for those synapses, so you're literally...it's a little bit like someone saying, "I've got five children and I can only feed four. I can either watch all five starve slowly or I can put one in a foster home and feed four," and that's basically the downsizing that's happening when you cannot support the neural network that you have.

And then we have a type that's actually type 1.5, which is glycotoxic. And we named it that because it has features of both type 1, inflammatory, and type 2, atrophic. So what happens is you develop insulin resistance, so you now have a change in signaling that actually occurs because of this chronic high insulin. So you actually phosphorylate your IRS-1, as shown very nicely by Professor Ed Goetzl over at UCSF. So you change the ratio of the serine/threonine phosphorylation to the tyrosine phosphorylation and you're literally changing your response to insulin, so that gives you the type 2 because you no longer have insulin as the supportive trophic factor to the extent it was previously. But of course, you're also glycating proteins with...and we measure this, of course, as hemoglobin A1C. But you're glycating many proteins, so you get now a response to that as well. So you have an inflammation in an atrophic and so that's why it's 1.5.

And then type 3 turns out to be completely different, and that is a response to toxins. So there is a toxic form, which we call toxic or vile Alzheimer's disease. In addition, there are people we called type 4 who have more of a vascular component and then type 5, which is more of a traumatic component, but they're really both related to these other ones. It's really about, do you have inflammation? Are you fighting something off? Do you have trophic support, and are you exposed to specific toxins?

Rhonda: Wow, and so in all of these different subtypes of Alzheimer's disease they all sort of have some of the same distinguishing pathological features like amyloid beta plaques, tau tangles between all of them.

Dale: So they all have amyloid plaques, they all have, by definition, tau tangles, but the presentation can be different. Now there are some overlaps, the type 1s and the type 2s are typically amnestic presentations more common with ApoE4, and that's true for the type 1.5s as well. The type 3s, the toxic ones are quite different. They often present with a non-amnestic presentation. It's executive dysfunction, problems with calculation, problems with visual perception, problems with word finding, so-called primary progressive aphasia, all of these things, they are really bi-parietal presentations as opposed to bi-temporal presentations, essentially. So these have often been called cortical presentations, which have been noted for years by people like Professor Mario Mendez, to be typical in younger presentations of Alzheimer's and often in ApoE4 negative individuals.

Rhonda: I think I also read one in your papers where you did this metabolic profiling there was a very prominent zinc deficiency in that.

Dale: Yes, so for reasons that we don't entirely understand yet, many of the people with the type 3, the toxic sub-type have low serum zinc, high copper-zinc ratios, and low triglycerides. The low triglycerides may turn out to be related to malabsorption, we don't know for sure yet, but we don't really understand why the people often have these low copper-zinc ratios.

Rhonda: What does that mean, the copper-zinc ratio, what is that?

Dale: The high copper-zinc ratio, low zinc.

Rhonda: Low zinc, yeah.

Dale: Yeah, so as, you know, copper and zinc actually are competitive, for example, in their absorption. And so, too much of one actually is often associated with too little of another. And then typically in our society, as you know, most of us are deficient in zinc. There are actually about a billion people on Earth is the estimate for zinc deficiency. It's a very common problem because if you have poor gastric acidity, which is common as we age, if you're taking PPIs for GERD, if you're taking something for reflux, you won't absorb the zinc very well, if you have copper piping which most of us do, the copper will often compete with the zinc. And so many people have a little too much copper and a little bit too little zinc. And in fact, it was noted over 30 years ago that people with high copper-zinc ratios tended to have dementia more than those with normal copper-zinc ratios.

Rhonda: Wow. So does this have something to do with it? I know there's like over 300 to 500 different enzymes in the body that require zinc. So does copper then bind to those enzymes and then sort of mess up the function or is that like the theory?

Dale: So, no. The theory is that, as you know, copper is a generator of free radicals. You know, copper can act like iron in that sense. It has a free electron in the D orbital which does not occur with zinc. So in general, as you indicated, in these various enzymes, and it's hundreds, just as you said, it is an important structural component and it has a very specific architecture with the enzymes that it serves, so it is a structural thing in general. And copper, to my knowledge, doesn't actually replace that. But for example, zinc is important in many things that are related to cognitive decline, it's important in diabetes, it's important in functioning of insulin, it's important, of course, in the trophic activity of insulin and, you know, on and on. It's important in immune responses. So, it actually has many effects that are related to cognition.

Rhonda: So it may even just be a biomarker for something underlying going on right in the toxic insult type of Alzheimer's disease you're talking about.

Dale: It something to keep in mind when you see that, and especially if the person presents, and these people tend to be very distinctive, the people who have type 3. So, they tend to be young, and we see them in their late 40s, mid 50s very commonly. We've seen them as late as starting their first symptoms in the mid-60s, but typically, their first symptoms are currying in the 40s and 50s. They are often women, they are often ApoE4 negative although not always. There are certainly people who are ApoE4 positive to have this. As you mentioned, they often have the low zinc, and then they typically present in a non-amnestic way. Interestingly, unless they are homozygous for E4, in which case they do present typically with an amnestic presentation, but the ones who are E4 negative typically present with problems, as I mentioned earlier, executive dysfunction problems.

And so I always ask people, are you having trouble organizing things? We had one person, for example, who was known for her tremendous organizing capability and as she started to get the problem she just lost it. She could not organize things that she could do before, it's a very common complaint. Or as I said, people will say, "Oh, I can't calculate a tip anymore, or I can't pay the bills anymore," anything that is math-related or visual perception or word finding, things like that.

Rhonda: You mentioned the ApoE4 a few times. Can you talk a little bit about just for people listening and watching, you know, what ApoE4 is, and it's a gene, and so why it plays a major role in Alzheimer's disease.

