Preventing Cognitive Decline

Dale Bredesen, MD

So great to talk to you, Heather. Congratulations on all the great work you are doing.

Heather Sandison, ND

Thank you. Well, you have paved the way. And so I want everyone to understand that I learned from Dr. Bredesen in 2017 the Bredesen protocol. Basically what he was describing in the end of Alzheimer’s. So I went to a weekend course where I learned how to apply essentially functional medicine, naturopathy medicine to the really kind of scary and intimidating world of Alzheimer’s for me as a provider. And nearly immediately when I got back, I started seeing patients get better. This still moves me to tears when I see it. It is just so overwhelming how much we can reduce suffering and improve lives. Dr. Bredesen, I want to dive into what can we do. You always are so great about giving people takeaways. So let’s just start with that. If there were one thing that you could do or suggest that someone do, if they are concerned about their cognitive function, what would it be?

Dale Bredesen, MD

Well, the thing that I always suggest to people is a cognoscopy. So get evaluated and what is happening as we started with this kind of very broad, we can not miss anything, but we are now getting a better and better look at what is actually going on in the brain of a patient as he or she is developing Alzheimer’s. And we know that that is going on for 20 years, typically before dementia occurs. So you have got a long run up there. And so getting evaluated and now there are better and better tests. So you can look earlier and more specifically. And, you know, a lot of people have said, well, I would not want that test because I would not want to know. Sticking your head in the sand is not the way to go. We now know that pretty much, that Alzheimer’s has gotten to be and it has gotten to the point where it is really optional. There is so much you can do and the earlier you know, the easier it is and the more complete you can really prevent this. For the vast majority of us, we should never have to worry about Alzheimer’s disease. Your generation and the young people should not fear this disease because you can check it out. You can get evaluated. You know what to do. You can get on an optimal protocol and everything is great.

And these new blood tests are going to tell us early, as I said earlier, and give us so much of a better picture. And now we are adding more that can actually be done to reverse the cognitive decline. And as you well know, pretty much 100% of people with SCI, that is the second of four phases. Subjective cognitive impairment, pretty much 100% of them will get better. And I always ask the physicians I talk to, have you ever seen a person who actually went on prevention, did the appropriate things, but still develop dementia? I have not heard about a single patient yet who when on appropriate prevention, when they had no symptoms and were scoring well and still developed dementia. So we really can in those, especially in those two first times, have a tremendous impact. And I just got another on Instagram yesterday, another guy who said, I’m four four and reverse my MCI and doing really great. It is just always wonderful to hear about that.

Heather Sandison, ND

It is so much fun. It is such a privilege to work with people. So these blood tests that you are talking about, this is one of those news articles that I was referring to. There are new blood tests even just this past year that are now available to test to see if you have a propensity towards or a risk for Alzheimer’s or maybe you are even already having those pathophysiological changes in your brain that are associated with Alzheimer’s. Can you walk us through that and what they mean?

Dale Bredesen, MD

It is a great point. To be fair, people have developed these based on the pathology of Alzheimer’s. So they really did focus on things that they thought were the causes but have become very clear. These are not the causes of the disease but these are mediators of the disease, these are your body responding. So there is one that is quite early, but not very specific. It is very sensitive, but not very specific and that is GFAP Glial fibrillary acidic protein. And what that is telling you is your brain’s astrocytes have recognized that there is something wrong and that they are now responding and that is an early change. But it does not tell you it could be some head trauma, it could be some stress, it could be frontotemporal dementia, anything, basically. But at least tell you, is my brain under assault? On the other hand, one that is much more specific is Phospho-tau.  The one that is commercially available today is Phospho-tau 181 but Phospho-tau 217. That seems to be a bit more specific and also perhaps a bit more sensitive is coming out soon. So probably in June or July, you will be able to get Phospho-tau 217. And so that will tell you, what is going on in your brain could lead down the road to Alzheimer’s disease. And again, it is not the cause, but what Phospho-tau is essentially telling you is tau is like bolts if you are trying to make a structure stable, you have got all these bolts along the way and on the microtubules that are holding out your neurites you bolt them down with Tau. 

Now when you want to pop that off because your body is saying, I have got to now move my resources into protection and I’m going to have a protective downsizing event so it is really a synaptoclastic activity. What it does is its Phospho-tau which pops it off the microtubules and allows them to collapse. So it is telling you your brain has the ongoing collapse of neurites so please get on treatment, please get on something to now bring these back up again and move you back from a synaptoclastic state to a synaptoblastic state. There is also neural filament light, which is telling you it is again, something different. Each of these is complementary. That one is telling you whether there is neuronal damage. That one is not specific as well. 

