 fantastic meeting I was there a few years ago at the AHS meeting. And I think we're all finding how important this is, both with respect to COVID-19 and with respect to cognitive decline. So let's see here how we're going to be able to go to the next for some reason. This is not allowing me to advance the slides. There we go. Okay, so I wanted to mention the semantics because I think this is so important. We've all slept through the recent FDA approval of adicenamab. And I think it's important for people to understand that this is not something that makes you better. This is not something that stabilizes. But in the best case in one trial at one dose, there was a slowing of decline as you can see here by about 22%. So if you have MCI, which is pre Alzheimer's or Alzheimer's disease, you lose about 3.4 points on a 30-point scale per year as you can see here. If you take a drug to slow it, you slow this by about 22%. And in contrast, I'll show you a trial that was recently posted. You can see it on Med Archive where we see instead of a slowing of decline, we actually see improvement in patients cognition. We also see improvements, by the way, in their MRIs as well as a number of other parameters. So as everyone realizes, this is a pandemic without a vaccine, unfortunately. So for perspective, we now know, of course, COVID-19 has killed now over 600,000 Americans. But in comparison, Alzheimer's will lead to the death of nearly 100 times that many of the currently living Americans. So about 45 million, as Professor Christine Yafi from UCSF has pointed out, it's now the third leading cause of death in the United States. So it's a major problem, really dwarfs the COVID-19 pandemic. And the big problem, of course, is with COVID-19, we understand it's a virus. We have sequence, we have sequence of the variants. So this is a disease that's relatively well understood. We know what to do about it. Even though the vaccines aren't perfect, they help dramatically. There are antivirals being developed. There are antibodies that are effective as well. So there are lots of ways to go. On the other hand, Alzheimer's, the big problem has been that it is controversial what actually causes this. So people will go after one thing or another. But as you know, there are over 400 failed clinical trials. So it's the fundamental nature of Alzheimer's that is missing. And that's why things have been so unsuccessful. So we'll talk about that today. And that's what my laboratory has been interested in for 30 years, what actually drives the neurodegenerative process. So here's, to put all that into a short couple of slides, here's the issue. We've as physicians been trained to treat things like pneumococcal pneumonia to write a prescription for various diseases. And this works great when you have a simple disease. So if you've got someone with pneumococcal pneumonia, of course, there's an increased risk with alcohol on board, with diabetes, with your B cell function not being up to snuff and many other variables. But the pneumococcus itself is so much more important than everything else that we as physicians can get away with simply writing a prescription for amoxicillin or cephalosporins or penicillin or what have you. Unfortunately, the diseases we're all dealing with, the diseases that are limiting our lifespan today are not simple diseases. They are fundamentally different. And let's take Alzheimer's as a simple example of these complex chronic illnesses. Insulin resistance increases your risk, pathogens, NF-Kappa B, various things that give you inflammation, mercury exposure, mycotoxins, organic toxins, homocysteine increase, and there are multiple other things. But as you can see, none of these, unlike a pneumococcal pneumonia, none of these outstrips everything else. So you can just write a prescription for that one thing. So we have to evaluate and treat and prevent these illnesses in a completely different way. And of course, this is where everyone's finding ancestral health is so critical to avoiding these complex chronic illnesses. What that means is if we're going to develop the perfect Alzheimer's drug, and we worked on this in the laboratory for years, and in fact, it would have to do this. And this is the problem. We're asking too much of a simple, single drug. The drugs do very well at what they target. And I think in the long runs, as part of an overall precision medicine protocol, they will be very effective. But asking a single drug to do dozens and dozens of different things is asking an awful lot of a single drug. So here's the problem. If you go in today to a classical clinic and you say, I'm having some problems with my cognition, they may tell you, oh, you've got Alzheimer's or you've got pre Alzheimer's or early Alzheimer's, there's some cause. We don't know it. It's one disease. We call it Alzheimer's. We're going to give you a monotherapy and it's not going to work very well. And you're going to die. Unfortunately, the research findings show something completely different. There are many, many different contributors. We initially identified 36. There are a few more now. Good news. It's not thousands, but it's dozens. It's not one. Therefore, this is not just one disease. There are