Dale: Yeah, so, Apolipoprotein E is a really fascinating story, and of course, Professor Robert Mahley discovered this decades ago, and it has turned out to be the most important genetic risk factor for Alzheimer's disease. Seventy-five million Americans have a single copy of ApoE4. And when I say that what I mean by that is, everybody has two copies of either 2, 3, or 4, and the most common one is ApoE3. So it's common for people to be a 3,3 as an example. However, about a quarter of the population, so about 75 million Americans have one copy of ApoE4, and that's actually the primordial one. It's the one that was present for about 96% of hominid evolution.

If you look at a chimp for example, it does not have ApoE4 but the hominids do, and still about 25% of the population today. Then about seven million Americans have two copies, so they're homozygous for ApoE4. Now, if you have zero copies, so if you're, for example, a 3,3 your overall lifetime risk for Alzheimer's is about 9%, so not terribly common disease but not zero. On the other hand, if you have a single copy of ApoE4 your lifetime risk is about 30% or so. If you have two copies, if you're homozygous, your lifetime risk is over 50%, and in some studies as high as 90%. So most likely you will get it. And of course, the vast majority of people don't know.

Now, in the past people said, "Don't check because there's nothing you can do about it," and that has completely changed. So there is a tremendous amount, and the reality is Alzheimer's should be a rare disease. It should essentially decrease to a very low level with the current generation. If everybody gets checked, we recommend that everybody 45 or over get a cognoscopy, it's a silly term but it's easy to remember. Everybody knows when you hit 50 you should get a colonoscopy, and if you hit 45 or over you should be getting a cognoscopy. You should be doing some testing and see where you stand, what are your risk factors, are you ApoE4 positive, do you have high homocysteine, methylation issues, inflammatory issues, nutrient issues, toxin issues, all these things, because they can all be addressed, and we can decrease the overall global burden of dementia.

Rhonda: So there's a variety of biomarkers that you are suggesting people can go and get measured?

Dale: Yes.

Rhonda: You know, to, this, what did you call it? The...

Dale: The cognoscopy.

Rhonda: Cognoscopy, yes. That's a nice term. So, including the genetic factor, ApoE4, seeing the ApoE4 and then you have a variety of biomarkers that you kind of just mentioned. Some of those, I think you also have published on before, talking about the insulin sensitivity as well, looking at insulin sensitivity and glycated hemoglobin. So maybe we can talk a little bit about some of those biomarkers and how...so you have this wonderful protocol, let's see, the MEND protocol.

Dale: Right, so it's now called ReCODE, so MEND was the very first addition, that was Metabolic Enhancement for Neurodegeneration. But as we have made 2.0 and 3.0 and we have made it more sophisticated, as I mentioned in the book, it's become ReCODE, which is for reversal of cognitive decline. And we now have over 3,000 people who are on this protocol with unprecedented, and we've published a number of the results. We actually have another thing that's just finishing up that reports another 50 people who have shown improvement.

Rhonda: Fifty, wow. So the publications that I had read you had shown, I think it was about 10 patients.

Dale: There was 10 and then there were another 10.

Rhonda: Another 10.

Dale: A different 10, yeah.

Rhonda: Right, and you showed that you were able to basically take a person that had Alzheimer's disease, some of them had to leave work because of their issues, and you put them on a protocol and they were not only were able to some of them return to work but they also seem to have brain mass returning and just so it was really phenomenal. So, some of these, some of the very complex diet/lifestyle intervention that you did here, maybe we can talk about some of the key ones starting with like this diet overhaul that...

Dale: Yeah, and I should say, you know, it goes back to one very simple principle. We've been trying to treat this disease without knowing what causes it. So I usually tell people it's as if you took your car into the mechanic because it wasn't working well, and the mechanic said, "Oh, Rhonda, no problem. This is called car not working syndrome and your car is going to die." And you say, "Well, wait a minute. I mean, shouldn't you figure out why, why something, what went wrong with it?" And I said, "Well, no, you know, the testing isn't reimbursed so we're not going to do that." And that's the unfortunate situation we've been in.

People say, "We don't know what causes it, there's nothing you do about it. There's nothing we can do, and you're going to die." And medicine is changing in the 21st century, as you know. It is becoming less about mono-therapeutics and more about programmatics. And at the center of this is to understand why complex chronic illnesses occur. When you have something like there's a simple illness like pneumococcal pneumonia, you find the pneumococcus, you treat the pneumococcus, and all the other underlying things, alcohol, diabetes, anything that could have been contributing is less important because you've got at the pneumococcal pneumonia, that's not the case with complex chronic illnesses.

With Alzheimer's there are dozens of things that can be contributing. And so what we want to do is address all of those. Yes, if you have pathogens, many people have, for example, Borrelia from Lyme disease or a Lyme co-infection like Bartonella or Babesia or Ehrlichia, things like that, then those need to be addressed. And of course, you need to change the underlying biochemistry. So as you indicated, there are specific biomarkers. So we want to know you are hsCRP, it's a marker of inflammation, of course, we want to know your homocysteine, the marker of methylation. If you're not methylated appropriately and your homocysteine is high, then you are at increased risk for neurodegeneration. And of course, it's been published that you have a more rapid decline in your cerebral grey matter volume and hippocampal volume if you have a high homocysteine.

Rhonda: Is that because of vascular reasons or what's the homocysteine mean?

Dale: Well, the publication did not distinguish. It just simply followed people over years and looked at the rapidity of the decline in volume and could show that not only was it more...and literally, you could put the rapidity of it on a graph with homocysteine, and it fit very nicely. But then if you improve the homocysteine and brought it back to normal and they're looking at less than seven as being normal not less than 13, which is often used in the labs.

Rhonda: Less than seven?

Dale: Seven as being normal, then in fact what happened was people actually stopped their decline and leveled off. So it suggested that this is a causal relationship, that it is a mediator of cognitive, well, of change in cerebral volume as well as cognitive decline.

