Addressing Root Causes of Neurodegenerative Diseases with Dr. Dale Bredesen

I very much enjoyed my conversation with Dr. Dale Bredesen – from his story of finding functional medicine (it’ll resonate with many of you, as it did me, I’m sure) to where the ReCODE program is now (pay attention to the large clinical trial now underway and the refinements of Dr. Bredesen’s thinking over the last decade), and the launch of The End of Alzheimer’s Program (a goldmine resource for clinicians and regular folks alike). Links on the podcast show notes page, be sure to check them out. Thanks for listening! ~DrKF

Addressing Root Causes of Neurodegenerative Diseases with Dr. Dale Bredesen

Why are we seeing an alarming increase in early-onset Alzheimer’s disease, with people in their late forties and early fifties developing this neurodegenerative condition? What are the six types of Alzheimer’s disease and how can the underlying contributors be addressed? Dr. Dale Bredesen is Founding President and CEO of the Buck Institute for Research on Aging and developer of the ReCODE protocol to treat cognitive impairment and Alzheimer’s disease. In this episode of New Frontiers, he talks with Dr. Fitzgerald about the pandemic of Alzheimer’s disease, which is now the third leading cause of death in the United States, and what he’s learned over decades as an expert in neurodegenerative diseases.

Dale E. Bredesen, MD, is internationally recognized as an expert in the mechanisms of neurodegenerative diseases such as Alzheimer’s disease, and the author of the New York Times bestseller The End of Alzheimer’s (Avery, 2017). He held faculty positions at UCSF, UCLA, and the University of California, San Diego, and directed the Program on Aging at the Burnham Institute before coming to the Buck Institute in 1998 as its founding president and CEO. He is currently a professor at UCLA.

• www.drdalebredesen.com
• Mean Oxygen Saturation during Sleep Is Related to Specific Brain Atrophy Pattern.
• Reversal of Cognitive Decline (ReCODE) Study (RECODE)
• Apollo Health
• ApoE4: https://www.apoe4.info/wp/

• DrKF FxMed Clinic: Patient consults with DrKF physicians
• Clinician Professional Development: DrKF FxMed Clinic Immersion
• DrKF FxMed Nutritional Residency Program

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine, and today is no exception. I am absolutely, absolutely, absolutely excited to be with Dr. Dale Bredesen. You know who he is, you’re familiar with his work, and likely many of you are using ReCODE in practice. It’s quite a gift, thank you for the work that you’ve done. Let me give you a little bit of background on Dr. Bredesen. He’s internationally recognized as an expert in the mechanisms of neurodegenerative diseases, such as Alzheimer’s. He’s the author of the New York Times bestseller, The End of Alzheimer’s, and that was 2017. He held faculty positions at UCSF, UCLA, and the University of California at San Diego. He’s directed the program on aging at the Burnham Institute before coming to Buck Institute in 1998 as its founding president and CEO. He is currently a professor at UCLA. Dr. Bredesen, welcome to New Frontiers.

Dr. Dale Bredesen: Thanks so much for having me, Dr. Fitzgerald.

Dr. Kara Fitzgerald: Your journey, I was struck by your story in that in 2011 you were clearly putting together this systems approach, you were realizing that a systems approach was essential to treating Alzheimer’s. As you attempted to push such a study through IRB, which I’ve been there, it was rejected. Because all of the other, you were clearly bucking the trend back then. I guess I have two questions but the primary one was, how did you move into systems thinking with regard to Alzheimer’s? Really how has your community of research clinicians received you?

Dr. Dale Bredesen: Yeah. We got to this from the test tube actually. We were looking at what drives the neurodegenerative process. We thought that this is in the area of greatest biomedical therapeutic failure, whether you have ALS, or Alzheimer’s, or Lewy body, or frontotemporal dementia, there hasn’t been anything effective to do about these illnesses. We wanted to understand why, what’s missing in the model? Could we understand the fundamental nature of these processes? When we looked at Alzheimer’s disease, which we did for many years and published lots of papers on this, what we saw was at the heart of this is a molecular switch APP that is literally pushed toward a synaptoblastic and supportive role or pushed towards synaptoclastic signaling, literally pulling back.

When we started to look at, “Okay, let’s get a medicine that pushes it toward the synaptoblastic side.” We actually screened thousands of drug candidates, and we identified several that have that interesting property. But as we got down to writing the original proposal for doing this clinical trial on a drug candidate, I realized, “Well, wait a minute. There are a lot of things that are actually pushing this in the same direction. Just trying to short circuit this by trying to block something is not going to have the effect that we want.” I was actually sitting in my office back in 2011 in front of the white board and scratching my chin and I thought, “Well, wait a minute. What if we start to add… maybe we do some brain training in addition. Maybe that’ll help increase trophic support and that may improve the electrophysiology, ok.

Then I thought, “Well, wait a minute. What about the hormonal alterations?” Obviously I was a little bit dim, but it took the light a few minutes to go off. Then I thought, “Well, wait a minute. From a disease that is 100% terminal, why would we withhold anything, any chance we could get?” Because there had never been examples of people turned around I thought, “Well, let’s do everything we can that fits the molecular biology.” You can literally trace pathways from estradiol, from NF-kB and inflammatory pathways directly to APP. I thought, “Okay, let’s see if we can change that balance by looking at the various pieces.” Of course at the time I knew nothing about functional medicine. I had heard of Jeff Bland back in 2008, but I knew nothing about this.

It was fortunate for us that there was so much out there already where people were looking at root cause medicine. Five minutes of looking at this, how could you want to do anything else? Of course, the idea of trying to trick nature to treat somebody with a drug that has absolutely nothing to do with what’s causing the problem makes no sense. I thought, okay, let’s go after the things that are actually doing this, and let’s see if we can understand for each person. Then of course as we started to look, we realized, different people, obviously, no surprise, have different things that are driving this pathophysiology. Of course, Alzheimer’s is just something that a pathologist tells you. It’s like saying your car doesn’t work because you have “car not working syndrome”. It doesn’t mean anything by its name. You really have to understand what is driving the process. Of course, that’s what has ended up making it so that you can actually make changes.