subtypes. There are more inflammatory patients with Alzheimer's. There are more atrophic, glyco toxic, toxic, vascular, traumatic. So therefore, no surprise, there are many personalized programs that you need to do to get the best outcomes. So let's dive now to the actually what's driving this problem. And a very interesting molecule, APP amyloid precursor protein that sits in your neurons, especially at synapses and to a lesser extent in other cells as well. This is a very interesting molecule because when things are good, it's a little bit like your CEO or a little bit like the president of your country, your country being my brain of stand. So okay, you're going to look at this. And now when things are good, then in fact, what happens is this is cleaved at a single site and it produces two peptides. So here's outside the cell, inside the cell, SAPP Alpha and Alpha CTF. These are signaling growth and maintenance. And by the way, this is very much analogous to what's happened to all of us in our country during COVID-19. What happened? We had an insult SARS-CoV-2. We were all told that we should shelter in place, social distance. We went into a protective downsizing mode. People lost their jobs, people didn't go to work, et cetera, et cetera. And what happened? Our country entered a recession. The same thing is happening to your brain and Alzheimer's. You had these various insults and you respond to those insults by in fact making a different outcome, a different signaling process where you now cleave APP at three sites, beta, gamma and caspase sites. And you could actually trace the molecular pathways from things like NF Kappa B associated with inflammation and various pathogens and reduction in estradiol and things like that to show that this is switching. You're switching your signaling from a growth mode to a protective downsizing mode. Again, the same sort of thing that happens when we interact with things like SARS-CoV-2. So this molecule APP is changing its signaling. And you can see here this A beta that's been vilified as the cause of Alzheimer's is really part of a protective downsizing response that your brain makes. It is an antimicrobial peptide and interestingly also has some antifungal effects and antiviral effects. So it's actually part of your innate immune system. And once again, there's a really interesting parallel with COVID-19. With COVID-19, you have the innate immune system running away. Your adaptive system hasn't managed to get rid of this. And so you die by cytokine storm. With Alzheimer's, you also have a chronic activation of the innate immune system. That's where the A beta is coming from. And in fact, you're not the adaptive system is not getting rid of the various insults that are actually causing this. And so you don't have cytokine storm. You have cytokine drizzle and it occurs over years and years and years. You're making this chronic inflammatory process that includes A beta and your brain has entered a protective downsizing mode. So what this means is that you've got these two signaling pathways for APP. Your probability of getting Alzheimer's is proportional to an integral over time of all the synaptoclastic signaling pulling back versus the synaptoblastic signaling. Now that's fine, but it doesn't tell you what test to order or how to treat it. But the good news is that is essentially approximately pretty good to a pretty good approximation associated with four major groups of processes. So anything that is causing chronic inflammation, again, you're going to make more A beta. So it's going to increase your risk genetics as well, contribute to that. No surprise. And then anything that's causing toxic burden. And those come in three different groups. Typically, it's in organics, things like the California wildfires with poor air quality, secondly, organic and mercury, things like that, organics, things like formaldehyde and benzene and toluene and glyphosate and things like that. And then third, biotoxin, things like trichothesenes and ocarotoxin A and gliotoxin. And then in the denominator, so energetic. So if your energetics are low, that increases your risk. And that's your cerebral blood flow, oxygenation, mitochondrial function, and ketones, the ability to have substrates to burn. And then finally, trophic effects, growth factors like BDNF and NGF and things like that. And then hormones, estradiol, testosterone, progesterone, pregnenolone, thyroid, all those things that support brain function, including insulin, by the way. And then finally, nutrients, so vitamin D, critical, vitamin B12, things like that. So this gives us now a look at what's actually causing the problem. Alzheimer's disease is fundamentally an insufficiency. The demand is chronically exceeding the supply. And you're responding by going into a protective downsizing mode. So instead of just writing a single prescription, we need to identify all the things that are contributing to this response of your brain. And then we need to get you back into balance. And I'll show you, we've recently had a trial on that that worked very well. So again, we tell the patients, imagine we've got a roof with 36 holes, a drug is an excellent patch for one hole. But we need to do