Rhonda: Independent of other biomarkers?

Dale: Independent of other biomarkers, yes. So we want to know that. We want to know whether you have glycotoxicity. So we want to know what is your fasting insulin. And again, people will accept it way off the scale. We have an unfortunate situation where classically we have accepted laboratory values as within normal limits, WNL, very arbitrarily as being within two standard deviations of the mean. That actually makes no sense physiologically, it just says that there's a distribution there, it doesn't say that that's optimal for your health. So we'd like to know what your fasting insulin is, and optimally, it would be less than five or less than five, although again, within normal limits goes much higher than that.

We'd like to know your hemoglobin A1C, which again, is a marker of, essentially over the last two months, your serum glucose. We'd like to know your fasting glucose. These three actually give you quite complimentary pieces of information, all related to this type 1.5 that I mentioned, the glycotoxic type. And then the atrophic, as you can imagine, there are lots of things. We want to know your vitamin D, and again, we want to see that it's optimal, not sub-optimal but within normal limits. We want to know your pregnenolone, progesterone, estradiol, testosterone, free T3.

And we'd like to know your brain-derived neurotrophic factor in your NGF. There's no simple way on a clinical lab test today to get those, so you have to infer them from other things, you know, what is your hippocampal volume? You know, what have you been doing? If you change these various things we've been talking about, you're likely to have a decrease. Have you been exercising? If you're not exercising your BDNF is likely to be lower. So we want to look at all of the trophic support for your brain because these are critical things if you're going to make and keep a large network of synapses, you need to have that support.

And then again, that balance changes for many of us as we age, especially if we are ApoE4 positive. ApoE4 gives you an advantage in that you have a hair trigger, essentially, for inflammation. You are responding...so if you live in a squalid environment like the Tsimane Indians that Professor Tuck Finch studied, for example, or the Agana Tribe that Tuck also has studied, you are in better shape if you're ApoE4 positive. But if you're not living in a pro-inflammatory, in an environment that's parasitic, then in fact you have this chronic inflammation that, again, good for when you're fighting things, good for if you step on a nail, good for situations that should be pro-inflammatory, but in the long run counterproductive.

So, you know, as you know, this is so-called antagonistic pleiotropy. This is something that can help you when you're young but actually can put you at risk for diseases that will shorten your lifespan. And typically, cerebrovascular disease, of course, Alzheimer's disease and as you know, ApoE4 is actually underrepresented in centenarians. So it has been a short-gevity gene as it were. Again, that is changing and can change by understanding what's actually being driven by this.

So we want to know all those markers and those for the type 2, and then of course, we want to know the markers for type 3. So we want to know if there are specific toxins and especially mycotoxins. So the toxins can be metalotoxins like mercury, relatively common one, they can be organic toxins like DDE, things like that, they can be biotoxins like trichothecene, ochratoxin A, aflatoxin, gliotoxin, these are toxins produced by various molds species like Stachybotrys and Aspergillus, and Penicillium, which are literally fighting us. I mean, they're literally saying, "Okay, I'm fighting back." And for example, one of the responses has been when you have mold growing on treated wood, they're recognizing something has changed, mold that have been treated with fungicide.

So these are things where just as we're seeing increasingly bacteria that are antibiotic-resistant as Professor Shoemaker has pointed out, Dr. Ritchie Shoemaker who's done so much work over the years on mold and mycootoxins and described what he calls CIRS, Chronic Inflammatory Response Syndrome. As we've had fungicides, as we've had, you know, buildings with leaks where we haven't recognized the danger from these. In fact, we've had more and more of this mold-related illness. So we want to know all those things for the types 3s. And of course, we also want to know have you had a history of head trauma, we want to know if you have vascular compromise, all of those things are critical.

Now, you mentioned the diet. So, yes, we want to start with the basics, but again, ultimately, it's a program that is customized to you based on what's actually causing your cognitive decline or your risk for cognitive decline. And so, the nutritional part we call Ketoflex 12/3 and it's for a very simple reason. So keto, so we want people to be in mild ketosis because that actually turns out to work better for cognition, and many people do better with their cognitive decline, just as Mary Newport showed, of course, with using coconut oil then that may or may not be the best way to do it for some people, other people like caprylic acid, MCT oil, other people are very good at generating endogenous ketones, which if you can do it, it's the best way to do it. And so we want to drive you into mild ketosis, which means a very low carbohydrate, high fat, good fats, diet, things like avocados and nuts and seeds and things like that. And there is a caveat out for people who are ApoE4 and a caveat for people have very low BMI, so we can talk about that.

The next piece is flexitarian, so you can be a meat eater or not. In general, we see meat as a condiment, but you know, again, as we evolved we tend to eat relatively small amounts of meat but that's fine. If you do, if it's going to be chicken, it should be pastured chicken, if it's going to be beef, it should be grass-fed beef. If you're going to have fish, great. Make sure it's wild caught not farmed fish. You don't want to have the fish with high mercury. Those are the large-mouthed, long-lived fish, tuna, shark, you know, swordfish, things like that, you want to stay away from those because they can contribute to your cognitive decline.

In fact, one of the people who called me a couple of years ago was a very successful businessman who had early Alzheimer's and already had PET scan proven, and they told him, "Come back in a year because you're not doing that badly yet, you're still in the NCI phase," but you could already see the signature of Alzheimer's on his PET scan. And when I listened to his story I said, you know, "You've got type 3, and you need to find out if you've got exposure to any toxins." And he said, "No, everything's great." Well, it turned out that he was eating large amounts of tuna sushi, and he happened to be genetically a poor excretor of mercury, also happen to have some dental amalgams. So he had extremely high organic mercury from the seafood, extremely high inorganic mercury from the amalgams, and then as well as...so he had the perfect storm. And his mercury's actually 7 times the 95th percentile for our country, just massive, massive mercury exposure, and he's done well with removing that.

