[Rhonda]: Hello everyone. I’m really excited to be sitting here withDr. Dale Bredesen, who is internationally recognized for his understanding of the mechanismsof neurodegenerative disease, particularly Alzheimer’s disease. He holds faculty positions at University ofCalifornia Los Angeles and the Buck Institute for Research on Aging. In fact, he was the founding president andCEO 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 talkquite a bit about today.It’s got a really interesting multi-prongedprotocol for preventing and also helping treat mild cognitive dementia and Alzheimer’s disease. So thank you so much, Dale, for having mehere at your place. [Dale]: Thanks very much, Rhonda. [Rhonda]: So maybe we can start a little bitby just talking about some of the characteristics and pathological distinguishing features ofAlzheimer’s disease and maybe what your thoughts are on what can cause Alzheimer’s diseaseor leads to it.[Dale]: Right, so it’s a good point becausecognitive decline, very common, and Alzheimer’s is the most common cause of cognitive decline,ultimately dementia. And by definition, this means that you haveamyloid plaques in the brain and phosphorylated tau tangles. So those are the two main pathological hallmarksof Alzheimer’s. But as you can see, that doesn’t tell youwhy you got it, it just is something you look at the brain, and of course, you can get somethingthat looks virtually identical without the amyloid and you can get amyloid without thecognitive decline. So, it’s a marker but it’s an imperfect one. [Rhonda]: Yeah, that’s a really good pointyou brought up. And do you have any thoughts on why thereare some people that do have amyloid plaques in their brain that aren’t demented and thensome 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 turningupside down now when it comes to our understanding of Alzheimer’s. It’s been over 100 years, of course, goingback to Alois Alzheimer’s publications back in 1906 and 1907, and there hasn’t been agood understanding of this disease. And of course, amyloid has been for yearsvilified and there’s no question, it is a neurotoxin. It does have toxic effects. The surprise has been that this is also aprotectant. It’s actually something that is made by yourbrain when you have specific insults.And for example, Professor Rudy Tanzi andProfessor Robert Moir of Harvard a few years ago showed that it is an antimicrobial. It also, as Professor Ashley Bush showed anumber of years ago, it’s actually quite a good binder of divalent metals like copperand zinc, and things like that, iron. And we showed a number of years ago, it isalso a response to a reduction in trophic support, so you actually get a change in signaling.So, there are multiple different insults andmetabolic changes that lead the brain to produce this stuff. And so I think there’s been confusion becauseit’s clear that when you produce it you’re at this increased risk for having a degenerativeprocess, but as you indicated, there are many people that produce it and they successfullyare protecting themselves, they don’t actually have the downsizing. What’s often been stated is those who thenhave inflammation on top of that seem to be the ones that do worse, and that’s a verygeneral idea, but really it is a set of things. And we identified and published, a numberof years ago, 36 different factors that all contribute to this, but they actually breakdown into just a couple of categories. So, any sort of pathogens, anything that’sgiving you inflammation, whether you have it because you have a leaky gut or becauseyou have P. gingivalis in your brain, or because you have Borrelia of Lyme disease, or you’vebeen exposed to specific fungi, things like that, all of these things can engender thatresponse.And in fact, we think more and more of amyloidas 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 doingyou’re now going to reduce your arable soil. You’re now living in a smaller country, andthat’s exactly what’s going on in the brain, you are downsizing the overall network. So, that’s what we call type 1 or inflammatoryor hot Alzheimer’s. And I should mention, it turns out ayurvedicphysicians from thousands of years ago who recognized dementia that was related to somethingthat was hot, that was abnormal and ultimately inflammatory, as well as that was relatedto dryness, which is what we call type 2, where you have decreased trophic support.It can be nerve growth factor, brain-derivedneurotrophic factor, estradiol, testosterone, pregnenolone, progesterone, thyroid, vitaminD, all of these things are critical to support of synaptogenesis. So we think of the signaling as being a ratioof 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’reactively pulling back and you’re reorganizing. And of course, this is going on all the time. You’re actively forgetting the seventh songthat played on the radio on the way to work yesterday and you’re actively forgetting alot but you’re remembering the key things, like where your keys are and where your sonis and all that sort of stuff.And so, there is a change in that ratio inAlzheimer’s disease because of type 1 with inflammation or type 2, which we call atrophicor cold, because you don’t have the support for those synapses, so you’re literally…it’sa little bit like someone saying, “I’ve got five children and I can only feed four. I can either watch all five starve slowlyor I can put one in a foster home and feed four,” and that’s basically the downsizingthat’s happening when you cannot support the neural network that you have. And then we have a type that’s actually type1.5, which is glycotoxic. And we named it that because it has featuresof 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 highinsulin.