The ROOT CAUSES Of Alzheimer's Disease & How To PREVENT IT | Dr. Dale Bredesen

Alzheimer's disease should be a rare illness. I did not come through a functional medicine background. I became interested in the brain when I was a college student and read a book called Machinery of the Brain by Dean Wooldridge and I got very excited about the brain and how it worked and began to be interested in the neuroscience of the brain. How does it actually work? What actually goes wrong? And so I went to medical school and trained in neurology. In neurology, there are a lot of diseases that we can't do much about and in particular, the neurodegenerative diseases, Alzheimer's, Parkinson's, Lewy Body, Frontotemporal Dementia, PSP, on and on, where we have not been successful. You could argue that it's the area of greatest biomedical failure. For the successes that we've had in HIV and the successes that we've had in cancer, we've not had successes in neurodegeneration. I went back to the lab then. after clinical training so that we could understand what are the mechanisms that actually drive these diseases? Why do you get neurodegeneration? And over the years with the collection of information, we began to see a pattern for what Alzheimer's disease actually is, why you have specific molecules involved, why they actually feed into a specific set of pathways. And we realized that Alzheimer's disease is really about a critical balance that has many, many different inputs to it, dozens and dozens of inputs, not from what we can see, thousands and thousands, but many, many inputs that we had to address. And so what happened was when we started to look at what are actually the things we tell the patients, so imagine 36 holes in a roof, you can cover one hole, it doesn't really help you that much. So we want to be able to address all of the different holes. And when we started doing that, we realized it actually fits in very nicely with what functional medicine has been doing in terms of approaches to many different things from brain disease to hypertension to type 2 diabetes to autoimmune problems. And we realized that what we were seeing from the test tube actually fit in very nicely with a functional medicine approach. So that's how I became interested in functional medicine. What has happened is that we are practicing medicine that's a century out of date, basically. While things have moved forward in Silicon Valley and things have moved forward with iPhones and look at what you can do today that you couldn't do even 10 or 15 years ago, medicine is still being practiced an old-fashioned way where we look for a specific diagnosis. We ask what? What is it? Is it measles? Is it a broken bone? You know, is it rheumatic fever? What is it? And then for each thing, what it is, we get the right prescription, we give them the right thing to do it. that's not the way physiology works. So what we need to do then is to ask in 21st century medicine instead of to ask what it is, to ask why it is. What are all the contributors? And so we need to close what I call the complexity gap. So for example, you have a computer that can fly a plane, for example, you have to match the program with the, with what is required for the plan with the complexity of what it takes. Now, in medicine, we have a tremendous gap. We have human organisms that are incredibly complex. They have complex chronic illnesses like neurodegeneration. And what do we ask? Serum sodium, serum potassium, a few things like this. It doesn't come close to addressing it. Therefore, what do we come away with? The idea that these diseases that are complex chronic illnesses are ineluctable, that you can't stop them, you can't see them coming, there's nothing you can do. but that is wrong. If you use larger data sets, if you look further at what is actually driving the problem, and we can see this from the laboratory research, here are the things that actually drive the problem. Then you can see that in fact there are specific contributors, and it's virtually never one. It's a combination of contributors that add up to an overall change that leads to a complex chronic illness, like one we would call Alzheimer's disease. So what's accurate to say is reversal of cognitive decline in pre-Alzheimer's and Alzheimer's disease. So what we've reversed is the cognitive decline. You can't say that you reverse the Alzheimer's because there's no pathology yet to say that it's gone. What we can say is that the cognitive decline, which continues down, has now changed and now reversed and now people have improved and we see this this is now several hundred people. We reported the first 19 in two different reports, but this is now in several hundred people. So we recommend, though, that everybody, just as everyone should get a colonoscopy when they turn 50, everyone should get a cognoscopy when they turn 45 or over. If you're 55, 60, whatever, check out where you stand and see you can do this with genetic testing, blood testing, functional testing, and if you're already symptomatic, than including imaging in that. But if you're not, you don't necessarily need to include the imaging, but you should know where you stand. And definitely, if you have one copy of APOE4, you have an increased risk for Alzheimer's disease over someone who has zero copies. And if you have two copies, of course, that's increased further and it's very likely that you will develop it during your lifetime. The reality is Alzheimer's disease should be a rare illness because if everyone simply checked ahead of time and got on the appropriate program, we would not see such a high incidence of Alzheimer's disease. So we do recommend that anyone, especially people who know that they're APOE4 positive or have a family history of Alzheimer's disease, get your cognostomy, get checked out, and get on an appropriate