It’s not a surprise this is happening in functional medicine with many complex chronic illnesses. I actually think this will be the century, just as the last century was the century of simple medicine and simple diseases like tuberculosis and pneumococcal pneumonia. The 21st century will be the century of functional medicine in which virtually all of these complex chronic illnesses will be largely, if not completely, eradicated, dampened down tremendously by use of these multipronged personalized precision medicine type of approaches where you can now go after the specific drivers. Interestingly, the science has really supported the functional medicine model much more than it has supported the model that I was trained in.

Not surprisingly, all of my colleagues are upset, “How dare you say that amyloid isn’t the be all end all? How dare you say that you’re going to do a multipronged trial?” It’s funny actually. But I think this is what happens. There’s so much disruption in Silicon Valley, which is right near here, and in medicine it’s so much about tradition and permission instead of disruption. We need a little more Silicon Valley, we need a little more disruption in medicine because it has failed to address these illnesses.

Dr. Kara Fitzgerald: I’ll tell you what, thank you. But, clearly you were poised to do this kind of thinking, but yes, I mean, one of the most satisfying aspects of practicing functional medicine is to do a drilldown into the multifactorial pathophysiology of any condition and begin to tease apart how you might actually help this human being sitting in front of you. Thank God it is. It’s deeply satisfying medicine and you a-ha’d upon that in 2011 and really the rest is history. I just so appreciate that you started to do that. I think that must make your world as a scientist all the more interesting as well to pull all those potential threads influencing.

Dr. Dale Bredesen: Well, it’s interesting. The science, what we saw in the test tube for all those years, fits so much better with a functional medicine approach and really doesn’t at all fit, in fact It shows you why the drugs won’t work. The other thing is, we had a personal experience with this. Our daughter, as she was going off to college, it became clear that she had a vasculitis and she had biopsy-proven vasculitis. We took her to two world experts on lupus. She had a high ANA, she had a high sed rate. I mean, she had all the symptoms, all the signs. Both of them said, “Yeah, she has early lupus and she’s going to need some steroids at some point.” They had virtually nothing to offer her.

Then we took her to a functional medicine physician, up in Seattle actually, who worked with Dr. Jonathan Wright. She said, “Well, yeah, I know exactly what’s going on. Yeah, she has the lab work of lupus and the symptoms of lupus, but she has an incredibly leaky gut and you need to fix the problem. This is the thing causing the problem.” She went on this very complex protocol and she did great. She’s now 12 years out from this doing absolutely great, has never had ‘lupus’ again. Interestingly, when she goes off her protocol, when she starts… she did have sensitivity to gluten among other things. She starts getting some of the chilblains stuff again and she gets rid of it when she goes back on. It became clear to me that standard medical care often ignores what’s actually causing the problem.

Dr. Kara Fitzgerald: What year was that? What year was that just…

Dr. Dale Bredesen: She went off to college in 2007, late 2007, early 2008.

Dr. Kara Fitzgerald: Was that the seed that ultimately led to your 2011 aha?

Dr. Dale Bredesen: Well, part of it, yeah. Of course, you see it once and you think, “Hmm.” But then you start seeing things coming out of the theory. I’ve always been interested in the theory. What are the principles that drive? Why does one person get ALS while another person gets Lewy body disease? Why is it that Alzheimer’s is so incredibly common? About 15% of the population will die from Alzheimer’s. It’s become the third leading cause of death in the United States. This is a major, major global… I mean, talk about pandemics. There are, of course, parallels between what we’re seeing with COVID-19 and what we’re seeing with Alzheimer’s disease. I always thought, “What’s missing? Why are we missing this?” We used to sit in the lab and say, “Okay, if we don’t solve this problem, what will the people in the future who solve this problem have thought of that we didn’t?”

Dr. Kara Fitzgerald: Right around then you would have been able to tuck into some of those fabulous Fasano papers, actually mapping intestinal permeability. I mean, in the nineties, when I was shadowing a doc before I went to school, he was talking about intestinal permeability all the time. But back then that was quack medicine, full tilt. To have it elegantly put out into the scientific community led by Fasano was really satisfying. I’ve got a couple pre-questions and then we’re going to move into talking about your book, but this is so interesting. When you were doing high throughput drug screening, I’m just curious, did you do any natural products? Was there anything that you were pinged on that you’ve since incorporated into your protocol?

The reason I’m asking you is because now of course there are preprints coming out, millions of them, just nosediving through since we’ve been in the COVID pandemic and we’re seeing a host of really interesting natural products as potential interventions. Of course, there’s a lot of science going on over in China using traditional Chinese medicine. It’s something I’m aware of right now and curious if you’ve got any comments there.

Dr. Dale Bredesen: Absolutely, and I think this is a really interesting area. Of course the issue is always, if you’re going to screen for things, then ultimately you want to screen for things that you can take into trial, that you can get tested, and then you can ultimately get approved because this is one of the issues. We are only allowed to do certain things. The FDA is going to approve certain things. In fact, one of the early criticisms, when we started seeing the first results with patients, a doctor said, “You can never get any of this approved by the FDA.” Actually, the first trial we proposed included a drug called tropisetron that we had discovered in the lab as being something that increased the synaptoblastic peptides of APP and decreased the synaptoclastic peptides.

It turned out to be an interesting drug that is a 5-HT3 antagonist, but it interestingly also interacts directly with APP, and it’s also an alpha7 nicotinic acid agonist. It has multiple effects as a single drug. We did look at some products and in fact galangin was one of the interesting things that came out of the screening initially. But we started by looking at all the things that had been FDA-approved but had never advanced for anything. The things that were good candidates, either that had been approved for something else, or that were out of use, or that were simply available as part of a screening library.

Dr. Kara Fitzgerald: Got it. Got it. It’s an interesting area.

Dr. Dale Bredesen: Absolutely.

Dr. Kara Fitzgerald: Since your first book, or really since you’ve started this system/functional approach to addressing Alzheimer’s, I mean, what have you seen in the eight year’s time you’ve been doing ReCODE? I mean, what are your current thoughts around it and where do you see the research, the science going?

Dr. Dale Bredesen: Yeah, that’s a great point. Let me take the second one first. Where I see this going is that this is the dawn of the era of treatable neurodegenerative disease. Again, as a conceptual scientist, I’d like to now take this, and we’re beginning to look at people with macular degeneration, ALS, frontotemporal dementia, and frontotemporal lobar degeneration, and Lewy body disease, and all these others, PSP, CBD, all these other neurodegenerative diseases. The concept is that all of these represent mismatches between the supply and the demand of a specific neural subsystem. You have these various subsystems, ones that are critical for plasticity, ones that are critical for motor modulation, ones that are critical, of course, for vision.