So we want to know those specific ones. And again, for fish, you want to think about the smash fish. And my wife, who's a family practitioner, you know, reminds me about this, you know, salmon, mackerel, anchovies, sardines and herring, and she is a real expert on the nutritional side and on the integrative medicine side. She told me 25 years ago, "Whatever you guys come up with in the lab, in your test tube..." I've spent my whole career looking at what is driving the molecular signaling that leads to neurodegeneration. She said, "You know, whatever you come up with, it's going to have something to do with what you're eating and your exercise." And I said, "No, no, no. It's going to be one domain of one molecule and we're going to get a drug for that thing and it's going to be over..." And of course, I should have listened to her 25 years ago, that she was right. It does have to do with programmatics not mono-therapeutics.

So then the 12/3 part of Ketoflex 12/3, a minimum of 12-hour fasts between when you finish dinner and when you start breakfast or brunch or lunch, if you are ApoE4 positive you're actually a better fat absorber, as you know, so you want to make that 14 to 16 hours. If you're ApoE4 negative, 12 to 14 hours. And be careful, if you have a very low BMI, you can lose weight on this Ketoflex 12/3 diet and so you have to liberalize typically once a week, have some sweet potatoes or something that's a little more carbohydrate-related. And of course, in the book we talk about the various things that you want to do with this diet, but 12 hours, that gives you time for autophagy, it gives you time essentially at night to induce your ketosis, to clean out your brain, of course, the glymphatic system, you actually have a change in the architecture of your brain as you're sleeping, you're actually essentially sweeping this stuff out, it's kind of amazing, actually.

And so, if you're eating with these very small windows of sleep and very small windows of fasting you're actually doing yourself harm and putting yourself at greater risk. And then similarly, you want three hours before bed after you finish your dinner. You don't want to eat right up until bedtime because your insulin's high, and again, that's hurting your cognition. That's again, giving you the same sort of insulin resistance problem, storing fat, you're doing all the things that are not helpful. So that's the dietary approach. And of course, you want to have organic. There are toxins in our food, it's unfortunate. We've got a tremendous a life-long exposure to toxins.

Of course, Bruce Ames, with whom you've trained, developed the Ames Test, which allows us now to look at carcinogens, but nobody has ever told us, "Well, hey, what about dementogens?" You're exposed every day to various dementogens, things like mercury, things like some of the organics that are in some of the health and beauty aids, and things like biotoxins. If you're living in a home that has leaks, you are exposed to dementogens and you need to know about that.

So that's the Ketoflex 12/3. We want it be...it's a plant-rich diet that Mark Hyman calls plant-rich as opposed to plant-based, but either way it is a plant-rich diet that can use some animal products, it's up to you. You want to be vegetarian, that's fine, you don't, that's fine too. That minimizes the toxins, you want to have a high, typically 70% or so calories from fat, and you can start out with using things like MCT oil or coconut oil to get your ketones up. We're finding that people who have higher ketone levels, 1.5 millimolar to 4 millimolar more beta-hydroxybutyrate tend to do better than those who are down lower.

Rhonda: ApoE4 positive or negative?

Dale: And ApoE4 positive or negative. Now interestingly, for the ApoE4s what we typically suggest, and this was actually originally suggested by Julie G. who started the website, apoe4.info. You essentially start with using the MCT oil to help you get your ketosis, but then switch after a month or two to more monounsaturates and polyunsaturates. Now you can essentially balance, so you have the best of both worlds. You follow your LDL particle number, your LDLP. You want to keep it below 1,000 so you can adjust how much MCT oil and how much of the monounsaturates and polyunsaturates so they have the best heart outcome, the best cardiovascular outcome, at the same time have the best cognitive outcome.

Be careful, if don't get your ketones up and you get your carbs down you're starving your brain, and so then people will say, "Oh my gosh, I just have no energy." So you want to use that. You want to basically be changing over to a more ketone-based metabolism for your brain. And then, as you indicated, you want to go back more toward the monounsaturates and polyunsaturates to make it heart healthy.

Rhonda: So for this, for the ApoE4 positive people you do recommend lowering the saturated fat intake because of the LDL.

Dale: After you become insulin sensitive, so after you want to drive yourself into insulin sensitivity, so you're able now to convert, because it takes a few weeks, as you know, to convert from a largely carbohydrate-based metabolism to a largely fat-based metabolism. So if you try to do it in a day you may end up with so-called keto flu, and it takes some time and you're now producing, it's a whole set of things you're producing, it's going to be less inflammatory, you're lowering your reliance on glucose, you're becoming metabolically flexible, and you're now essentially developing a use of the ketones and it does takes a few weeks. And it's helpful to do things like exercise and things at that time to help you convert.

Rhonda: And then the fasting, the overnight fasting of at least 12 hours, or like you said, if you're ApoE4 positive possibly even increase that to 14 hours. That's interesting that you're talking about why you're sort of transitioning into the becoming more ketogenic that you may actually have to increase your saturated fat intake because you have to really...it is kind of hard to go into ketosis without really just having a lot of fat. And so, it's something I have not experimented with yet. I found out I had an ApoE4 allele and so I've definitely become extremely interested in Alzheimer's disease and what I can do to prevent it because, as you mentioned, you know, not everyone with one ApoE4 gets Alzheimer's disease. It's a very complex diet-lifestyle interaction, at least it appears to be.

Dale: And no one should, and that's the key. This should be largely ended with the current generation. Everybody should get checked, everybody should get an optimal personalized program, that is the medicine of the 21st century.