more. Therefore, of course, we need to train physicians. We know that the traditional Chinese physicians quite good at understanding the whole body, but they didn't know about DNA and RNA and things like that. Modern physicians, very good with DNA, RNA, informatics, things like that. But they tend to focus on one area, like the brain. And so we really need to bring this together and train a new kind of physician who really gets both, you know, the whole picture as well as understanding the molecular basis of these complex chronic illnesses. So when we want to go and treat the goals for treatment and prevention, and I will go through this in the trial, I'll talk a little bit about the trial in just a minute, we need to optimize your energetics. We need to typically get people into mild ketosis, make sure their cerebral blood flow is okay, make sure they don't have sleep apnea, make sure they're not dropping their oxygenation at night. We need to create insulin sensitivity. This is incredibly common. About 80 million Americans have insulin resistance, as you know, major problem. And again, comes right back to ancestral health, trophic support, growth factors, hormones and nutrients. As I mentioned, we need to resolve inflammation. And of course, Professor Charles Sirhan from Harvard has taught us all the importance of not just anti-inflammatories, but resolving inflammation. But beyond that, we need to understand what was causing it in the first place and remove that. We may need to treat specific pathogens. And of course, if you have neuropathologists looking into the brain, what they have described in patients with Alzheimer's, herpes simplex, P. gingivalis from poor dentition, various fungal species, HHV6A on and on. So in fact, this is a change in a microbiome in the brain. Again, you are responding in a protective downsizing way. Detoxification, as everyone knows, this is becoming a more and more critical issue. So many of us are exposed to various toxins. And then interestingly, the people who've done best have also included some form of stimulation, brain training, light stimulation, for example, things like violite, magnetic stimulation, like MIRT, things like that. And then again, we want to bring the adaptive system to improve that and reduce the inflammation associated with the innate immune system. And then after that, we'd love to remove the amyloid beta, but removing that first when it's actually part of a protective response really doesn't make biological sense. And then ultimately, regeneration, synaptogenesis, whether through stem cells, intranasal, trophic factors, there are a number of ways to do that. So I want to just then talk a little bit about the trial. I'm really honored to be working with three absolutely outstanding functional medicine physicians, Dr. Anne Hathaway, Dr. Cat Tubes and Dr. Deborah Gordon. And we've completed the first trial and now just in the planning stages for a larger trial. So this is the first trial in which instead of predetermining a treatment, which if you think about it, really doesn't make sense. For each person, we look at all the potential contributors and then we treat those. So you're targeting those. So this is a precision medicine type of approach. Interestingly, we were turned down by the IRB back in 2011. We tried to do the first comprehensive trial for Alzheimer's, turned down again in 2018 after we published many, many anecdotes. We published 100 anecdotes of people with documented improvement, finally got approved in 2019. We completed the trial in December 20. It's now on Med Archive. And so small proof of concept trial, 25 patients, very similar actually in terms of where they were in their dementia to the adecanumab trials. So these were people who had mocha scores of 19 and above. And then we compared personalized precision medicine approach to historical outcomes. And we look at the root cause, just the things that I just talked about. So look at the Montreal Cognitive Assessment, 0, 3, 6, and 9 months. We looked at CNS vital signs, which is a much more sensitive indicator. So it gives us a better overall dynamic range. We then looked at AQ 21, which is the partner's assessment of how they're doing. AQ 20 or AQ change score. Is the partner's assessment of did they get better? Then we also looked at MRI with volumetrics at the beginning and at the end of the trial. So here's just one of many pieces of data here. You can see here the improvement. And this turned out to be highly statistically significant. So people improved their neurocognitive indices over nine months. And to summarize all the things, first of all, 76% of their patients improved their mocha scores. 