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/threoninephosphorylation to the tyrosine phosphorylation and you’re literally changing your responseto insulin, so that gives you the type 2 because you no longer have insulin as the supportivetrophic factor to the extent it was previously. But of course, you’re also glycating proteinswith…and we measure this, of course, as hemoglobin A1C.But you’re glycating many proteins, so youget now a response to that as well. So you have an inflammation in an atrophicand so that’s why it’s 1.5. And then type 3 turns out to be completelydifferent, and that is a response to toxins. So there is a toxic form, which we call toxicor vile Alzheimer’s disease. In addition, there are people we called type4 who have more of a vascular component and then type 5, which is more of a traumaticcomponent, 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 exposedto specific toxins? [Rhonda]: Wow, and so in all of these differentsubtypes of Alzheimer’s disease they all sort of have some of the same distinguishing pathologicalfeatures 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 andthe type 2s are typically amnestic presentations more common with ApoE4, and that’s true forthe 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 withcalculation, problems with visual perception, problems with word finding, so-called primaryprogressive aphasia, all of these things, they are really bi-parietal presentationsas 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 typicalin younger presentations of Alzheimer’s and often in ApoE4 negative individuals. [Rhonda]: I think I also read one in yourpapers where you did this metabolic profiling there was a very prominent zinc deficiencyin that. [Dale]: Yes, so for reasons that we don’tentirely understand yet, many of the people with the type 3, the toxic sub-type have lowserum zinc, high copper-zinc ratios, and low triglycerides. The low triglycerides may turn out to be relatedto malabsorption, we don’t know for sure yet, but we don’t really understand why the peopleoften have these low copper-zinc ratios.[Rhonda]: What does that mean, the copper-zincratio, what is that? [Dale]: The high copper-zinc ratio, low zinc. [Rhonda]: Low zinc, yeah. [Dale]: Yeah, so as, you know, copper andzinc actually are competitive, for example, in their absorption. And so, too much of one actually is oftenassociated with too little of another. And then typically in our society, as youknow, most of us are deficient in zinc. There are actually about a billion peopleon Earth is the estimate for zinc deficiency. It’s a very common problem because if youhave 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 havecopper piping which most of us do, the copper will often compete with the zinc. And so many people have a little too muchcopper and a little bit too little zinc. And in fact, it was noted over 30 years agothat people with high copper-zinc ratios tended to have dementia more than those with normalcopper-zinc ratios. [Rhonda]: Wow. So does this have something to do with it? I know there’s like over 300 to 500 differentenzymes in the body that require zinc.So does copper then bind to those enzymesand then sort of mess up the function or is that like the theory? [Dale]: So, no. The theory is that, as you know, copper isa generator of free radicals. You know, copper can act like iron in thatsense. It has a free electron in the D orbital whichdoes not occur with zinc. So in general, as you indicated, in thesevarious enzymes, and it’s hundreds, just as you said, it is an important structural componentand it has a very specific architecture with the enzymes that it serves, so it is a structuralthing in general. And copper, to my knowledge, doesn’t actuallyreplace that. But for example, zinc is important in manythings that are related to cognitive decline, it’s important in diabetes, it’s importantin functioning of insulin, it’s important, of course, in the trophic activity of insulinand, you know, on and on.It’s important in immune responses. So, it actually has many effects that arerelated to cognition. [Rhonda]: So it may even just be a biomarkerfor something underlying going on right in the toxic insult type of Alzheimer’s diseaseyou’re talking about. [Dale]: It something to keep in mind whenyou see that, and especially if the person presents, and these people tend to be verydistinctive, the people who have type 3. So, they tend to be young, and we see themin their late 40s, mid 50s very commonly. We’ve seen them as late as starting theirfirst symptoms in the mid-60s, but typically, their first symptoms are currying in the 40sand 50s.They are often women, they are often ApoE4negative although not always. There are certainly people who are ApoE4 positiveto have this. As you mentioned, they often have the lowzinc, and then they typically present in a non-amnestic way. Interestingly, unless they are homozygousfor E4, in which case they do present typically with an amnestic presentation, but the oneswho are E4 negative typically present with problems, as I mentioned earlier, executivedysfunction problems. And so I always ask people, are you havingtrouble organizing things? We had one person, for example, who was knownfor her tremendous organizing capability and as she started to get the problem she justlost it. She could not organize things that she coulddo before, it’s a very common complaint. Or as I said, people will say, “Oh, I can’tcalculate a tip anymore, or I can’t pay the bills anymore,” anything that is math-relatedor 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 peoplelistening and watching, you know, what ApoE4 is, and it’s a gene, and so why it plays amajor role in Alzheimer’s disease. [Dale]: Yeah, so, Apolipoprotein E is a reallyfascinating 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 singlecopy 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 anexample. However, about a quarter of the population,so about 75 million Americans have one copy of ApoE4, and that’s actually the primordialone. It’s the one that was present for about 96%of hominid evolution. If you look at a chimp for example, it doesnot have ApoE4 but the hominids do, and still about 25% of the population today. Then about seven million Americans have twocopies, 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 terriblycommon disease but not zero. On the other hand, if you have a single copyof 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 peopledon’t know.Now, in the past people said, “Don’t checkbecause there’s nothing you can do about it,” and that has completely changed. So there is a tremendous amount, and the realityis Alzheimer’s should be a rare disease. It should essentially decrease to a very lowlevel with the current generation. If everybody gets checked, we recommend thateverybody 45 or over get a cognoscopy, it’s a silly term but it’s easy to remember. Everybody knows when you hit 50 you shouldget a colonoscopy, and if you hit 45 or over you should be getting a cognoscopy. You should be doing some testing and see whereyou 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, becausethey can all be addressed, and we can decrease the overall global burden of dementia.