Rhonda: Yeah, I wanted to ask you about this because, so a colleague of yours, Dr. Eric Verdin at the Buck Institute, I spoke with him a few months back on a very interesting paper he had published, I believe was cell metabolism, where he had given animals a cyclic ketogenic diet, and there was just, you know, improvement in health span in general but what was really, really robust was the improvements in cognitive function and brain aging and it was just, you know, hands down like clear that that diet really helped delay brain aging. And so, you know, of course, those weren't ApoE4 positive mice but...

Dale: But this is the exact same thing we're seeing with people, and especially people with early cognitive decline. Now, as you go later and later, it's more and more difficult, but we have seen people even with MoCA scores of zero show improvement. So, yes, I think the work that you quoted supports that notion, that in fact, having ketones is actually quite helpful for cognition.

Rhonda: Beneficial. Do you think, and here's a couple of questions related to that, and that is, you know, is that...you know, probably multiple things, but one, because you're obviously going to have improved insulin sensitivity, you're not going to have high blood glucose levels and all the inflammatory processes associated with that. Also the ketones, as you mentioned, are used by the brain quite nicely. And interestingly, it actually spares...are you familiar with the glucose sparing, what happens with the...yeah, so glucose gets spared to make NADPH, a precursor for glutathione so that helps repair damage.

But I'm wondering if people like myself, I don't really practice a ketogenic diet but I also don't...I eat a very healthy diet. I definitely try to make sure I don't eat anything refined, no refined carbohydrates or processed food or things like that. But the thing is, is that my...so my fasting insulin's really good and my blood glucose and all that's really good. So, for me going on ketogenic diet, do you think there would still be more benefit even though the whole, you know, insulin sensitivity thing...maybe it would still improve, I'm not sure.

Dale: Well, I think the only way you're going to know is to try it.

Rhonda: To try it, yeah.

Dale: And you know, you can even do so all sorts of online evaluations for your own cognitive ability. And I do think that many of us are sub-optimal in our metabolism, and we know this. One of the problems, of course, is that there have been a lot of assumptions made during the 20th century. Yes, it's fine to have processed foods, it's just as good, you know, it's fine to have more sugar, on and on and on, which just simply have turned out to be wrong. And it has to do with sleep, it has to do with exercise, all sorts of things. We were built, as human creatures, to do certain things well and to do other things we weren't built for. If we all were jumping out of a third-story windows as something to do that would be fun that would not go over well for us. And to some extent, we're doing the same thing with the way we're living.

So, obviously, you've managed to stay fit and to have a good fasting insulin and all these sorts of things. However, a little bit will depend on what you're actually doing, for example, where is your hemoglobin A1C? For example, is there some inflammation there or not? The bottom line is that we were not made as human organisms to consume the amount of simple carbs that we typically are exposed to. So to some extent, just as we're being exposed to all these other toxins, of course, sugar is one of them. And whether you try to be exposed to it or not often we are exposed to it from all sorts of different foods and things like that.

Rhonda: Going out to eat, you never know.

Dale: Going out to eat...there's also the whole issue of leaky gut. So many people...and this wasn't even known as a problem when I was in medical school but it's become very clear that it's very common. It does contribute to chronic inflammatory conditions like arthritis and like cognitive decline. So, I think that having a high-fat diet has been helpful for many people, but what you can suggest is, look, if you ever have any cognitive decline get in as early as possible and then consider this. In your case, of course, as you indicated, you're interested in prevention because you already know that you're ApoE4 positive, so it might be worth trying it just to see, but you know, obviously, you're doing a lot of other things right currently.

Rhonda: And measuring a lot of different...you know, other cardiovascular-rated biomarkers is also good so you're going to measure things like LDL particles, number and size, and triglycerides, and all those things as well to make sure that the changes you're making are actually going to be good for you. I think that's very important. So the diet and then exercise and the sleep is really important. You mentioned the glymphatic system, you know, there's...to my knowledge, really, is there two major ways that amyloid beta plaques are cleared from the brain, one is the glymphatic system?

Dale: Well, of course, there are multiple. There's the ratio of formation to clearance is critical. And of course, you're going to be forming more and keeping more if you actually have a state of inflammation or of responding to a pathogen. So actually, you know, there was a really interesting test developed by Professor Milan Fiala at UCLA, developed about almost 10 years ago now. And what he was looking at was taking peripheral blood mononuclear cells, so you're essentially taking the blood macrophages, and you're now simply challenging them. He would give them amyloid, and just look to see how good are they at phagocytosing, at eating and getting rid of the amyloid. And the surprise was, all the people who have Alzheimer's are very poor at eating and getting rid of this amyloid. It was as if they're literally trying to keep the amyloid around. Then we realized, yeah, this is a state.

So, as you know, it's become clear that you change, your cells change states. You have the metabolic flexibility, you have burning this, burning that for fuel, one of the states you change back and forth between a pro-inflammatory state, essentially an NF-KappaB-mediated state, and on the other hand, an anti-inflammatory, a state that is involved more with SIRT1. These two actually have multiple sites of mutual inhibition. So you're literally flipping back between these different states, and the people who had cognitive decline are poor at getting rid, they're literally keeping this amyloid around. And he looked at their M1 to M2 ratios, essentially inflammation to resolution, he saw two patterns.

The people who don't eat the amyloid and who have the cognitive decline either have a pro-inflammatory state where they have a lot of M1 and very little M2 or he found that they literally had an atrophic state, the same thing we saw as type 2, where they simply could not produce enough of this to resolve. So they literally had very low levels. And so in fact, getting the right levels, about two-and-a-half to one, was associated with the best outcomes. So, you do have this phenomenon, and so yes, as you know, you've got everything from insulin degrading enzyme, Neprilysin, macrophage clearance, glymphatic system, and on and on and on. There are multiple ways but as long as you're in that state where you're using multiple mechanisms to keep this stuff around, you're not going to be very good at metabolizing it.