All these things. What’s interesting is, because of evolution we’re… evolution is trying to help us to outdistance our competitors, all of these have Achilles heels. If you simply don’t have quite enough complex 1 activity in the long run you can get Parkinson’s disease. If you’re not supplying enough oxygen to your macular, because this is an area where the Achilles heel is metabolism. It is extremely active metabolically. If you fail on that side, you can get macular degeneration. Of course lipids are important there, and inflammation is important there, are all these sorts of things. But each of these has its own systems medicine. We should be able to take the same idea and generalize it being specific for the underlying biochemistry of each of these degenerative conditions. That’s the way that we’re going.

We have something called the ARK Project, which is doing just that. It’s taking very small numbers of people just as we did with Alzheimer’s. You have to start somewhere. It’s funny, we’ve had a lot of criticisms saying, “You don’t have a phase three published crossover, double blind placebo-controlled trial.” Well, come on, this is like telling the Wright brothers that they didn’t stay up long enough. The people that are doing the drugs are developing the next lead balloon and saying, “One of these lead balloons is going to fly,” and the lead balloons are not flying. Okay, we didn’t stay up long enough, but yes, we’ve now… we got turned down, as you said, in 2012, we got turned down again in 2018, we finally got approved to do the first trial in 2019.

We’re in the middle of it now. It’s scheduled to be completed in December. It’s really been exciting, and we’re working with three absolutely outstanding functional physicians, Dr. Ann Hathaway, Dr. Kat Toups, and Dr. Deborah Gordon. Very excited to be working with them. This is the first trial in history in which, instead of predetermining a treatment and saying, “Okay, we’re going to give you Aricept, or we’re going to give you a lifestyle change,” whatever it is, it is not predetermined. Instead, what you do is you look at all the different things, identify the root causes just as functional medicine does, and then address those things. I think that’s the way of the future and the way to… that’s the way to develop drugs. Because they will compliment this approach. Just as we always talk about, 36 holes in the roof and you got to patch the different holes. The drugs are excellent patches, typically for one or two holes. But you’ve got to get the rest that are in there.

Then as far as what we’ve learned, a tremendous amount. We’ve got people now who are over eight years, who in all likelihood would be in nursing homes at this point, who have sustained their improvement and are still back at work and still doing very, very well. But along the way, we’ve found some very important things. For example, one of the things we didn’t recognize at the beginning was how absolutely critical nocturnal hypoxia turns out to be. People don’t check this enough.

There was a really interesting research study that showed if you just graph the mean SpO2, where is your oxygen sitting at night on average, and you compare that to the volumes of specific nuclei within the brain, there’s a direct correlation, including critical areas for Alzheimer’s disease such as the hippocampus. If you’re walking around and you’re dropping into the eighties and we even see people in the low seventies at night, you are really doing yourself a disservice. Often people will say, “Well, I don’t have sleep apnea. I don’t snore. I’m fine.” When you look into it, in fact there are major problems. That’s a critical area.

Of course, so much that’s come up about dentition and oral pathogens, P. gingivalis, T. denticola, F. nucleatum, P. itermedia, on and on. All these various pathogens that turn out to be critical. When you look at the brains of patients with Alzheimer’s, what do you see? You see those same pathogens and you see things like herpes simplex and HHV-6A, and borrelia, and candida. These chronic pathogens are gaining access to our brains one way or another. A beautiful study published on candida in rodents, showing that it gains access even without a damaged blood-brain barrier. Very interesting. It’s turning out that this is a scenario. What we call Alzheimer’s is actually about a protective response to these various insults.

We continue to see new pieces, but everything that is reported, everything that we see, fits in beautifully with this concept that this is a protective response that you are literally on the synaptoclastic signaling side. I think that the model is predictive of what we’re seeing and is going to allow us to make continued evolution and improvement of the overall approach, which admittedly is not perfect. It’s where we started, and then we continue to make enhancements over time.

Dr. Kara Fitzgerald: Beautiful. I’m just so excited about it. Thank you for embracing functional medicine and jumping in and being a very elegant, well-stated spokesman for what we’re trying to do here.

Dr. Dale Bredesen: Well it’s the truth.

Dr. Kara Fitzgerald: Yeah. I’ve got a couple of questions just based on what you’ve said. First of all, I did see that clinicaltrials.gov, and I’m familiar with those physicians, they’re all fabulous. I was very excited to see it. Any preliminary results you can share, any preliminary data that you’re able to talk about yet?

Dr. Dale Bredesen: Yeah. As you know, I mean, I can’t say anything before it’s finished. It’ll be finished in December, it’ll be published next year. But I can say I’m very enthusiastic.

Dr. Kara Fitzgerald: I’m so excited about it. The other thing that I wanted to ask you about, so you’re talking about teasing apart these other neurodegenerative conditions using this functional lens and understanding the specific neuropathophys that’s occurring in each of them. But one of the things that I wanted to say that I found, and again I found it to be satisfying in functional medicine, is that there are a lot of shared underpinnings. The very unique pathophysiology of a given condition is almost the icing at the top. Okay, so we’re seeing leaky gut, we’re seeing inflammation driven by all these. Anyway, speak to that concept.

Dr. Dale Bredesen: That is a great point. It’s very interesting, again, you’ve got the thesis, the antithesis, and the synthesis here. Yes, you could take the polar opposite view and say, “Everything is the same, the system is breaking down.” But then you wouldn’t have… It’s like, why does one person get one disease, and one person get… Now, again, as Jeff Bland says, it’s a disease delusion. It’s all that the system has failed. I think Jeffrey is fantastic and he’s really changed the world with functional medicine. At the same time, that’s an intriguing question to me, what does separate these things?

From where I’m sitting, it seems that yes, the system has to all work together. You’re an organism, and so you got all these systems working together. But you can, to some extent, look at the subsystems. For example, as we talked about earlier, the macula has certain requirements to do well. People who get macular degeneration don’t necessarily get Alzheimer’s, or Parkinson’s, or anything else. Some do, but most of them don’t. Something is different there in what has failed. Similarly for frontotemporal… on and on, you can take each disease. When you then look at each of these subsystems, let’s take what happens in Parkinson’s. In Parkinson’s, you’ve got this highly energy-demanding system that is dependent heavily on mitochondrial function, and interestingly, on mitophagy. You shut down mitophagy you don’t recycle your batteries essentially, you end up with Parkinsonism. You shut down complex 1, you end up with Parkinsonism.