[Rhonda]: So there’s a variety of biomarkersthat you are suggesting people can go and get measured? [Dale]: Yes. [Rhonda]: You know, to, this, what did youcall it? The… [Dale]: The cognoscopy. [Rhonda]: Cognoscopy, yes. That’s a nice term. So, including the genetic factor, ApoE4, seeingthe ApoE4 and then you have a variety of biomarkers that you kind of just mentioned. Some of those, I think you also have publishedon before, talking about the insulin sensitivity as well, looking at insulin sensitivity andglycated hemoglobin. So maybe we can talk a little bit about someof those biomarkers and how…so you have this wonderful protocol, let’s see, the MENDprotocol. [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 havemade it more sophisticated, as I mentioned in the book, it’s become ReCODE, which isfor reversal of cognitive decline.And we now have over 3,000 people who areon this protocol with unprecedented, and we’ve published a number of the results. We actually have another thing that’s justfinishing up that reports another 50 people who have shown improvement. [Rhonda]: Fifty, wow. So the publications that I had read you hadshown, I think it was about 10 patients. [Dale]: There was 10 and then there were another10. [Rhonda]: Another 10. [Dale]: A different 10, yeah. [Rhonda]: Right, and you showed that you wereable to basically take a person that had Alzheimer’s disease, some of them had to leave work becauseof their issues, and you put them on a protocol and they were not only were able to some ofthem return to work but they also seem to have brain mass returning and just so it wasreally phenomenal.So, some of these, some of the very complexdiet/lifestyle intervention that you did here, maybe we can talk about some of the key onesstarting 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 withoutknowing what causes it. So I usually tell people it’s as if you tookyour 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 andyour car is going to die.” And you say, “Well, wait a minute. I mean, shouldn’t you figure out why, whysomething, what went wrong with it?” And I said, “Well, no, you know, the testingisn’t reimbursed so we’re not going to do that.” And that’s the unfortunate situation we’vebeen 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 goingto die.” And medicine is changing in the 21st century,as you know. It is becoming less about mono-therapeuticsand more about programmatics. And at the center of this is to understandwhy complex chronic illnesses occur. When you have something like there’s a simpleillness like pneumococcal pneumonia, you find the pneumococcus, you treat the pneumococcus,and all the other underlying things, alcohol, diabetes, anything that could have been contributingis less important because you’ve got at the pneumococcal pneumonia, that’s not the casewith complex chronic illnesses.With Alzheimer’s there are dozens of thingsthat can be contributing. And so what we want to do is address all ofthose. Yes, if you have pathogens, many people have,for example, Borrelia from Lyme disease or a Lyme co-infection like Bartonella or Babesiaor Ehrlichia, things like that, then those need to be addressed. And of course, you need to change the underlyingbiochemistry. So as you indicated, there are specific biomarkers.So we want to know you are hsCRP, it’s a markerof inflammation, of course, we want to know your homocysteine, the marker of methylation. If you’re not methylated appropriately andyour homocysteine is high, then you are at increased risk for neurodegeneration. And of course, it’s been published that youhave a more rapid decline in your cerebral grey matter volume and hippocampal volumeif you have a high homocysteine.[Rhonda]: Is that because of vascular reasonsor what’s the homocysteine mean? [Dale]: Well, the publication did not distinguish. It just simply followed people over yearsand looked at the rapidity of the decline in volume and could show that not only wasit 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 andbrought it back to normal and they’re looking at less than seven as being normal not lessthan 13, which is often used in the labs. [Rhonda]: Less than seven? [Dale]: Seven as being normal, then in factwhat 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 cognitivedecline.[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 thescale. We have an unfortunate situation where classicallywe have accepted laboratory values as within normal limits, WNL, very arbitrarily as beingwithin 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 yourhealth. So we’d like to know what your fasting insulinis, and optimally, it would be less than five or less than five, although again, withinnormal limits goes much higher than that. We’d like to know your hemoglobin A1C, whichagain, 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 complimentarypieces of information, all related to this type 1.5 that I mentioned, the glycotoxictype. 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 neurotrophicfactor in your NGF. There’s no simple way on a clinical lab testtoday to get those, so you have to infer them from other things, you know, what is yourhippocampal volume? You know, what have you been doing? If you change these various things we’ve beentalking about, you’re likely to have a decrease.Have you been exercising? If you’re not exercising your BDNF is likelyto be lower. So we want to look at all of the trophic supportfor your brain because these are critical things if you’re going to make and keep alarge network of synapses, you need to have that support. And then again, that balance changes for manyof us as we age, especially if we are ApoE4 positive. ApoE4 gives you an advantage in that you havea hair trigger, essentially, for inflammation. You are responding…so if you live in a squalidenvironment 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 situationsthat should be pro-inflammatory, but