program that will minimize your risk for developing full-blown Alzheimer's disease. We've all heard a lot about the gut microbiome and its importance in various diseases, but it is true that the rhinocerebral microbiome is also critically important. And in fact, the neuropathologists have been telling us for many years that whatever causes this pathology of Alzheimer's disease looks, if you look at the neuropathology of it, looks as if it has come from the nose. It is the rhinencephalon, the nose brain, that is typically affected in this illness. And as they've said over the years, we just don't know what is, what that agent or agents are. Well, the reality is that if you look at what happened with neurosyphilis, and in some ways, Alzheimer's disease is the neurosyphilis of the 21st century. If you look at what happened in neurosyphilis, you had a single organism, Treponema pallidum, which set up a chronic inflammation in the brain for years and years that led to, it could lead to dementia. frequently did. With Alzheimer's, it's different. What we see as Alzheimer's, the amyloid, the tau, the changes that we see in pathology are the result of a protective response, and that's 180 degrees from what people have claimed. This is a protective response to three fundamental different insults, and one of them is infection, chronic infection or inflammation. And so when you look at the brains of Alzheimer's patients, what has been reported. Organisms from the mouth, like P. gingivalis, organisms from the lip, like herpes simplex virus 1, and then various fungi and molds that are actually living in your sinus. So in fact, your rhinocentral microbiome is going to turn out to be very important. And some of the work, for example, on looking at biofilms, looking at so-called marcons that actually secrete specific factors that reduce the trophic support to your brain and enhance cognitive decline. This supports the idea that ultimately you want to have an optimized rhinoscinal microbiome. Not terribly surprising from what we're seeing with the gut, the oral microbiome, the skin microbiome. These microbiomes are turning out to be critical for complex chronic illnesses like Alzheimer's disease. So the amyloid, again, is a protective response and there's some nice work coming for example, from Robert Moyer and Rudy Tanzi at Harvard showing that it's an antimicrobial peptide. We've also seen previously that when you have trophic withdrawal, you change the balance of the molecule that is the precursor for amyloid. So amyloid comes from a parent molecule called amyloid precursor protein, which functions as a molecular switch so that it actually can go in a trophic direction, which supports neurite formation, elongation and inhibits programmed cell death. Or it can be cleaved in an alternative way that pushes it in an antitrophic in a downsizing direction. So you're going back and forth with this switch. When you're young, then you know you are balancing these beautifully. But as you begin to get older, you can be too much on the wrong side of this, which produces the amyloid. So yes, the things that push that in the direction that is ultimately going to give you what we call Alzheimer's disease, although we recognize subtypes of these, but what we call Alzheimer's disease can be inflammation, chronic infection, can be trophic withdrawal, or can be exposure to toxins. So for example, amyloid is a very good binder of various metals like iron or like copper, things like that. So all of these things can push you in the direction that we associate with with Alzheimer's disease. Hence, the amyloid is literally a protective response under these conditions. Toxins contribute in many different ways. As you know, there are many, many different mechanisms for toxins to contribute to many human diseases. We're exposed to toxins at an unprecedented level, unfortunately. One of the things that's critical though, and especially the biotoxins, things like mycotoxins, is that, and these are a little different than the metallo-toxins, for example, so different mechanisms. But in the biotoxins, one of the mechanisms is that these activate your innate immune system. So you essentially take two steps when you're exposed to a pathogen. You've got step one, which is a general activation. It's a little bit like if you had a bomb, you know, a terrorist who had bombed some area, The first thing that would happen is that you would go into a general alert level and people would stay home, people wouldn't go out. You'd have this general alert. The second step would be much more specific. You would have some film potentially that had been caught of the person. Now you would know which person to respond to. So in the immune system, the first part is called the innate immune system and the second part, the more specific part, is called the adaptive immune system. So these toxins trigger the innate immune system. For people who respond better, they ultimately have an adaptive response. They get rid of the toxin. You don't have more exposure. Things are good. But with continued exposure or with a poor response where the innate system responds, but the adaptive system does not respond, and Dr. Richie Shoemaker and his group have done a lot of nice work in this area, then you get this chronic activation of the innate immune system. and guess what one of the things is for that innate immune system, amyloid beta. So you've now got this chronic activation which is producing the very stuff that is collecting in the brains of the Alzheimer's patients. So it turns out that amyloid is also a very good binder of metals, especially divalent metals, things like mercury and copper, and things that can be in a divalent state like iron, for example. Actually, the epidemiological work suggests that there may turn out to be some other metals as well that