Rhonda: This paper that you are referring to, I do remember reading a paper that you had published a few years ago where you had taken this, essentially, I guess, you can use that as a biomarker if the people with Alzheimer's disease are not clearing amyloid beta plaques via phagocytosis with their monocytes effectively, that's sort of kind of a surrogate marker for what's going on in the brain potentially, right?

Dale: Right, and this is Professor Fiala's test.

Rhonda: Right, and you had done a small study where you had given people some omega-3 supplements along with some antioxidants and vitamin D, and it improved their phagocytosis of the amyloid plaques in the periphery, and also I think their cognition, some individuals had improved cognition, ApoE4 negative ones, I remember.

Dale: Right, and so I was a co-author on that paper with Professor Fiala. So again, he invented the test and he's now doing, you know, the small number of things that you described there. What we're doing is a much larger set where we're doing more of a program but clearly that is an important part of it. And of course, Professor Serhan [SP] from Harvard has shown that resolution is a critical part. You have the inflammatory part but then you have to have the resolution part. And if you don't have that resolution part, again, a change in mode, then you're stuck with this chronic inflammatory state. And so things like omega-3s and omega-3 derived maresins and things like that are actually involved with the resolution, resolvins, named for that very event.

Rhonda: Of resolving inflammation?

Dale: Right.

Rhonda: I remember in that paper, and I've also done some reading on this because I have a paper that hopefully will be published quite soon on ApoE4-related Alzheimer's disease and particularly with respect to omega-3. So there's some evidence that for whatever reason, fish, when people that have ApoE4 are given fish or eaten fish they're protected against Alzheimer's disease, but DHA supplementation, it's not the same at least for ApoE-positive individuals. And it's kind of been mystery as to why that is.

Dale: And by the way, Professor Paul Clayton from Oxford has discussed this numerous times and written about this. And his argument is that, of course, fish have much more than just DHA and EPA and things like that, so they have antioxidants, things like the secoiridoids and things like this, whether you find them in plants or animals that actually are protective, because you have to remember you're looking at something with multiple sites of desaturation so it's very sensitive to oxidation. And so you have to protect that, and you're absolutely right. Again, this idea that we had in the past that, you know, fish, hey, it's just as good just to get that oil out, it's not just as good. And although the oil can be helpful, you better make sure that it's not oxidized, and you know, better to get it in its appropriate setting.

Rhonda: Very interesting, some interesting papers had come out from a few labs, one from Salem Norman. Norman Salem, sorry. He had shown in animals, if you take animals and give them a human ApoE 3, 4, 2, and then feed them DHA orally, there was a transport defect in DHA across the blood-brain barrier. And so I kind of review this work on a variety of other papers as well, you know, where there's a couple of major mechanisms by which DHA is transported across the brain. Are you familiar with some of those? One is the through a free fatty acid and the other one's through an actual transporter called the Mfsd2a transporter, which is actually in a phospholipid form, DHA is in a phospholipid form. And so, it appears that there may be different ways, you know, that DHA gets across the brain, and one of the ways is potentially not working quite as well in ApoE4 individuals, at least that's my writing theory. But once the paper's accepted I'll send you a copy. So it's super, super interesting.

Dale: Yeah, and of course, as you know, I mean, Professor Wurtman from MIT has spent years looking at what does it actually take nutritionally to make synapses? And his point was you need the DHA and you need acetylcholine as well. And so again, if you're going to be helping people to change that balance toward the synaptoblastic you want to make sure that they have plenty of those precursors as well as the appropriate signals, reduction of inflammation, all these other things that are actually part of an overall orchestrated event.

Rhonda: The other interesting thing is that DHA, and I didn't know this previously until I had been digging into the literature, it also seems to be important for some of the glucose transporters on the blood-brain barrier. And so if you're DHA-deficient those glucose transporters aren't working as well and you're not getting glucose into the brain, which is another real hallmark of Alzheimer's disease. So that's another interesting thing. So, a couple of interesting things I wanted to ask you about were kind of off-topic but not particularly. You mentioned this type 3 sub-type. Would the herpes virus fall into that?

Dale: So, yeah. So herpes virus could give you type 1 or type 3 depending on what you're actually responding to. If it's just a chronic inflammation then it would be a little bit more like a type 1 with chronic inflammatory, but you're right. You know, again, many groups have said, "Okay, it's about herpes. Okay, it's about P. gingivalis, it's about Fusobacterium nucleatum, it's about Candida. And the reality is, all of these are capable of inducing the signal, this change where you're making the amyloid as part of a protectant. As you know, it's essentially part of your innate immune system.

So if you're responding in that way it can be any of those things, it's not just one every single time, as far as anyone knows. So, yes, you alluded to the recent work on herpes and especially, of course, six and seven. And so, yes, not surprisingly. You know, one of the things we see frequently with the various patients is chronic exposure and chronic presence of the various herpes family viruses, CMV, EBV, HSV, HHV, all those things.

Rhonda: The last thing I kinda wanted to mention just because I wanted you to know about it in case you weren't aware of it, there's some really interesting research coming out of Finland. Are you familiar with saunas and the protective...

Dale: Of course.

Rhonda: Oh, okay.

Dale: Yeah, of course, dramatic effects, and fits very beautifully with everything we've been talking about. And certainly, what happens when you have a sauna, yes, you may induce some heat shock protein, great, that's important, and it can be important in folding of proteins, but what also happens, of course, is that you detox. And these people who are doing this repeatedly...you know, some nice work by Dr. Genuis from Canada who showed that if you look at composition of sweat compared to the blood there are certain toxins that are very high, cadmium being the big one, over 1,000 times increase in sweat, so a good way to get rid of cadmium, but a good way to get rid of other things as well.

Rhonda: Mercury as well, right?

Dale: I think you're right with mercury.

Rhonda: Yeah, BPA comes out as well.