in the long run counterproductive.So, you know, as you know, this is so-calledantagonistic pleiotropy. This is something that can help you when you’reyoung but actually can put you at risk for diseases that will shorten your lifespan. And typically, cerebrovascular disease, ofcourse, 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 byunderstanding what’s actually being driven by this. So we want to know all those markers and thosefor 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 toxinsand especially mycotoxins. So the toxins can be metalotoxins like mercury,relatively common one, they can be organic toxins like DDE, things like that, they canbe biotoxins like trycothesinson, ochratoxin A, aflatoxin, gliotoxin, these are toxinsproduced by various molds species like Stachybotrys and Aspergillus, and Penicillium, which areliterally fighting us.I mean, they’re literally saying, “Okay, I’mfighting back.” And for example, one of the responses hasbeen 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 seeingincreasingly 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 anddescribed what he calls CIRS, Chronic Inflammatory Response Syndrome.As we’ve had fungicides, as we’ve had, youknow, buildings with leaks where we haven’t recognized the danger from these. In fact, we’ve had more and more of this mold-relatedillness. So we want to know all those things for thetypes 3s. And of course, we also want to know have youhad a history of head trauma, we want to know if you have vascular compromise, all of thosethings 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 actuallycausing your cognitive decline or your risk for cognitive decline. And so, the nutritional part we call Ketoflex12/3 and it’s for a very simple reason. So keto, so we want people to be in mild ketosisbecause that actually turns out to work better for cognition, and many people do better withtheir cognitive decline, just as Mary Newport showed, of course, with using coconut oilthen that may or may not be the best way to do it for some people, other people like caprylicacid, MCT oil, other people are very good at generating endogenous ketones, which ifyou 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 avocadosand nuts and seeds and things like that. And there is a caveat out for people who areApoE4 and a caveat for people have very low BMI, so we can talk about that. The next piece is flexitarian, so you canbe a meat eater or not.In general, we see meat as a condiment, butyou know, again, as we evolved we tend to eat relatively small amounts of meat but that’sfine. If you do, if it’s going to be chicken, itshould 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 highmercury. Those are the large-mouthed, long-lived fish,tuna, shark, you know, swordfish, things like that, you want to stay away from those becausethey can contribute to your cognitive decline. In fact, one of the people who called me acouple of years ago was a very successful businessman who had early Alzheimer’s andalready had PET scan proven, and they told him, “Come back in a year because you’re notdoing that badly yet, you’re still in the NCI phase,” but you could already see thesignature of Alzheimer’s on his PET scan.And when I listened to his story I said, youknow, “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 largeamounts 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 fromthe seafood, extremely high inorganic mercury from the amalgams, and then as well as…sohe had the perfect storm.And his mercury’s actually 7 times the 95thpercentile for our country, just massive, massive mercury exposure, and he’s done wellwith removing that. So we want to know those specific ones. And again, for fish, you want to think aboutthe smash fish. And my wife, who’s a family practitioner,you know, reminds me about this, you know, salmon, mackerel, anchovies, sardines andherring, and she is a real expert on the nutritional side and on the integrative medicine side. She told me 25 years ago, “Whatever you guyscome up with in the lab, in your test tube…” I’ve spent my whole career looking at whatis driving the molecular signaling that leads to neurodegeneration.She said, “You know, whatever you come upwith, 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 moleculeand 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 her25 years ago, that she was right. It does have to do with programmatics notmono-therapeutics. So then the 12/3 part of Ketoflex 12/3, aminimum of 12-hour fasts between when you finish dinner and when you start breakfastor brunch or lunch, if you are ApoE4 positive you’re actually a better fat absorber, asyou 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 typicallyonce a week, have some sweet potatoes or something that’s a little more carbohydrate-related.And of course, in the book we talk about thevarious things that you want to do with this diet, but 12 hours, that gives you time forautophagy, it gives you time essentially at night to induce your ketosis, to clean outyour brain, of course, the glymphatic system, you actually have a change in the architectureof your brain as you’re sleeping, you’re actually essentially sweeping this stuff out, it’skind of amazing, actually. And so, if you’re eating with these very smallwindows of sleep and very small windows of fasting you’re actually doing yourself harmand putting yourself at greater risk.And then similarly, you want three hours beforebed after you finish your dinner. You don’t want to eat right up until bedtimebecause your insulin’s high, and again, that’s hurting your cognition. That’s again, giving you the same sort ofinsulin 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 exposureto 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 evertold 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 andbeauty 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 thatMark Hyman calls plant-rich as opposed to plant-based, but either way it is a plant-richdiet that can use some animal products, it’s up to you. You want to be vegetarian, that’s fine, youdon’t, that’s fine too. That minimizes the toxins, you want to havea high, typically 70% or so calories from fat, and you can start out with using thingslike MCT oil or coconut oil to get your ketones up. We’re finding that people who have higherketone levels, 1.5 millimolar to 4 millimolar more beta-hydroxybutyrate tend to do betterthan those who are down lower.