84% improved their neurocognitive indices on CNS vital signs. Cognitive subtests, so verbal memory, executive function, psychomotor speed, cognitive flexibility, and others, all were statistically significantly improved in these patients. And then interestingly, for some of the drug trials, the people may make a minimal improvement, but the families can't tell. So now we also asked the partners what happened here. And the partners showed that, yes, they noticed the improvement in these people. They all underwent brain training and all improved their scores on brain training. And interestingly, their MRIs also improved. And so the gray matter volume, gray matter volume in people with Alzheimer's or MCI decreases over time. In people who are normal, it actually decreases slightly over time. With this group of people, even though they had diagnosis of MCI or early Alzheimer's, their gray matter actually increased in volume. And interestingly, their hippocampal volume, the same sort of story. Normally, there's a slight decline with people who are symptomatic. There's a rapid decline. These people had a minimal decline, but it was actually less of a decline than normal controls. So they did very, very well in all of these, by all of these different criteria, they improved. So we've published a number of papers on, initially on the anecdotes that I mentioned. As I mentioned, we also put on a Met Archive, the initial results of the trial, have a couple of books out there on this, and actually one called The First Survivors of Alzheimer's is coming out next Tuesday. Seven different patients talked about their own stories about how they were told that there was nothing that could help them and how they then went on to improve. And the most important thing is we have people now who are over nine years who have sustained their improvement. So the idea is when you actually get at what's causing the problem, people do much, much better. So the implications for the future. So cognitive decline is reversible. What we found is for most of these people, cognitive decline is reversible. Now, the likely contributors, interestingly, the few people who didn't get better, it was very striking. You could see why. And so, for example, we had one person who had a very high mycotoxin level in the home and in the urinary samples who just said, I'm not going to address that. I'm not going to deal with that. I'm not leaving the home. And so no surprise, this person did not get better. So the good news is we can seek the various things that are actually potentially causing the cognitive decline and address those. And we can understand what is missing. We can do troubleshooting to see. Now, it's important to point out, as I mentioned earlier, this is for people with mocha scores of 19 and above. What about the ones who have lower scores? These are people who have very significant Alzheimer's disease. We have anecdotes of people, even with mocha scores of zero, who improved, but they didn't come back to normal. They improved a little. They could dress themselves again. They could speak again. They could interact better, but they didn't get all the way better. So we're really interested ultimately in, can we now design a trial that will be for people, we would call this CERA. This is a severe Alzheimer's reversal attempt. We'd like to know, what does it take to make people who are farther along better? And we don't know if that can be done yet. So as I say, we've seen some anecdotes, but we need to do a trial in that. Then, of course, one of the things is the trial that we finished absolutely shows you can improve most of these people, but it doesn't show that it's feasible in everyday practice. This is a relatively complicated protocol. We're looking at a lot of different variables so that we can address them. So we're very interested to see whether we can make this easier and easier, simplify this. Perhaps we just look at the top couple of things with a computer-based algorithm, all these different things. Maybe there are just a few that we can identify and treat to get just as good outcomes. We don't know yet. So this does provide strong support for a larger randomized controlled trial, and that's what we're in the midst of planning at the moment. And then a similar approach, we're interested in, okay, there is a unique biochemistry and genetics for each of these diseases. So if we modify this for frontotemporal dementia or Lewy body disease or vascular dementia or macular degeneration, etc., can we get it just as good? Can we get just as good results? Because virtually all these diseases are either untreatable or poorly treatable. The good news is we've already seen improvement in people with Lewy body. We're in the midst now of a small trial for people who have macular degeneration. Again, it's a different chemistry, but it's the same general idea. There is a mismatch between the supply, the supply and the demand that is chronic. So the good news here is that if you combine the fact that you can make people better in the early stages with the fact that in fact most people wait too long, if we can just get people to come in earlier, really can make this disease optional. So today, if everybody comes in for prevention or early reversal, then this can be an optional disease. And let me just stay for one moment on that point. I think one of the things that's hurt our patients and that's hurt us as physicians looking and evaluating these patients is the concept that is called mild cognitive impairment, MCI. This is like telling someone they have mildly metastatic cancer. It's a late stage of the disease. So when you develop Alzheimer's, you basically have four stages. You have a pre-symptomatic stage where already PET scans are abnormal if you bother to do them and