Again, and again, it’s that same sort of phenomenon. Of course, it has other interactions proteolysis, critical. Ubiquitination and proteolytic degradation, critical. The genetics teach us a lot about what these systems need, where their Achilles heels are. But when you then look at them, yes you’re right, there’s a lot of core similarity. You do have to look at systemic inflammation, you do have to look at leaky gut. As they say now, leaky gums. All these various things. How are you perfusing your brain at night. But you also have, as you said, the icing. You have the thing that is directing you toward one disease or another and addressing those critical aspects is going to be a little different for each thing. It will allow us to get at each of these diseases.

It will also prioritize. Even though you may end up with a similar list for Alzheimer’s and Parkinson’s, it’s going to be a different priority. You’re going to focus in Parkinson’s more on complex 1, and more on ubiquitination and proteolytic degradation, and a little more on mitochondrial function. What’s interesting to me, when you don’t have enough for that system, the system tries to allow you to survive as best you can without that. What do you do? You don’t have the motor modulation, so you give up the ability to have your hands sit and be at rest. You now get the tremor. What happens when you walk, you have to walk more slowly. You don’t have the ability to go quickly because you’ve lost that motor modulation.

What happens, the so-called righting reflex. If you push someone who has Parkinson’s, they fall down more easily. In all the things you’ve lost that fine control that takes so much energy. Each of these things has its own different flavor. That actually make sense when you look at how the system works together, and getting at this, I think, is going to tell us how to treat each one.

Dr. Kara Fitzgerald: It’s extraordinary, it’s just so interesting and just very exciting for me. I wanted to just say, a lot of clinicians listen to this, a variety of stripes. I think the important things here for us, well, as you say in your book, for global adaptation of the functional medicine model, we need a team approach, and we need a lot of providers with different credentials. Because there are shared foundations, because we have to optimize total system functioning, there are practitioners who can become expert in doing that. There are coaches, there are nutritionists that can work with these basic components that all of us do in our practice.

Then there will be people who are focusing on the icing, the phenotypic expression, doing the drilldown on that top layer of the biochemistry imbalances that require different kind of interventions and different degree, how aggressively we approach dosing with different products and so forth. But it’s this collaborative model of people trained in functional medicine, different credentials coming together and delivering this. That’s how I think we’re going to bring systems medicine forward and have it be affordable. It’s a side step but…

Dr. Dale Bredesen: I think that’s a good point. I think for one thing, just as we had global programs to vaccinate against polio or smallpox things like that, we now need to take global programs to vaccinate against Alzheimer’s disease and Parkinson’s disease. This is not the same sort of vaccination. This is not about injecting people. I talk about that in the new book, that we need to have programs now that take a population which 15% of the people are going to die from Alzheimer’s and it’s going to affect so many other people. This is a trillion dollar plus global problem, and now make it so that this is actually a rare disease. There are specific programs. It’ll be a new way to think about vaccinating people. It will be a functional medicine model.

It’s been amazing to me, I agree. Functional medicine needs to fit in with drug development, and drug testing, and with standard allopathic medicine. It’s been surprising to me how much resistance there’s been to something which is clearly getting results in so many different chronic conditions. Unfortunately, it’s been much more about politics, and power, and control, and finances than it has been about outcomes, which is unfortunate.

Dr. Kara Fitzgerald: Of course, we are poking the bear a little bit and so we’re seeing the volume a little louder in those ways. Incidentally, just going back to COVID. Of course as Jeff says it’s a pandemic within a pandemic. With a pandemic of the fact that most individuals here, I think in this country, or most adults are somewhere on the cardiometabolic continuum with some level of insulin resistance and all of these things of course are part of underlying Alzheimer’s pathogenesis. I think just in addressing COVID, your new vaccine, the vaccine for the 20th century, is essential, is absolutely needed.

Dr. Dale Bredesen: Absolutely no question. I think that you’re right. I mean, we’re living an unhealthy lifestyle in general, most of us. We’re seeing that as early cognitive decline. I mean, we never used to see people… when I was training in the eighties, we never saw people in their forties, fifties with real Alzheimer’s disease. We always thought of it as a disease of the sixties, seventies, eighties, and nineties, and it’s turned out to be a disease of the forties, fifties, sixties, and seventies. Now we see it as one of the most common presentations, people who are often in their early fifties, even late forties who are developing Alzheimer’s. As you indicated, this is one way that you see this.

Another way is that people die of COVID-19 when they shouldn’t be dying of COVID-19. They’ve got the cytokine storm. Of course, all of the same risk factors that we see with Alzheimer’s disease playing out over decades have been compressed into two weeks with COVID-19 where hypertension, and insulin resistance, and obesity, and all of these, hypovitaminosis D and zinc deficiency, which a billion people on earth have. Yeah, these are all present and we see different outcomes. COVID-19 has just throwing this all into relief, unfortunately.

Dr. Kara Fitzgerald: Yes. Well, if we actually make this a game-changing moment as you suggest we might, then hopefully it will be for naught all the lives that we have lost. Incidentally, autism, which you mentioned not seeing Alzheimer’s in younger people at the beginning of your career, the meteoric rise in autism I think has shared properties. But instead of digressing again, I want to talk about the six types and any kind of… In hindsight, as your experience has evolved and many practitioners are working with you now, speaking to what seems to be the major players of these six types. If you can outline them and maybe your thoughts on them in your current 2020 lens. Yeah, go ahead.

Dr. Dale Bredesen: Yeah, again, this fits so beautifully with the science. When you look at what drives APP, you can trace a molecular pathway from NF-kB. You activate inflammation with whatever pathogen you like or whatever poor lifestyle choice or leaky gut, or what have you, NF-kB of course enters the nucleus, affects hundreds of genes. Among those, it affects the beta and gamma secretases which come out, interact with APP, and cleave it to drive you down the synaptoclastic pathway. As we started to look at, what’s driving us for each person, we found that some people, the major problem seems to be systemic inflammation, just as you see with cardiovascular disease and just of course increases your risk for some cancers. You see this, it’s changing your APP signaling. You can, again, trace the pathway.