[Rhonda]: ApoE4 positive or negative? [Dale]: And ApoE4 positive or negative. Now interestingly, for the ApoE4s what wetypically suggest, and this was actually originally suggested by Julie G. who started the website,apoe4.info. You essentially start with using the MCT oilto help you get your ketosis, but then switch after a month or two to more monounsaturatesand polyunsaturates. Now you can essentially balance, so you havethe best of both worlds.You follow your LDL particle number, yourLDLP. You want to keep it below 1,000 so you canadjust how much MCT oil and how much of the monounsaturates and polyunsaturates so theyhave the best heart outcome, the best cardiovascular outcome, at the same time have the best cognitiveoutcome. Be careful, if don’t get your ketones up andyou get your carbs down you’re starving your brain, and so then people will say, “Oh mygosh, I just have no energy.” So you want to use that. You want to basically be changing over toa more ketone-based metabolism for your brain. And then, as you indicated, you want to goback more toward the monounsaturates and polyunsaturates to make it heart healthy. [Rhonda]: So for this, for the ApoE4 positivepeople 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-basedmetabolism to a largely fat-based metabolism.So if you try to do it in a day you may endup with so-called keto flu, and it takes some time and you’re now producing, it’s a wholeset of things you’re producing, it’s going to be less inflammatory, you’re lowering yourreliance on glucose, you’re becoming metabolically flexible, and you’re now essentially developinga use of the ketones and it does takes a few weeks. And it’s helpful to do things like exerciseand things at that time to help you convert.[Rhonda]: And then the fasting, the overnightfasting of at least 12 hours, or like you said, if you’re ApoE4 positive possibly evenincrease that to 14 hours. That’s interesting that you’re talking aboutwhy you’re sort of transitioning into the becoming more ketogenic that you may actuallyhave to increase your saturated fat intake because you have to really…it is kind ofhard to go into ketosis without really just having a lot of fat. And so, it’s something I have not experimentedwith yet. I found out I had an ApoE4 allele and so I’vedefinitely become extremely interested in Alzheimer’s disease and what I can do to preventit 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 thekey. This should be largely ended with the currentgeneration.Everybody should get checked, everybody shouldget an optimal personalized program, that is the medicine of the 21st century. [Rhonda]: Yeah, I wanted to ask you aboutthis because, so a colleague of yours, Dr. Eric Verdin at the Buck Institute, I spokewith him a few months back on a very interesting paper he had published, I believe was cellmetabolism, 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 improvementsin cognitive function and brain aging and it was just, you know, hands down like clearthat that diet really helped delay brain aging. And so, you know, of course, those weren’tApoE4 positive mice but…[Dale]: But this is the exact same thing we’reseeing with people, and especially people with early cognitive decline. Now, as you go later and later, it’s moreand more difficult, but we have seen people even with MoCA scores of zero show improvement. So, yes, I think the work that you quotedsupports that notion, that in fact, having ketones is actually quite helpful for cognition. [Rhonda]: Beneficial. Do you think, and here’s a couple of questionsrelated 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’renot going to have high blood glucose levels and all the inflammatory processes associatedwith that.Also the ketones, as you mentioned, are usedby the brain quite nicely. And interestingly, it actually spares…areyou familiar with the glucose sparing, what happens with the…yeah, so glucose gets sparedto make NADPH, a precursor for glutathione so that helps repair damage. But I’m wondering if people like myself, Idon’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 eatanything refined, no refined carbohydrates or processed food or things like that.But the thing is, is that my…so my fastinginsulin’s really good and my blood glucose and all that’s really good. So, for me going on ketogenic diet, do youthink there would still be more benefit even though the whole, you know, insulin sensitivitything…maybe it would still improve, I’m not sure. [Dale]: Well, I think the only way you’regoing to know is to try it. [Rhonda]: To try it, yeah. [Dale]: And you know, you can even do so allsorts of online evaluations for your own cognitive ability. And I do think that many of us are sub-optimalin our metabolism, and we know this. One of the problems, of course, is that therehave been a lot of assumptions made during the 20th century. Yes, it’s fine to have processed foods, it’sjust as good, you know, it’s fine to have more sugar, on and on and on, which just simplyhave turned out to be wrong. And it has to do with sleep, it has to dowith exercise, all sorts of things.We were built, as human creatures, to do certainthings well and to do other things we weren’t built for. If we all were jumping out of a third-storywindows 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 thingwith the way we’re living. So, obviously, you’ve managed to stay fitand to have a good fasting insulin and all these sorts of things. However, a little bit will depend on whatyou’re actually doing, for example, where is your hemoglobin A1C? For example, is there some inflammation thereor not? The bottom line is that we were not made ashuman organisms to consume the amount of simple carbs that we typically are exposed to. So to some extent, just as we’re being exposedto all these other toxins, of course, sugar is one of them. And whether you try to be exposed to it ornot 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 thewhole issue of leaky gut. So many people…and this wasn’t even knownas a problem when I was in medical school but it’s become very clear that it’s verycommon. It does contribute to chronic inflammatoryconditions like arthritis and like cognitive decline. So, I think that having a high-fat diet hasbeen helpful for many people, but what you can suggest is, look, if you ever have anycognitive 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, soit might be worth trying it just to see, but you know, obviously, you’re doing a lot ofother things right currently.