will turn out to be important. For example, if you look at the RNA that is going to lead to the amyloid precursor, that RNA actually has a region that binds to iron. You interact and you actually increase the production of the APP, of the amyloid precursor in the presence of iron. So we actually identify, there are six different subtypes, but they all are related to those three major processes. So what happens is you have this balance and you've got many different things that are on the side, what we would call synaptoblastic, just like if you look at osteoblastic, someone who has osteoporosis, has too much osteoclastic activity for the amount of osteoblastic activity. They've gone in the wrong direction. Same story with Alzheimer's. There is a whole set of signals that are synaptoblastic, that are forming synapses, and they're supported by things like nutrients. There's a whole set of signals that are synaptoblastic that are literally pulling back and downsizing. And the things that are signaling on the synaptoclastic side fall into three general groups. So they are inflammatory things, be they inflammatory due to pathogens, chronic pathogens like Borrelia and molds and chronic viruses and chronic bacteria, things like that, or sterile inflammation such as people eating trans fats and too much sugar and things like that, advanced glycation end products, stuff like that are all that's what we would call type 1. Then there is a type 2. If you suddenly withdraw trophic support, nerve growth factor, BDNF, estradiol, progesterone, pregnenolone, testosterone, free T3, thyroid, B12, vitamin D, all these things are critical support factors. If you withdraw them, especially suddenly, then you will move to the wrong side of that balance and in fact enhance your likelihood of developing amylase. So we call that type 2. There is a type 1.5 which has some of both and that's what we call glycotoxic. So people who have chronically high insulin and glucose, so people headed for pre-diabetes and type 2 diabetes, but this happens before you actually get to type 2 diabetes, you're already at increased risk. They have both the inflammatory part because of things like the advanced glycation end products, and they have the atrophic part because they have insulin resistance. So insulin is no longer functioning as a trophic factor in the way it did before. So they have a little bit of type 1 and a little bit of type 2, so we call that type 1.5. Then there's a separate group and they present very differently. The so-called type 3s, these are people who've been exposed to things like biotoxins like mycotoxins, or metallo-toxins. And these people often have instead of an amnestic presentation where they will come in with difficulty storing new information, they often have cortical presentations. So problems with calculation, problems with visual perception, problems with word finding, problems with organizing. These are the things that they often present with. It is a different presentation. They're often younger people. So very different story. And these people virtually all end up turning out to have an exposure to these various toxins. So we call that type 3 and it has to be treated differently actually. And then there's a type 4, which is a vascular contribution, and type 5, which is traumatic contribution. But they largely go by these same three major mechanisms. So the most important thing initially is to get in early and to find out how far along you are. and then as you say, the subtypes, we want to know people frequently have more than one. So you might find someone who's 70% type 1 and 30% type 2, that sort of thing. So yes, they have then a personalized approach to addressing type 1 and type 2. So there are a lot of things that we can all do to give ourselves Alzheimer's. Most of us don't want to do that, but if you look through all the things that you can do to give yourself Alzheimer's, disease. In fact, a lot of us are doing most of these already. And one of them is to eat a very high carbohydrate diet, a pro-inflammatory diet, a diet that gives you insulin resistance. You drive up your insulin levels and you develop a change. And there's some beautiful work from Professor Ed Getzel at UCSF showing that if you actually look at neural exosomes. So these are tiny fragments of cells that you can find in the blood that are derived from neurons. You can actually see this change where you see that the signaling molecule, IRS-1, which normally should have high tyrosine phosphorylation, low serine/threonine phosphorylation. The tyrosine is the on switch. The serine/threonine is the off switch because of chronically high glucose and insulin insulin levels, it has switched. So you now have high on the off button and low on the on button. So you're not getting the same signaling that you had before. So you are literally changing your brain chemistry by this chronically high consumption of a high carbohydrate diet. The reality is we did not evolve as human beings to have a high simple carbohydrate diet. but we are awash in simple carbohydrates now. So there may be a number of links between leaky gut and Alzheimer's, but an obvious one is that with leaky gut, you produce a state of chronic inflammation. And inflammation, unquestionably, is pro-Alzheimer's. For example, just the activation of NF-kappa B, one of the inflammatory mediators, some of the genes that this affects turn out to be the very ones that the amyloid precursor protein to produce the amyloid. So you are putting yourself in a pro-Alzheimer state if you have chronic inflammation. And leaky gut is a great way to produce chronic inflammation. In addition, of course, you end up with fragments of bacteria that actually end up in the brain. You can see them sticking literally at the site of the amyloid plaques. so leaky gut is something that we all