This is your typical… we often see this with a 65-year-old man who’s got a high hs-CRP, and now is suffering cognitive decline. That’s a typical patient. This is something, of course, that could be addressed with things like SPMs and things like that. Of course, identifying what’s driving the problem to begin with, are there specific pathogens? Is this leaky gut? Is this something else? But then we found other people that are just very different looking. You have people where it’s an atrophic problem. They don’t have a lot of systemic inflammation. They may not have many toxins to which they’re exposed, but they simply don’t have the currency to support that massive neuronal network.

You’ve got over 500 trillion synapses. You got a major supercomputer inside your skull. Of course it takes a lot of energy, a lot of support to keep that going. These are people, and the typical one, again, would be a 75-year-old woman who has zero estradiol, zero progesterone, low thyroid, low pregnenolone, low DHEA, low vitamin D is just, is dry. This is something, again, that the ayurvedic physicians noticed many years ago. These are people who have an atrophic, they look atrophic, they act atrophic. In fact, what’s interesting about them is they don’t support the neural network, but they’re not inflamed. They’ll often say, “I feel all right. I don’t have great energy, but I’m okay.” They’re still driving, they’re still playing tennis. They’re still doing just fine.

They’ll often complain, “Hey, what are you doing?” And the spouse will say, “Well, yeah, because you can’t remember anything new.” This is the canary in the mine. This is the thing that goes first. Because if you think about it, if I gave you the choice, Kara, waking up tomorrow morning and either you would forget how to speak, or how to do your job, or how to calculate, or you would forget the Friends rerun from tonight. That’s an easy choice. You can live for a long time, very effectively, with the things you’ve learned to date. You’ve kept the most important thing. That’s atrophic or type 2. These people, you need to optimize all these different factors to see improvement in them.

Then type 1.5. We named it that because it does have features of both. It is glycotoxic, this is sweet Alzheimer’s disease. It’s because you get the inflammatory component from the glycation of the proteins. We measured with hemoglobin A1C, but of course many proteins get glycated and so they change their function, they can change their structure. They can be recognized as foreign, and you can get an inflammatory response to them. On the other hand, you also of course develop insulin resistance. You’re now not getting that signaling. The years and years, we grew neurons in dishes, you always had to include insulin, transferrin, and selenium, which are critical for keeping the neurons alive. If you don’t have good insulin signaling, that’s a bad sign for your brain.

Of course, all of this has to be internally consistent. This is one of the things that has just driven me crazy about the Alzheimer’s field. There’s no internal consistency. People just say, “My theory is X. It doesn’t comport with 90% of what’s published, but that’s my theory.” It has to comport with the epidemiology, the pathology, the microbiology, the toxicology, all these. Of course, ultimately you have to be able to make people better when you deal with whatever your model system is. That is insulin resistance, no question. The epidemiology show us that that is a critical piece. That’s type 1.5.

Type 3 is very different. These people look different, they act different, and you have to treat them different. These are the people who have toxins, and they come basically in three groups as you know, the metals and the inorganics things like air pollution or mercury, things like that. Then second one is organics, toluene, benzene. If you’re out there in the middle of burning paraffin candles 24/7, you are at increased risk for cognitive decline. Then the third one is the biotoxins. Of course, as we see again and again, and again, mycotoxins are huge in this. So common, so much exposure to these. Until you get people on a detox protocol, you’re not going to make them better. These people look different. This is the 52-year-old woman who presents with executive dysfunction rather than memory loss, or has some of both, but largely just can’t put it together, can’t organize things anymore.

They often will have some of these non-amnestic syndromes. They may have primary progressive aphasia or posterior cortical atrophy, things like that. But they often are the non-amnestic. Often are the ApoE2/3s, 3/3s. Although some of them do have ApoE4. These are people who may start with depression. They have HPA axis dysfunction. They have some of the things of SERS. Interestingly, most of them don’t have classic SERS, but they are effecting their synapses, and so you’ve got to get them on detox and identify what the toxins are.

Then type four is vascular, and so many of these people have poor perfusion. They either have poor perfusion because they’re not exercising enough or because they’ve got atherosclerosis. They may have poor oxygenation at night, as we talked about earlier, or during the day. For whatever reason… Again, this system is not a system that has a great foundation. The leading mitochondrial physiologist, Professor David Nicholls, who worked at the Buck Institute with us years and years ago, said one time that, “Mitochondria, we used to think of them as things that were pretty solid like a Chevy, they’re not. These things are like Maserati’s, they’re going 100 miles an hour and going to go 200 miles an hour. Anything that goes wrong can be a problem.” These systems fail, and you’ve got to keep, as you get older, optimal oxygenation, blood flow, et cetera.

That’s type four, and then type five is of course traumatic. If you get head injuries, if you’ve got repeated injuries to your head, you are at increased risk for cognitive decline. It could end up being Alzheimer’s if you’ve got amyloid there, or it could end up being called CTE if it’s mainly a tauopathy. But to some extent CTE is, you cleared out the amyloid fine, but you still have the tauopathy, you still have the degeneration. You really have to think about that. Their presentation is different and the classic triad is depression, aggression, and dementia. These are people that will often beat up their spouses before they are diagnosed as having CTE, for example, unfortunately. These often look different. You have to look at them differently even though they all have the pathology of Alzheimer’s disease, of course, except CTE, which often has cleared the amyloid.

Dr. Kara Fitzgerald: Let me just, of these different presentations, you talked about the 52-year-old woman who’s suffering with biotoxin or mycotoxicity. I mean, can that be a slow onset or can that be… I mean, it can be either, slow or relatively sudden I believe.

Dr. Dale Bredesen: Sorry to interrupt. We’ve seen people who were dealing we know for 15 years and had symptoms for 15 years, but they’ve successfully fought it. One of the interesting things about this is we see so many of these people presenting at menopause, or perimenopause, or after the conclusion of menopause and we wondered why. I was like, “Why is this so common at that time?” It looks like what’s going on is that you have this combination of, as Chris Shade has pointed out, as you’re losing your progesterone, that’s a critical detoxer. It’s part of the detox program. That’s part of the problem. But the other thing is, as you know, you have an osteoclastic burst for about seven years.

You’re doing everything for years and years to deal with these toxins. You’re excreting them, you’re metabolizing them, you’re sequestering them. Now you’ve lost some of the sequestration and you’re re-releasing these back into the bloodstream. For whatever reason, this is a common presentation. Yes, we’ve seen people who are relatively successfully dealing with it for years and we see other people where it just is overwhelming. Some of these people, of course, because they have poor detox apparatus genetically.