[Rhonda]: And measuring a lot of different…youknow, other cardiovascular-rated biomarkers is also good so you’re going to measure thingslike LDL particles, number and size, and triglycerides, and all those things as well to make surethat 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 sleepis really important. You mentioned the glymphatic system, you know,there’s…to my knowledge, really, is there two major ways that amyloid beta plaques arecleared from the brain, one is the glymphatic system? [Dale]: Well, of course, there are multiple.There’s the ratio of formation to clearanceis critical. And of course, you’re going to be formingmore and keeping more if you actually have a state of inflammation or of responding toa pathogen. So actually, you know, there was a reallyinteresting test developed by Professor Milan Fiala at UCLA, developed about almost 10 yearsago now. And what he was looking at was taking peripheralblood mononuclear cells, so you’re essentially taking the blood macrophages, and you’re nowsimply challenging them. He would give them amyloid, and just lookto see how good are they at phagocytosing, at eating and getting rid of the amyloid. And the surprise was, all the people who haveAlzheimer’s are very poor at eating and getting rid of this amyloid. It was as if they’re literally trying to keepthe amyloid around. Then we realized, yeah, this is a state.So, as you know, it’s become clear that youchange, your cells change states. You have the metabolic flexibility, you haveburning this, burning that for fuel, one of the states you change back and forth betweena 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 ofmutual inhibition. So you’re literally flipping back betweenthese different states, and the people who had cognitive decline are poor at gettingrid, they’re literally keeping this amyloid around. And he looked at their M1 to M2 ratios, essentiallyinflammation to resolution, he saw two patterns.The people who don’t eat the amyloid and whohave the cognitive decline either have a pro-inflammatory state where they have a lot of M1 and verylittle M2 or he found that they literally had an atrophic state, the same thing we sawas 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’rein that state where you’re using multiple mechanisms to keep this stuff around, you’renot going to be very good at metabolizing it.[Rhonda]: This paper that you are referringto, I do remember reading a paper that you had published a few years ago where you hadtaken this, essentially, I guess, you can use that as a biomarker if the people withAlzheimer’s disease are not clearing amyloid beta plaques via phagocytosis with their monocyteseffectively, 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’stest. [Rhonda]: Right, and you had done a smallstudy where you had given people some omega-3 supplements along with some antioxidants andvitamin D, and it improved their phagocytosis of the amyloid plaques in the periphery, andalso I think their cognition, some individuals had improved cognition, ApoE4 negative ones,I remember. [Dale]: Right, and so I was a co-author onthat paper with Professor Fiala. So again, he invented the test and he’s nowdoing, you know, the small number of things that you described there. What we’re doing is a much larger set wherewe’re doing more of a program but clearly that is an important part of it.And of course, Professor Serhan [SP] fromHarvard has shown that resolution is a critical part. You have the inflammatory part but then youhave 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 derivedmaresins and things like that are actually involved with the resolution, resolvins, namedfor that very event. [Rhonda]: Of resolving inflammation? [Dale]: Right. [Rhonda]: I remember in that paper, and I’vealso done some reading on this because I have a paper that hopefully will be published quitesoon on ApoE4-related Alzheimer’s disease and particularly with respect to omega-3.So there’s some evidence that for whateverreason, fish, when people that have ApoE4 are given fish or eaten fish they’re protectedagainst Alzheimer’s disease, but DHA supplementation, it’s not the same at least for ApoE-positiveindividuals. And it’s kind of been mystery as to why thatis. [Dale]: And by the way, Professor Paul Claytonfrom Oxford has discussed this numerous times and written about this. And his argument is that, of course, fishhave much more than just DHA and EPA and things like that, so they have antioxidants, thingslike the secoiridoids and things like this, whether you find them in plants or animalsthat actually are protective, because you have to remember you’re looking at somethingwith multiple sites of desaturation so it’s very sensitive to oxidation.And so you have to protect that, and you’reabsolutely 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 bettermake sure that it’s not oxidized, and you know, better to get it in its appropriatesetting. [Rhonda]: Very interesting, some interestingpapers had come out from a few labs, one from Salem Norman.Norman Salem, sorry. He had shown in animals, if you take animalsand give them a human ApoE 3, 4, 2, and then feed them DHA orally, there was a transportdefect in DHA across the blood-brain barrier. And so I kind of review this work on a varietyof other papers as well, you know, where there’s a couple of major mechanisms by which DHAis transported across the brain. Are you familiar with some of those? One is the through a free fatty acid and theother one’s through an actual transporter called the Mfsd2a transporter, which is actuallyin a phospholipid form, DHA is in a phospholipid form. And so, it appears that there may be differentways, you know, that DHA gets across the brain, and one of the ways is potentially not workingquite as well in ApoE4 individuals, at least that’s my writing theory.But once the paper’s accepted I’ll send youa 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 takenutritionally to make