Dale: BPA, especially the hydrophobic toxins, the non-hydrophilic stuff tends to be very good in the sweat, but others as well. And so that's why it is very helpful, and many of us don't do enough of that sort of thing. And as has been pointed out, whether you're doing it through sweat and exercise or whether you're doing it through saunas, whether you're doing it through other mechanisms, yes, it's good to get. And then you want to use a non-emollient soap immediately thereafter, things like Castile soap or whatever you like that's non-emollient and get rid of the stuff so that you don't get re-penetration.

Rhonda: Yeah, the other thing is that cardiovascular effects with the sauna and that may also be related to dementia as well. So, is that something that you'd consider using in your protocol?

Dale: Oh, it's part of the protocol.

Rhonda: It is part of the protocol?

Dale: Oh, absolutely.

Rhonda: Excellent.

Dale: Now, we recommend that people...and especially if someone has type 3, that's even more important. But as a general rule, you know, part of this is, again, as my wife says, resilience, part of this is resilience. We're taking people who are sub-optimal in their metabolism, in their inflammation, in their toxic status, in their lifestyle status, in their sleep, in their stress levels, these are surprisingly important. One of the first people who came through was a very intelligent physician. And as we went through each thing he said to me, "Well, you know, I don't believe that, you know, that's not a cure for Alzheimer's, that's not a cure for Alzheimer's." He had well documented early Alzheimer's, PET scan proven, amyloid PET positive, FTG PET positive, hippocampal atrophy, the whole nine yards.

And as we went through each thing, you know, he was telling me, "Well, I don't believe this." I said, "Look, this is not about one thing, this is about a program that is optimal for you." And actually, he's done extremely well, and he's now four years into the program and still doing very, very well. So, it is about changing signaling within your synaptobalstic to synaptoclastic ratio, providing the right support for that, DHA, acetylcholine and Vitamin D, and appropriate hormones, and BDNF, and all these things, and making sure that you don't have chronic exposure. And as you mentioned, sauna is actually a very powerful way to help reduce overall toxic burden. It is surprising how much toxic burden most of us are living with.

Rhonda: So talking about the importance of intervening in multiple ways because there are so many different pathways that lead to inflammation, that can lead to insulin resistance, that can lead to toxic burden, one of the really...something that made major headlines over the past few years is the failed clinical trials targeting amyloid beta plaques, multiple clinical trials, I mean, it's just one after the other.

Dale: And actually, we've had a number of people who have tried to remove their amyloid with antibodies who've actually gotten worse with that happening. So you have to go back to, why is there? And it's tough because yes, it is both part of the mediator, it's not the cause of Alzheimer's, it's a mediator, and I think that's been one of the problems. People want to say it's the cause, it's a mediator, and there are many upstream things contributing to that. So, on the one hand, it's a mediator of the pathophysiology. On the other hand, it's also a protectant, it's a response to things like pathogens.

And so there's a double-edged sword there. It's fine, I think, in the long run, it'll be fine to remove the amyloid, but you've got to remove the cause of it first. Now, of course, people have just tried to go earlier, earlier, earlier and can we actually see some improvement? So I think it won't be surprising if you can get a little improvement early on, but again, it's a little bit like saying if we fire the CFO we can all spend a little more for a while. Well, if we're still going to go into the red, we want to make sure that we're spending for the right things. We want to know why your amyloid is there to begin with, we want to remove all those things, then remove the amyloid as opposed to just blindly removing this mediator and leaving the various inducers.

Rhonda: Right, and with Alzheimer's disease it's so...you know, as you've been talking about for the last hour, there are so many different things that can lead to it, so many causes, so many things in the environment, in our diet, things that are not present in our diet, that it's difficult to just find that one monotherapy and target it. And things are always much more complex. Like it seems like, well, amyloid plaques in your brain, of course you want to get rid of those. They're destroying synapses, and well, as you mentioned, it has a function, it has a really important function. And for the longest time, I remember I was trying to...this was some years ago, I was trying to understand what the normal function of amyloid beta, even amyloid precursor protein, like what is it doing? Why is it in there?

Obviously, we have this whole elaborate system, we have these enzymes that cleave it in this right position, and it forms this 42 amino acid fragment, I mean, that's all happening for a reason. It doesn't seem like it would be programmed into our biology to cause dementia. And so I think it really is important to understand what the normal function is of the amyloid beta. And also with the tau, phosphorylated tau, and tau protein as well, is that something that you find quite often in the people that have the amyloid burden and are affected, they often also have tau tangles in...?

Dale: Oh yeah. Now, tau imaging is still kind of in its infancy, so most people, we don't know. So, they may have an amyloid-positive scan but they haven't have a tau scan. However, they are clearly in Alzheimer's, and as I say, we do know that many of them do from cerebral spinal fluid. So these people that we've reported, I mean, these people have the low ATI that is associated, you know, amyloid tau index, so they have a low a-beta 42s in the CSF and they have the high phospho-tau and total tau in the CSF, the ones that have been evaluated. So, indirectly from that, we can say they definitely had tau, they're likely to have phospho-tau tangles. And again, if you look at what this is doing, it makes a lot of sense. When you are trying to pull back on a connection then you need to collapse the superstructure.

And what is the phosphorylation of tau do? It allows it to pop off the microtubules so you have a rapid collapse of the structure. So no surprise when you're in this mode of you're trying to fight this off, you're trying to change, you're trying to pull back on your structure, you're going to phosphorylate your tau, pop it off, the microtubules, and you're going to die back, and that's exactly what you see. So again, it's not, you know, that the tau is not the cause of the problem, it is a mediator based on what's going on genetically with pathogens, with toxins, with metabolic changes, with innate immune system, and you know, with trauma. So the things that are driving this are the things that we want to target.

Rhonda: Yeah. What percentage of people would you say is more common to have your sub-type 1, 1.5, 2, the inflammation and insulin resistance and the neurotrophic? Are those the most common would you say types of Alzheimer's disease?