Dr. Kara Fitzgerald: Of these six types, is there any one that has a better prognosis?

Dr. Dale Bredesen: Oh, absolutely. The toughest one is the toxin. The people who have biotoxicity, it’s tough because you’ve got to really stick with it and you just hold their own for a while. As you know, if you detox them too rapidly, they can go into decline once again. If you don’t detox them at all, they naturally decline. That’s the toughest one. The ones that are easiest are type 1.5, where it’s really a sugar problem. If you return insulin sensitivity and you return, you start reducing their glycotoxicity, and you get them into ketosis. Those are the big three and they don’t have a large vascular component already, and obviously these things go together. But if they don’t have that, they typically turn around and fairly, within a few months.

Similarly, if you have pure type 1 and it’s just an inflammatory process, you could reduce the inflammation quickly and see people begin to turn around. Then of course, for the long run, you want to identify what’s causing the inflammation and deal with that. But those two tend to do very well. Similarly, if you’ve got a vascular problem and you’d begin to improve that, of course, as Dean Ornish did with cardiovascular disease 30 years ago, then you can see people improve. The type twos and the type fours a little more slowly, but certainly can improve. Sometimes just oxygenation, they can improve.

Then type five is a little bit like type two because ultimately, it’s an atrophic process. You haven’t had the support. You’ve, in this case, damaged the synapses instead of decreasing the trophic support for them. But you’ve got to get that support back and reinitiate synaptic formation. This is where I think things like stem cells are ultimately going to be helpful. Stem cells alone, a little bit like trying to rebuild a house as it’s burning down. But you first want to get rid of the fire. You do all the right things with a functional medicine approach then add the stem cells. Those are the ones that are easier versus harder to turn around.

Dr. Kara Fitzgerald: Still, obviously early is best. We’ll talk about your ideas around what all of us need to be doing. But you’ve reported on turning around late stage cognitive decline. I think I like the idea of preparing the terrain to receive stem cells, that makes total sense, otherwise they’re they’re useless. Some of the pharma that you were talking about earlier would certainly come in. But you’ve successfully worked with ApoE4 as well. I mean, we were talking about that… Yeah, go ahead.

Dr. Dale Bredesen: They tend to do better. ApoE4s tend to be easier to turn around. We don’t know why that is, but maybe because they have a more inflammatory component. We found in the lab that ApoE4 actually has a transcriptional effect that, a subset of your ApoE enters the nucleus and binds to 1700 different promoters. You couldn’t tell a better story for Alzheimer’s. It includes things like SIRT1 and estrogen receptor. Really striking that you can see how it impacts the cell and how it changes the programming toward a more pro-inflammatory, and of course protective. If you’re eating meat filled with microbes, that really helps you. Of course, if you’re living in a squalid third world country, if you’re living in… if you’re a Chimane Indian from Bolivia, you do better with ApoE4 than without ApoE4.

No question. What we’ve realized is that there is a rate-limiting step. You may have 15 things wrong, which we see all the time. Let’s say out of those 15, one of them may turn out to be the rate-limiting step. You can improve the other 14. If you don’t hit that rate-limiting step, you’re not going to see a change in trajectory. Then once you hit that, you get a little improvement, or you get a change in the rapidity of the decline. Well, then you’ve got to find the next rate-limiting step. I call this ascending rate-limiting steps. You’ve got to figure those out one by one. With functional medicine, you’re hitting multiple of them. You may see the person turn around, but first what you’ll see is changing that downhill trajectory.

Now, if you’re late stages, this accelerates. I mean, that’s what prions do. You’re now getting this accelerating. It’s an amplifying process. It’s really tough. It’s the difference between correcting a plane that’s just had its nose down slightly, and now you’re just pulling the nose up again versus one that is in a death spiral. That is really tough to change. You’re going to have to change a lot of things to get that to improve. Interestingly, I got a critical letter about six months ago from a guy who said, “You’re always telling people come in early or else forget it.” He said, “Look, my wife had a MoCA score of zero. She got on the program, she’s dressing herself again. She’s interacting with us again. She’s changed our lives. We’re so happy. Now, she still has a low MoCA score, but she’s doing much better than she was. How dare you tell people not to do this?”

We’re stuck in this. Yes, please, get on as early as possible and preferentially do this with prevention of cognitive decline. That’s the future for all of us. But if you don’t do prevention, please start as early as possible because there are some cases where it’s late.

Dr. Kara Fitzgerald: Right, right. Yeah, you talk about Claudia in your book, which is another 78-year-old woman, pretty late stage and you turned her around as well. We always need to do it. We need to be doing the work with anyone, but I… Yeah, prevention for sure. I just want to circle back and underline, for folks who might’ve missed it, the statement on ApoE4 that you said that it’s actually one of the easier ones to turn around. It’s inflammation, it’s relatively straightforward. So many of our patients, and providers as well, who know that they’re ApoE4 positive, there’s a lot of anxiety around it and it does indeed need to be tended to. But the fact that it is addressable, as you’re stating, is huge.

Dr. Dale Bredesen: Absolutely. Which is not to say that every single person with ApoE4 gets better, they don’t. But we do see it by the way. Again, it is how much of this you can do. Part of this is just, if you can comply with these various pieces, most people will improve. But it’s hard. To be fair, it is hard. One of the things we’re trying to do right now is to simplify it. If we can tell you for sure, yeah, there might be 20 things to do or 25 things to do, but really these top five are 95% of it, that will be really helpful. There are 75 million Americans who have a single copy of ApoE4 and about 30% of them will develop Alzheimer’s unless we do something about it. There are 7 million Americans approximately who are double copy or homozygous for ApoE4, and the majority of them will develop Alzheimer’s disease.

We’d like to have people identify that and get on appropriate prevention or early reversal, because this should be something where they virtually never get Alzheimer’s disease. There’s a tremendous amount you can do here. That’s the hope for the future. This idea that, stick your head in the sand and don’t figure out whether you’re ApoE4 positive, because there’s nothing you can do about it. Nothing could be further from the truth. There’s a tremendous amount of you can do about it.