synapses? And his point was you need the DHA and youneed acetylcholine as well. And so again, if you’re going to be helpingpeople to change that balance toward the synaptoblastic you want to make sure that they have plentyof those precursors as well as the appropriate signals, reduction of inflammation, all theseother things that are actually part of an overall orchestrated event. [Rhonda]: The other interesting thing is thatDHA, and I didn’t know this previously until I had been digging into the literature, italso seems to be important for some of the glucose transporters on the blood-brain barrier.And so if you’re DHA-deficient those glucosetransporters aren’t working as well and you’re not getting glucose into the brain, whichis another real hallmark of Alzheimer’s disease. So that’s another interesting thing. So, a couple of interesting things I wantedto 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 type3 depending on what you’re actually responding to. If it’s just a chronic inflammation then itwould 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 aboutFusobacterium nucleatum, it’s about Candida. And the reality is, all of these are capableof inducing the signal, this change where you’re making the amyloid as part of a protectant. As you know, it’s essentially part of yourinnate immune system.So if you’re responding in that way it canbe 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 onherpes and especially, of course, six and seven. And so, yes, not surprisingly. You know, one of the things we see frequentlywith the various patients is chronic exposure and chronic presence of the various herpesfamily viruses, CMV, EBV, HSV, HHV, all those things. [Rhonda]: The last thing I kinda wanted tomention 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 havea sauna, yes, you may induce some heat shock protein, great, that’s important, and it canbe important in folding of proteins, but what also happens, of course, is that you detox. And these people who are doing this repeatedly…youknow, some nice work by Dr. Genuis from Canada who showed that if you look at compositionof sweat compared to the blood there are certain toxins that are very high, cadmium being thebig one, over 1,000 times increase in sweat, so a good way to get rid of cadmium, but agood 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, andmany of us don’t do enough of that sort of thing. And as has been pointed out, whether you’redoing it through sweat and exercise or whether you’re doing it through saunas, whether you’redoing it through other mechanisms, yes, it’s good to get. And then you want to use a non-emollient soapimmediately thereafter, things like Castile soap or whatever you like that’s non-emollientand get rid of the stuff so that you don’t get re-penetration. [Rhonda]: Yeah, the other thing is that cardiovasculareffects with the sauna and that may also be related to dementia as well. So, is that something that you’d considerusing 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…andespecially if someone has type 3, that’s even more important. But as a general rule, you know, part of thisis, again, as my wife says, resilience, part of this is resilience. We’re taking people who are sub-optimal intheir 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 wasa very intelligent physician. And as we went through each thing he saidto 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 wholenine 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, andhe’s now four years into the program and still doing very, very well. So, it is about changing signaling withinyour 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 avery powerful way to help reduce overall toxic burden. It is surprising how much toxic burden mostof us are living with. [Rhonda]: So talking about the importanceof intervening in multiple ways because there are so many different pathways that lead toinflammation, that can lead to insulin resistance, that can lead to toxic burden, one of thereally…something that made major headlines over the past few years is the failed clinicaltrials targeting amyloid beta plaques, multiple clinical trials, I mean, it’s just one afterthe other.[Dale]: And actually, we’ve had a number ofpeople who have tried to remove their amyloid with antibodies who’ve actually gotten worsewith that happening. So you have to go back to, why is there? And it’s tough because yes, it is both partof the mediator, it’s not the cause of Alzheimer’s, it’s a mediator, and I think that’s been oneof the problems. People want to say it’s the cause, it’s amediator, and there are many upstream things contributing to that. So, on the one hand, it’s a mediator of thepathophysiology. 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’llbe fine to remove the amyloid, but you’ve got to remove the cause of it first. Now, of course, people have just tried togo earlier, earlier, earlier and can we actually see some improvement? So I think it won’t be surprising if you canget a little improvement early on, but again, it’s a little bit like saying if we fire theCFO we can all spend a little more for a while.Well, if we’re still going to go into thered, we want to make sure that we’re spending for the right things. We want to know why your amyloid is thereto begin with, we want to remove all those things, then remove the amyloid as opposedto just blindly removing this mediator and leaving the various inducers. [Rhonda]: Right, and with Alzheimer’s diseaseit’s so…you know, as you’ve been talking about for the last hour, there are so manydifferent 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 findthat one monotherapy and target it. And things are always much more complex. Like it seems like, well, amyloid plaquesin your brain, of course you want to get rid of those. They’re destroying synapses, and well, asyou mentioned, it has a function, it has a really important function.And for the longest time, I remember I wastrying to…this was some years ago, I was trying to understand what the normal functionof 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 aminoacid fragment, I mean, that’s all happening for a reason. It doesn’t seem like it would be programmedinto our biology to cause dementia. And so I think it really is important to understandwhat 