want to avoid if we're trying to avoid cognitive decline. You have to remember that the amyloid precursor protein actually is an integrating receptor. So it is sampling many, many different things, trophic factor support like nerve growth factor and brain-derived neurotrophic factor, sampling things like estradiol level, testosterone level, pregnenolone level, and nutrient levels, things like vitamin D. So in fact, the reality is as you start to add, you have more of these things, you are increasing your risk. So it's not typically one thing. Now, having said that, there are certain things that in our world situation, people are particularly poor. So for example, there are 1 billion people on earth who are zinc deficient. So that is a relatively common contributor. And by the way, zinc is important in appropriate use of insulin. So in fact, it will increase your likelihood of having the very poor state of insulin usage that is associated with cognitive decline. Vitamin D, another very common, many, many people are deficient in vitamin D. Magnesium, another one, very, very deficient. And for people who are taking proton pump inhibitors, of course, they're at increased risk for having still lower zinc and still lower magnesium and low B12. B12 is another one that's been recognized for many years as being important in cognitive decline. So it's many, many different nutrients. And again, with our poor soils that we now have, our depleted soils, the processed foods that we're eating, we're all all contributing to our own cognitive decline. So yes, you want to do the best you can with food and that includes things like prebiotics and probiotics. But yes, it's also helpful to know. And so rather than saying, well, we suggest you eat this or do that, we think check the biochemistry, see where you stand and you can actually see when you do need supplementation and when you can do it with food and a great. Of course, food is the best way to do it. the things that you want to start with are diet, exercise, sleep and stress reduction. Those are the big four. But if those aren't enough, then of course you want to add additional things like specific supplements, herbs and brain training, another critical one, social interaction, on and on, meditation. As a scientist who spent many years in a lab, I've been shocked to see I never thought I would be telling people you should be doing things like meditation and relaxing your stress because I always thought we'd be developing a very targeted mono-therapeutic pill that's going to help you. This is not a mono-therapeutic disease. The mono-therapeutics can be helpful but in the background of the whole program. So as a researcher, we're typically not running a clinic. We're typically training many practitioners who run clinics in right now seven different countries and all over the US who then will look and interact with us and look at specific markers. So yes, you want to know again how far the person is along, what are the drivers of the process, their biochemistry and their genetics, and then their functional status. And then you want to go from there to look at what is an optimal program. So we developed an algorithm and software that will evaluate how much of each subtype a person has and then from there develop an initial program. Of course, the final decisions are up to the patient and the physician, but this at least gives you some background to understand what is driving the process. The whole idea of RECODE, which is reversing cognitive decline, is to obtain larger data sets in order to determine specific subtypes and give us an optimal plan for how to reverse cognitive of decline. It's worked very well so far in the first few hundred people. The first steps are to determine your subtype, to determine your status, and then to look at the beginnings: optimal diet, optimal exercise, optimal sleep, optimal stress reduction. Those turn out to be very helpful for many, many people. Then beyond that, what else can you do to optimize your biochemistry? brain training and specific brain training that focuses on the underlying pathophysiology, very helpful. And then beyond that, specific supplements can be very helpful, right place at the right time, things that, for example, increase brain derived neurotrophic factor, which increases to a small extent with exercise, of course, very important, but also can be increased still further with specific supplements. than specific herbs that have been used for thousands of years. When these are used as monotherapies, they're not as helpful. So there have been many studies that looked at one monotherapy or another monotherapy and said, oh yeah, we don't see much of an effect of this. Yes, you need to have it as an overall concert. If you were to ask somebody, what's the instrument that makes the orchestra? Well, there's not one instrument. It's all playing together. And this is a network. This is a network function and a network dysfunction. So you need to hit all of the different linchpins in the network in order to make this function. And that includes bioidentical hormone replacement where indicated. It includes specific addressing of specific pathogens. So if you have a chronic Lyme infection that hasn't been recognized, it should be treated. If you have Other tick-borne co-infections Babesia, Bartonella, Ehrlichia, others. These things are important. They're critical to treat. And if you're going to get your optimal cognition, you need to address those things. You need to optimize your immune system function. So you may need intranasal VIP. You may need the Shoemaker protocol for SIRS-related which are markers specifically for mycotoxin and other inflammagen exposures. Until you address the things that are actually causing your cognitive decline, you're not going to get the optimal outcome. One of the most