already CSF is abnormal, but you don't have symptoms. Then you have a period of SCI, subjective cognitive impairment, which lasts on average for 10 years where you're still scoring normally on your cognitive testing. You know there's something wrong. Often your spouse, your co-workers may know there's something wrong. That's subjective cognitive impairment. So we have a huge window to treat successfully. The third of four stages is called mild cognitive impairment. That should be called advanced stage Alzheimer's disease. It is a late stage of the underlying pathophysiological process. But doctors send these people home and say, that's just mild cognitive impairment. Come back next year. And in fact, we should be jumping on this earlier. And then of course, the fourth and final stage when you begin to lose activities of daily living is called Alzheimer's disease. So I think that there's much, much more that we can all be doing to prevent and reverse cognitive decline and make Alzheimer's disease a rare disease just as it should be. So let me end there. Certainly humankind has been through periods where leprosy was a big concern, was a scourge, when polio was a scourge. And most of us don't wake up in the morning worrying about leprosy or polio. But in fact, the biggest worry epidemiologically for aging Americans is loss of cognition. Alzheimer's shall become a former scourge. And I think it's up to all of us to hasten this. And of course, as we find a lot of these different pieces are pointing right back toward ancestral health. So I'll end there. I'm happy to take some questions. And let me stop the share here and turn it back over to Aaron. Again, thank you, Aaron. Apologies I couldn't be there because of the Delta variant. But it's certainly, certainly good to be getting a little bit of my normal after going through cardiac arrhythmia with this thing. It's good to be getting back to normal. It was great having you here, Dale. And so I'm really appreciate, we all really appreciate you coming to speak to us. And so you can hear me through this microphone? Absolutely. Okay, great. So we're set up for questions. Do you want to go ahead? Okay, for brain training, which do you think is better video games or erecting this on the screen or doing puzzles? Yeah, that's a great point. And you know, Mike Mersnick really started this whole field and started brain HQ, Posit Science. And I think he's made a good point, which is that for many of these games, there's no published information that suggests that they help they might, we just don't know. So they've really focused on getting information published. Some of the specific ones that they use like Hawkeye and double decision really have very good data that suggests that these help as you know, double decision really reduced even 10 years later was associated with a reduction in your likelihood of developing dementia. So that's the one we suggest only because yes, the other ones may help, but there's just not much data out there. I do worry about those people that just say, Oh, just do brain games. That doesn't, you know, we don't know they might work, they might not work. So I like brain HQ because of the published data. Say myself and my parents, possibly my grandparents are all patients of yours. So afflicted with Alzheimer's or, you know, pre cytokine drizzle. We have a preschool age children and we're worried about familial predisposition. What advice would you give the grandparents, great grandparents or parents of those preschool age children? Are there antecedents that might even be recognizable at that age and what should we be doing besides healthy eating and healthy activity and healthy sleep? This is a great point. And in fact, everybody I think should be on prevention or at the latest earliest reversal. So first thing, do you know, is this APOE4 related? Is this APP, PS1, PS2? What is the genetic cause of this predisposition? So maybe it's a combination or we don't know because not everyone is going to have access to their specific diagnosis, right? I mean, it takes a while and who's going to put the time into it. But there's cognitive decline. And we just want to generically do what's best for our preschool aged offspring. What if I'm a pediatric healthcare specialist, so I want to give this advice to parents if you have any. So yeah, again, if it really is running in the family very strongly, you certainly want to do that. And that's easy to do these days. I mean, there are all sorts of genetic tests you can start with 23 and me and just see if this is APOE related. And there's, you know, Athena diagnostics will look at APP, PS1 and PS2. If there's truly, if this is truly familiar, now, as you know, familial Alzheimer's only represents 5% of Alzheimer's. So for most people, it is just more risk just as you have cardiovascular risk. And so that's pretty straightforward. APOE4 is the common one. There are 75 million Americans who are APOE4 positive. Most of them don't know it. They have a 30% risk. If they have, if they're homozygous, they have well over 50% risk. So you're absolutely right. Everybody should be on prevention. Now, for the rare person with things like APP mutations, we recommend that they start at 25. But