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 thathave 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 scanbut 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 ETI that is associated, you know, amyloid tau index, so they havea low a-beta 42s in the CSF and they have the high phospho-tau and total tau in theCSF, the ones that have been evaluated. So, indirectly from that, we can say theydefinitely 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 connectionthen you need to collapse the superstructure. And what is the phosphorylation of tau do? It allows it to pop off the microtubules soyou have a rapid collapse of the structure. So no surprise when you’re in this mode ofyou’re trying to fight this off, you’re trying to change, you’re trying to pull back on yourstructure, you’re going to phosphorylate your tau, pop it off, the microtubules, and you’regoing to die back, and that’s exactly what you see.So again, it’s not, you know, that the tauis not the cause of the problem, it is a mediator based on what’s going on genetically withpathogens, with toxins, with metabolic changes, with innate immune system, and you know, withtrauma. So the things that are driving this are thethings that we want to target. [Rhonda]: Yeah. What percentage of people would you say ismore common to have your sub-type 1, 1.5, 2, the inflammation and insulin resistanceand the neurotrophic? Are those the most common would you say typesof Alzheimer’s disease? [Dale]: And so this is a really good point. So, initially, what we saw was that many peoplehad this type 1.5, glycotoxicity is so common. In fact, again, Professor Getzel from UCSFhad a nice paper a few years ago showing that everyone he evaluated using exosomal analysishad the signature of insulin resistance in the nervous system, whether they had it peripherallyor 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 overallexosomes, and showed that they all had the signature. This was this change in phosphorylation ofIRS-1. So clearly that’s a very common thing. But what we’re finding is rarely do peoplehave purely type 1.5, 1 or 2. So, although type 3, this toxin type representedonly about 15% or 20% of all of the methapure [SP], over 50%, so typically in the 60% to70% range had at least some suggestion of the type 3. So in fact, most people have some sort oftoxin exposure, pathogen exposure, that sort of thing. So what it’s turning out is that it’s moreabout what’s your mixture. Are you predominantly the type 3 with a littlemixture 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’vegotta…many people have to go on bio-identical hormones replacement, you’ve got to optimizethe support for your brain.And then the hardest of all is the type 3because you’re having to find out…for example, some people have very high ERMI scores, that’sEPA Relative Mold Index. If you’ve got mycootoxins being produced andyou’re living in them, you need to get out of there. Or if you’re working in them, you need toget out of there. And until you do that you’ve got this chronicexposure. [Rhonda]: Is there a test people can do tosee 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 governmenthas set up this so-called EPA Relative Mold Index, and you want to get a score that’sless 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 clothsand you can go around and take x.areas that you are concerned about, send it in, and theywill actually do by PCR analysis, looking for evidence of these various species.And if you’ve got species that happen to producea lot of toxins, it’s a concern. Then you can actually measure the toxins inurine tests. So you can get an idea, and then again, youcan actually see with your detox… [Rhonda]: Is that a consumer product thatyou could get? [Dale]: Yeah, so you can get. There are a couple of companies now that domake 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, butthey don’t if they’ve done this test, the things that they can do in their diet andlifestyle 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 ofoverlap 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. TerryWahls has published a lot, and actually has done a lot of studies now on using a similarsort of approach for multiple sclerosis, and has seen excellent results including in herselfwith taking this sort of an approach.So, again, looking at the drivers, and lookingat 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, theseare 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 isone of the one of most common things. [Rhonda]: What are the major…inflammatorymarkers 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 doCyrex, for example. So Cyrex array 2, Cyrex has a whole set ofdifferent markers for different antibodies. So, if you have a leaky gut you’re often goingto respond to things like LPS coming from your gut. Then there’s a Cyrex array 3 that looks atvarious of the domains of gluten and glyodin 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 companythat developed these. [Rhonda]: Excellent. I haven’t have heard of that one. So for the Genova diagnostics, is that themetabolic 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’sthe one who developed these various assays for Cyrex that are now being used by the Cyrexcompany, an excellent immunologist. [Rhonda]: And that’s consumer available aswell? [Dale]: And that’s available, yeah. [Rhonda]: Excellent. I’ll definitely check those out. [Dale]: So the reality is, you know, it’san era in which just like I’m going to take an Uber, for example, you don’t necessarilyhave to call the taxi anymore. In this era we can actually get a lot moredata, the quantified self is becoming more and more popular and more and more common. And it’s something to some extent of the responsibilityfor 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 RandomHouse. And the only thing you can do is, is you cango to the website, drbredesen.com, look at it there. And we are responding too, there are a lotof comments on the first book that is coming out now in 26 different languages, a lot ofcomments saying, “We want more specifics about what URLs do we use? Where do we go?” So we’re actually now putting that in a secondbook 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 goodluck with your work. [Rhonda]: Thank you..