exciting things is to see people get better because I was taught that these people don't get better and I thought that I would die still studying transgenic mice and cells in culture. culture and things like that. So to see people changing their lives has been very exciting. And for example, we had one person who got much, much better and still at three and a half years doing very, very well. He had had PET scan proven APOE4 positive, repeated neuropsych evaluation, Alzheimer's disease, and has done extremely well. And one of the things he said is, I've allowed myself to talk to my grandchildren about the future once again. He had given up on talking about the future because he knew that the future didn't include him. And so he's gone back to doing that. Another person said that her husband, the nuance in his guitar playing has come back, which was really exciting to hear. Another person was going to commit suicide before first being evaluated and treated. And has done very, very well and of course did not commit suicide. Actually said to her family member after, Did you know that I had Alzheimer's disease? And the family member said, well, of course I did. It was obvious from your symptoms, but I didn't want to say anything to you about it. Another person said that it has allowed her to enjoy life again and to get out and do the things that she always enjoyed doing. doing. Another one said that she went back to playing golf and she was able to remember what everyone was doing and her own strokes on the course and that thing. So now a little harder for people to cheat because she actually is seeing who's doing what on the golf course. So just to see the changes, we had another young woman who said, My mother is back. My mother is back interacting with the family. again. So these sorts of things are really exciting to hear. So there's no question that epidemiology shows that women are at greater risk than men. It's not 100% clear yet why that is. One of the guesses is that women have a more rapid decline in hormonal support. Men have a slower decline. As they go through andropause, it's a slower decline. And we know that sudden declines are one of the things that changed the APP signaling. There are other possibilities. We don't know all of them yet, but there's no question that about 65% or so of the Alzheimer patients are indeed women. And in fact, today, your chance of developing Alzheimer's disease during your lifetime, if you're a woman, is greater than your chance of developing breast cancer. And so, of course, Maria Shriver has done a wonderful job of pointing out that this is really a woman-centric illness. Yes, men do get it and they do represent about a third of the patients. And by the way, about 60% of the caregivers are women. So there's really an undue burden on women of Alzheimer's disease. We've always recognized, as with other complex chronic illnesses, that the earlier you intervene, the better. The best, of course, is pre-symptomatic if not then during SCI, subjective cognitive impairment, which may last for a decade, and if not then during mild cognitive impairment, MCI, and if not then during early Alzheimer's. But recently we have seen people even late in stages, a person recently with a MOCA score of one, who has indeed shown definite improvement. So we don't know where the cutoff is, but what we do know is the earlier you the better overall you're going to do. So the people who are later on can get improvement, but they may not get improvement all the way back to normal. So we're still trying to understand what can we do to the people to help the people who are farther along to actually improve them dramatically. My advice to anyone who's starting to experience cognitive decline is do not wait. We've taken the other approach in the past saying, well, it's probably not Alzheimer's. Well, we keep saying that until, oh, it is Alzheimer's and there's nothing we can do about it. So what I recommend is everybody come in as early as possible. If there's no problem, great. Get on prevention. Make sure that you never have a problem. By the way, the current program makes you healthier. So, you know, the side effect is some weight loss, some better insulin sensitivity and some better energy. that's not such a bad side effect. So get in as early as possible and get evaluated. We have the ability now to evaluate and to reverse cognitive decline that we haven't had in the past. What we need, of course we need many more people to come through, we need clinical studies. So what we've had so far are patients coming through who we see get better, but we need a standard clinical trial Now here's the problem with that. Standard clinical trials change one variable. So we actually, this all started with a clinical trial that was proposed, the first comprehensive clinical trial proposed for mild cognitive impairment, pre-Alzheimer's, back in 2011. And it was rejected by the institutional review boards because it was too complicated and because the feeling was that people wouldn't do the things that we'd ask them to do. And as the IRB said to us, you guys obviously don't understand how to do a clinical trial because you're changing more than one variable. And we said, obviously, you guys don't understand Alzheimer's disease because it's not a one variable disease. So for the future, what we need to do is develop a way in which we can have a programmatic approach and have that approved for a clinical trial. so a fundamental change has to occur in the way that we do these trials.

If you love that last video, you should check out the next one for sure on getting to the root cause of all disease. When we hyper-hygenized ourselves, our food's purified, and when we're not playing in farms and dirts, when we're exposed to all the horrible diet we have in America, all these factors drive this.