everybody else, 45. When you hit 45, just as when you hit 50, you want a colonoscopy. When you hit 45, or if you're older than 45, please get a cognoscopy. It's simple. It's some blood tests. It is a simple online cognitive assessment. And if you're symptomatic, you should have an MRI with volumetrics. But if you're not, don't worry about that. So what you should then tell them, yeah, don't worry about them when they're little. Yes, don't feed them a lot of sugar. Don't bring them up in moldy homes of the obvious, the ancestral. But when they get 45, they should get serious about getting on prevention, getting an initial report, just to see, do they have insulin resistance? It's all the things we talked about. It's well documented. It's in the books that I wrote. It's also in the articles we published, which are publicly available. Does that answer your question? Hi. In the slide that you showed the results of your pilot trial, it looked like the effect was plateauing around the nine month mark. And then at the 12 month mark, the variation was growing a lot. I was wondering if you could, do you agree with that? And if so, what do you make of it? It's a great point. And it's because of the pandemic. So we had people who were improving. You're absolutely right. And then the pandemic hit. So we were doing this in the middle of that. And then some of them started staying in. They weren't getting out. They weren't getting where they should. They weren't going to the gym anymore. And so we did have some more variability. And we addressed that in the paper as well. That final point was the nine month point. So it's zero, three, six and nine months. And so you're absolutely right. We lost a bit with that during the pandemic with changes. So that's the answer. Very interesting. Thanks. Yeah. Thank you so much for a great talk. I was wondering what you think about red light therapy for Alzheimer's and also what your opinion is about limiting Wi-Fi inside the home. Yeah, it's a great point. So we did find that people who had stimulation and some used violite, some have used MIRT, things like that, they do tend overall to do better. As far as what, you know, is it red light? Is it something else? That's a separate issue with red light because of macula, of course. You know, blue light, not so good for your macula. As you know, there's some nice work out of MIT from Lee-Wai Tsai and others looking at frequencies. And interestingly, people keep coming back to this 40 hertz. There seems to be something helpful about 40 hertz stimulation. And that's been interesting even with sound. And so there does seem to be something helpful there. Again, if you go back to the theory, you don't want to drive a brain when it's got tons of insults. But as you're now removing the insults and you're now improving the supply and reducing the demand, then just as you do for a weightlifter, you can now start doing more. So yes, I agree with you. I do think that stimulation, especially at appropriate frequencies, whether it be light, magnetic, sound, et cetera, does seem, you know, repeatedly, we're seeing better improvements when you include that. Cytokine storm, when typically does that precede cytokine drizzle? Like what age are you arranged that you might see that? Yeah, so all I was saying, yeah, I was just making the analogy with COVID-19. As you know, with COVID-19, you go through a period. Basically, you're not able to clear the virus. And so what happens is your cytokines just go crazy. And so you have this cytokine storm and you die from the cytokine storm. And so therefore, ironically, you're treating an infectious illness with things like dexamethasone to actually you're suppressing, even though it's not great, yes, you're going to allow the virus to survive more. On the other hand, it's life-saving. So my point is simply that by analogy, with Alzheimer's, you don't die of that cytokine storm because you don't have that massive, it's not an acute illness. However, you are dying over decades because you have a chronic inflammatory response. Your innate system is activated and stays activated for years. And in some people, you can actually see increases in IL-6 and IL-A, TNF-beta and things like that. But for many, basically what you're seeing is you're making more A-beta. It's part of the innate immune system. And interestingly, prion protein has been shown also to interact with A-beta and to be a part of this response of your body. So more and more, we see these neurodegeneration-associated proteins, alpha-synuclein, tau, prion protein, A-beta, all to have antimicrobial effects. So again, we have to change the way we think about this to say, instead of saying, oh, someone got an aggregated protein and that was the problem, no, they're responding to insults. And yes, there's this cytokine drizzle that's occurring that is killing you in the long run, but not the way cytokine storming. That's the idea. Okay. Well, let's give another round of applause to Dr. Bredesen. I want to thank you again, Dr. Bredesen, for sharing your time. I know you're busy, man. You have another meeting coming right up, but we hope to see you at Future Symposia. I hope to be there. Thanks again for the invitation, Aaron. Take care.