Dale: And so this is a really good point. So, initially, what we saw was that many people had this type 1.5, glycotoxicity is so common. In fact, again, Professor Getzel from UCSF had a nice paper a few years ago showing that everyone he evaluated using exosomal analysis had the signature of insulin resistance in the nervous system, whether they had it peripherally or not. It was really striking.

Rhonda: Exosomal analysis.

Dale: So this is exosomes that he analyzed, and specifically, he selected the neural exosomes, which represented about 10% of the overall exosomes, and showed that they all had the signature. This was this change in phosphorylation of IRS-1. So clearly that's a very common thing. But what we're finding is rarely do people have purely type 1.5, 1 or 2. So, although type 3, this toxin type represented only about 15% or 20% of all of the methapure [SP], over 50%, so typically in the 60% to 70% range had at least some suggestion of the type 3. So in fact, most people have some sort of toxin exposure, pathogen exposure, that sort of thing. So what it's turning out is that it's more about what's your mixture. Are you predominantly the type 3 with a little mixture of 1.5? And by the way, the easiest to deal with, type 1 and 1.5, you can improve that, as you can imagine, with things like resolvants.

Rhonda: Inflammation and...

Dale: Inflammation and glycotoxicity.

Rhonda: ...insulin sensitivity.

Dale: You can improve with diet, exercise, sleep, stress, stuff like that. Improving the atrophic is a little harder. You've got to get all the right things, you've gotta...many people have to go on bio-identical hormones replacement, you've got to optimize the support for your brain. And then the hardest of all is the type 3 because you're having to find out...for example, some people have very high ERMI scores, that's EPA Relative Mold Index. If you've got mycootoxins being produced and you're living in them, you need to get out of there. Or if you're working in them, you need to get out of there. And until you do that you've got this chronic exposure.

Rhonda: Is there a test people can do to see if they've got this type of mold in their house?

Dale: Oh yeah. There's an easy test. In fact, you can go on...I think the government has set up this so-called EPA Relative Mold Index, and you want to get a score that's less than two, again, as Dr. Shoemaker recommended years ago. And you can easily get it, go on mycometrics.com. They literally send you some little cloths and you can go around and take x.areas that you are concerned about, send it in, and they will actually do by PCR analysis, looking for evidence of these various species. And if you've got species that happen to produce a lot of toxins, it's a concern. Then you can actually measure the toxins in urine tests. So you can get an idea, and then again, you can actually see with your detox...

Rhonda: Is that a consumer product that you could get?

Dale: Yeah, so you can get. There are a couple of companies now that do make urinary mycotoxins tests.

Rhonda: Okay, and so for people that don't, let's say, you know, they don't have the toxin exposure, or they don't think they do, but they don't if they've done this test, the things that they can do in their diet and lifestyle to prevent the Alzheimer's disease would be the major things to reduce inflammation, which are a lot of things, diet, lifestyle, exercise, sleep, and then again, a lot of overlap there with improving insulin sensitivity and fasting glucose levels and all that.

Dale: Getting your hemoglobin A1C down, all those things, getting on a plant-based...and by the way, you probably know that Dr. Terry Wahls has published a lot, and actually has done a lot of studies now on using a similar sort of approach for multiple sclerosis, and has seen excellent results including in herself with taking this sort of an approach. So, again, looking at the drivers, and looking at what are we actually responding to, and are we having more of an auto-immune response, like with MS,or are we having more of an innate immune system response with Alzheimer's, these are critical for dealing with these complex chronic diseases.

Rhonda: Do you look at markers for gut health, because you were talking about...

Dale: Absolutely, I mean, gut health is one of the one of most common things.

Rhonda: What are the major...inflammatory markers or the...is there like an actual marker for gut health that's more direct?

Dale: Oh absolutely, oh yeah. So, there are a couple of ways to go. There is Genova test, a doctor's data test, there are different tests, there's like stool analysis sort of thing, but you can also do Cyrex, for example. So Cyrex array 2, Cyrex has a whole set of different markers for different antibodies. So, if you have a leaky gut you're often going to respond to things like LPS coming from your gut. Then there's a Cyrex array 3 that looks at various of the domains of gluten and gliadin and so who you can look at that. And then there are various auto-antibodies, etc. So yeah, these are very helpful to know.

Rhonda: Can you spell Cyrex?

Dale: Yeah, its C-Y-R-E-X is the company that developed these.

Rhonda: Excellent. I haven't have heard of that one. So for the Genova diagnostics, is that the metabolic metabolism test or is there a gut one?

Dale: There's a gut health one specifically, GI effects. And then, so yes, so Dr. Aristo Vojdani, he's the one who developed these various assays for Cyrex that are now being used by the Cyrex company, an excellent immunologist.

Rhonda: And that's consumer available as well?

Dale: And that's available, yeah.

Rhonda: Excellent. I'll definitely check those out.

Dale: So the reality is, you know, it's an era in which just like I'm going to take an Uber, for example, you don't necessarily have to call the taxi anymore. In this era we can actually get a lot more data, the quantified self is becoming more and more popular and more and more common. And it's something to some extent of the responsibility for our longevity and for our health is resting more and more with us. If you want to learn more about the protocol, please go take a look at the book, and it's called "The End of Alzheimer's" from Random House. And the only thing you can do is, is you can go to the website, drbredesen.com, look at it there. And we are responding too, there are a lot of comments on the first book that is coming out now in 26 different languages, a lot of comments saying, "We want more specifics about what URLs do we use? Where do we go?" So we're actually now putting that in a second book that will be out next year.

Rhonda: Excellent. Well, thank you so much for this conversation, Dr. Bredesen, for your wonderful research.

Dale: Yeah, thanks very much and then good luck with your work.

Rhonda: Thank you.