Dr. Kara Fitzgerald: That’s a very empowering message, thank you so much. With that, let’s talk about prevention. I mean, you think that all of us need to be doing a cognoscopy. I want you to just talk about what that is because it’s more than just one intervention. This would be evaluation, but then, what we all need to be doing for foundational brain health, maybe with a little bit of an eye towards the ApoE4 folks.

Dr. Dale Bredesen: Absolutely. Yeah. We all know that when we turn 50 we should get a colonoscopy. Actually my wife and I, when we went to get this, we said, “Okay, this is a pain, but let’s…” we did it on Valentine’s Day as his and hers so that we could get this over with and then go out to eat together. We’re like, “Okay.” It’s just something you have to get past. But in fact, nobody tells you, just as nobody tells you about dementigens but they tell you about carcinogens. Nobody says, “Hey, you need to have a cognoscopy. You need to know where you stand. We recognize, and we recommend that everybody should be getting checked when they’re about 45. If you’re over 45 fine, go and get a cognoscopy.

It’s simple, it’s three things. Number one, it’s blood and urine tests that tell you whether you have ongoing inflammation or insulin resistance, or you’ve been exposed to toxins so forth and so on. The critical things that unfortunately the vast majority of physicians are not checking, which allows dementia to sneak up on you unfortunately. The second piece of the cognoscopy is a simple online cognitive assessment. It’s simple. It takes about 30 to 40 minutes and it’ll tell you, “Okay, are you doing really well?” As an example, I mentioned this in the book, a woman who said, “I’m here for prevention. It’s in my family, we’ve got the dementia in my family.” She turned out to be ApoE4 positive, single copy. She said, “I think I’m still in pretty good shape.” Well, she scored a 23 on the MoCA, so she clearly already had very significant MCI. She’s now scoring 30, she’s doing absolutely great. Sometimes you don’t realize you are in those early or even mid-MCI phases unless you check. Get that, that’s the second piece of the cognoscopy.

Then the third piece is optional for people who are completely asymptomatic and score well on cognitive assessment, and that is an MRI with volumetric. But if you’ve got symptoms, if you’re not scoring well on the test, please include the third part which is an MRI with volumetric. Check your hippocampal volume. You could be walking around with a hippocampal volume of fifth percentile or it might be 90th percentile, and that is a prognostic indicator and also an indicator, whether you may be heading down the wrong pathway. Now, you’ve heard about this recent blood test for phospho-tau 217. Phospho-tau is really telling you whether you have the signaling in the brain that is telling you pull back. That is part of synaptoclastic signaling.

This test is not available yet. The hope is that it may be out next year. It’s claimed to be specific and pretty sensitive. We’ll see as time goes. Previous tau tests have not panned out, unfortunately, including the one that I thought was the most promising, which was the neuroexosomal tau. It just hasn’t turned out to be that helpful, but we’ll see. Over time, this will be fantastic to have. Again, if someone tells you, “Yeah, you’re 10 years away from Alzheimer’s,” great, get on… really, it’s not then prevention, but it’s now presymptomatic treatment. That’s the cognoscopy and we recommend that everybody who’s 45 or older, especially if you think you may be having early symptoms and especially if there’s any family history of Alzheimer’s, and especially if you have ApoE4 as an example. All these things make sure because, again, we can all together make this a rare problem.

Dr. Kara Fitzgerald: Yeah, that’s right. I have to remember to circle back to you at the end to direct people, clinicians in particular, where they can go through the training and how we can make this happen. Because all of us should be doing this in our practice routinely. Ketosis is big, I think, for most of the types. Do you want to just speak to that? We’re heading to the end and I want to ask you about ketosis, the dementigens, and then just a little bit on microbes in the next few minutes.

Dr. Dale Bredesen: Absolutely. Ketosis is absolutely huge and we don’t see too many people who get better without any degree of ketosis. That seems to be because, as you know, you can actually see it on a PET scan that you have an energy gap. This is an emergency. When you are having cognitive decline, you see this decreased glucose utilization in the temporal and parietal regions that is associated with Alzheimer’s. How can you bridge this gap? As Stephen Cunnane has shown, you can do this with ketosis and it is absolutely crucial. No question. Again, and again, and again, we see the people who get into decent ranges, 1.0 to 4.0 millimolar beta-hydroxybutyrate tend to do the best. You’re now bridging that gap and giving the brain the actual fuel that it needs. Now, again, if you’re not getting oxygen there, you’re not doing yourself any favors. If you’re not getting blood flow there. Again, all of this has to work together. If you fail at any point, that is your rate limiting step.

Dr. Kara Fitzgerald: You’re talking about blood, measuring ketones in blood. Meaning beta-hydroxybutyrate.

Dr. Dale Bredesen: Yeah, and obviously we’re testing a breathalyzer which is the one that’s best right now, I think, in terms of actually… it’s got some promise. That may be something that we can use. In the past, as you know, the breathalyzers haven’t been particularly helpful, and so it’s always been through blood. But I hope in the long run it won’t be that everyone’s got to stick their fingers so often, and we’ll be able to do this more simply through that. But that is a huge area for improving people with cognitive decline.

Dr. Kara Fitzgerald: Are you recommending exogenous ketones?

Dr. Dale Bredesen: Yes. Here’s the thing, in the long run, we’d like to get everyone to be able to do endogenous ketosis. Again, this is where you’re looking at what’s the lesser of the two evils. We recognize taking a bunch of MCT oil can be a problem for your LDL particle number. Fine, if you’re ApoE4 positive, you don’t have to take coconut oil or MCT oil. Okay, take exogenous ketones. One that’s been good. KE1 is one that I think is nice. It’s a combination of esters and salts, but there are lots of others. There are esters out there and salts, and there are all sorts of vendors that can provide this. We are agnostic, whatever works the best for people, that’s what we want to do.

What we recommend at the beginning is, please just get yourself into ketosis. Then after the first month or two, you can think about, “Now, let’s see. Can I get myself into endogenous ketosis?” Some people like to do that at the beginning, it’s fine. There’s actually been published data showing that people with cognitive decline, whether you give them ketones or whether you drive them into ketosis, both of them improve your cognition because you’re bridging that gap. I know some people are very much against exogenous ketosis, but it’s better than nothing. It is going to at least get you that ….

Dr. Kara Fitzgerald: It’s fuel.

Dr. Dale Bredesen: Your brain is starving for fuel. I like the idea of look, let’s get it going. Then once we do that, now we have bought ourselves some time. We’re at least giving your brain what it needs. Then let’s now start fixing these things and other things, is it getting enough oxygen? Do you have nocturnal hypoxia, et cetera. Then get yourself in the long run. Julie Gregory, who’s the one who founded apoe4.info and actually worked on the handbook with my wife and with me to do this. We have a scientist, we have a clinician, and we have a user who’s done extremely well, and can tell you the practical things together. In her case, it did start with exogenous ketosis, but has moved over into endogenous ketosis and has done spectacularly well for over eight years now. Yes, we use exogenous ketones, but try in the long run to do endogenous.

Dr. Kara Fitzgerald: For the sake of time, I’m not going to pick your brain. I have a lot more questions. Go to the book, The End of Alzheimer’s Program, there’s a more granular discussion. Other resources would be, I’m assuming, Julie’s site apoe4info.com-

Dr. Dale Bredesen: Drbredesen.com and mycognoscopy.com. You can get a cognoscopy now directly, so it’s easy to do.

Dr. Kara Fitzgerald: Good. Okay. No excuse folks for us not to be doing them on ourselves and directing our patients. A little bit on the dementigens. What are the big players here, and how are we guiding our patients to remove them taking care of ourselves?

Dr. Dale Bredesen: Yeah. Great point. In fact, we’re discovering ones that we didn’t know about. Just as we talked about earlier, on the metal side it’s mercury, there are others that contribute iron, copper, things like that. These high copper, zinc ratios are associated, that’s been known for decades. Then air pollution of course has emerged as an important one, especially these small particles. Of course that recent article on fish seems to… they need to have about an equal magnitude of effect on these. It seems to protect you. Then some of the organics that we didn’t know about, so benzenes, toluenes, glyphosate, formaldehyde, things like that, propylene oxide, acrolein. We’ve had examples of some of those recently.

Then the mycotoxins, these are big ones. Trichothecenes, major problem, ochratoxin A, gliotoxin. These things unfortunately affect multiple systems, your immune system, they affect your kidneys and liver, they affect your detox. You’ve got all sorts of problems and they of course affect your nervous system. These are the dementigens, and unfortunately, most of us don’t know when we are getting exposed, and there isn’t a simple, an AIMS test for a carcinogen. We need to be more aware of these things. We need to get ERMI scores and HERTSMI-2 scores for our homes and our places of work.

We need to look – we need to be aware of how much fiber we eat. We need to do better genetics. Look, I give great credit to Dr. Sharon Houseman Cohen who set up IntellxxDNA. Of course ,there are others as well, but you want to know whether you have null alleles in some of your glutathione-related genes, such as GPX and GST and things like that. For those of us who are poor detoxers we are at risk for detox-related problems.

Dr. Kara Fitzgerald: Yes. Yeah. Well, and we all have… you can’t avoid SNP’s and detox, I guess. It depends on what your collection is and how you might address it. This can get to be, just as a clinician, it can get to be a pretty onerous investigation, essential, but big. The clinical trial that you’re doing, the fact that you guys are working on what are the main starting areas. Eventually, Dale, hopefully the labs will follow you and begin to release panels where you can look at a number of different types of toxins under one house and not have to go to multiple places.

Dr. Dale Bredesen: Technology is complicated as you know.

Dr. Kara Fitzgerald: Yeah, it’s complicated.

Dr. Dale Bredesen: We’re dealing with a huge problem. This is a complicated, complicated organism that we’re trying to fix. I think this is where, in the long run, AI is going to be helpful to us to tell us, “Okay, it’s really, yes, there are lots of problems, but you can get 95% of them with these five things.” We’re experiencing that. Of course, that’s where your excellence and experience as a physician come in.

Dr. Kara Fitzgerald: Yeah, you’re absolutely right. We need AI and then we need the high throughput lab technology so we can look at a bunch of stuff and it’s relatively affordable. Yeah, that’s right. That’s exactly right. Okay, so what do I want to wrap up here with? I appreciate you bringing oral health to the fore, and you mentioned those microbes earlier in the… yes. Then any… what do I want to say, if anything else? All right, I have one more question on that front. In looking at your book. I mean, most of us have titers to the various herpes. I don’t know that I’ve ever seen them get zeroed out. Now, if you follow them you might see some change. But that’s a pretty high bar. Just speak to that.

Dr. Dale Bredesen: Yeah. We didn’t recommend that they be zeroed out of course, so we’re not expecting them be zeroed out. What we’re simply saying is, be aware that this may be one of the contributors. If you happen to have early antigen from EBV, if you happen to have… a lot of people, as you know, will have these high titers across the board. You’ve got this ongoing response, and be aware of it. As you know, beautiful studies out of Taiwan showing that people who had recurrent HSV-1 one on their lips, who treated it, had a much lower risk for dementia than those who, when they went untreated, when they were not dealt with at the time. It’s something to be aware of. We don’t expect them to go to zero. On the other hand, if you don’t have those, then you’re focusing on other things.

Dr. Kara Fitzgerald: Good. Okay. Well, listen, it was just a really wonderful conversation with you. I appreciate it so much. I could continue to ping you for another couple hours, but I know other people want to talk to you. Where do clinicians go to get ReCODE training?

Dr. Dale Bredesen: Yeah, so we have ReCODE training. If you go to apollohealthco.com and the new training is coming out next month, ReCODE 2.0. We’ve got some wonderful people, Dr. Neil Nathan is part of this, Dr. Cyrus Raji, Dr. Ann Hathaway, Dr. Chris Shade and on and on. Wonderful people who are doing the training and Dr. Sharon Houseman Cohen is part of this as well, so that we’re trying to hit all the critical areas so that people can learn best and get best outcomes.

Dr. Kara Fitzgerald: I’m absolutely excited about that. Folks, everything will be on our show notes. We will get as many citations. I know Dr. Bredesen mentioned a lot of papers, so we’ll try to pull those from his team and we’ll post those there. We’ll post all of the links to the training, to the new book, to everything that you need to be able to access this amazing body of knowledge. Dr. Bredesen, thank you so much for joining me today on New Frontiers.

Dr. Dale Bredesen: Thanks so much, Kara, for having me. I really appreciate it. Thanks for all the great work you’re doing.

Dr. Kara Fitzgerald: Absolutely.

Dr. Dale Bredesen: All right, stay safe.

Dr. Kara Fitzgerald: Thanks, ciao.

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