It does not tell you that it is Alzheimer’s. It goes up and ALS, for example. But you can at least look to see, do I have ongoing neuronal damage. And then the last one is A-beta 40/42 ratio, and that is really telling you am I in a state where I am pro-inflammatory? Where my 42 is going down in the blood and the 40 so the ratio goes down as you have this pro-inflammatory state. So these are all different bits of information that you can glean that will tell you if you are in this process. And of course, then you can actually look at what begins to, what is actually causing it. And you are looking at things like homocysteine and you are looking at leaky gut and you are looking at all the things that we always talk about that are so crucial. Now we are able to see that your brain is actually responding to those things.

Heather Sandison, ND

Okay. So, If I understand this correctly, these are new to me too as a clinician. The way I use like a hs-CRP, which is a measure of inflammation in the system. It basically tells us something is wrong, but it is very nonspecific. Now, these are measures of more or less inflammation in the brain but they are not going to tell me why the brain is inflamed. And that is going to be a really interesting question. If those basically say, yes, something is up, something is wrong, something is out of balance, then it kind of inspires us to do more detective work to understand why is it the toxins, is it infections, is it stress, is it sleep issues, hypoxia, any of the list of things that we talk about all the time, again. But they are going to be something we can use to maybe even track change over time. Is that accurate? We can get sort of a baseline, and say yes or no. This is an issue, put our protocol to work and then tested again and make sure it is going in the right direction. Is that right?

Dale Bredesen, MD

That is exactly right. It is not just inflammation there are other insults as you mentioned that can do this so fast. Phospho-tau is a good example. It is telling you that you are pulling back on things. So if anything is causing that so now what you want to do is treat this person and you want to see this Phospho-tau go down. And what they have seen is it takes about six months to be in a state. Now, what is interesting, we are always looking for what is better. So MRI takes some time to change. We saw it. We saw definite changes within nine months in our trial. Cognitive testing can happen fairly quickly but it is relative although you can quantitate it, there is some subjectivity and people would like biomarkers as well. There is electrophysiology. You can look at changes in P300 and things like that. But most clinics are not set up to do electrophysiology. So here are some simple blood tests that will help you to optimize things. And they can say, okay, Heather, you are really going in the right direction because this Phospho-tau has just plummeted. Or they may say, you know, Heather, there are actually a few things you might have missed here or you may have not checked for yet. Maybe you have to push a little harder on this or push a little harder on that. And because it is come down a little bit, but it has not come down too much. And I should mention in the anti-amyloid antibodies, what they were showing is that as a monotherapy, they had to push massively. They had to remove 75% of the amyloid, which of course, has all sorts of side effects just to see a tiny reduction in the Phospho tau. My hope is that with the appropriate things being done, we will really be able to see a much greater reduction in town. We will see Phospho-tau should go down as we do the right things for these people.

Heather Sandison, ND

How exciting and how fun to be able to measure these things. As a clinician having these tools and our tool belt is really exciting for me. So you just mentioned some of these amyloid antibody treatments. Would you take us through those? Because I think a year ago when we were having this conversation, Aducanumab was available, but now they are doing so. Would you just help us think through like when that would be appropriate to use, if ever?

Dale Bredesen, MD

This is a great point. Here is the problem. In the 1990 so 30 years ago, it was suggested that amyloid may be the major bad actor here let’s just remove the amyloid and everyone got excited about that and let us develop things that will remove the amyloid. Initially, it was tried with active immunization, and that led to unfortunately some deaths because you were creating a tremendous amount of inflammation within the brain, just the opposite of what you wanted to do. And so people said, “Well, let us then make antibodies and do this passively. We will administer the antibodies”. Now virtually all of them have failed. So Bapineuzumab, no one improved. There was no improvement overall in people with Bapineuzumab. Solanezumab has huge studies, no improvement there. Crenezumab, Gantenerumab all of these things unfortunately have failed. 

Then as you mentioned a year ago came Aducanumab. Now it failed in some studies but in one study at one dose, there was a 22% slowing. And so in a bizarre FDA decision because all of their consultants had recommended against it, they said, since we know that you are removing amyloid, that is probably going to be good for you. So even though it does not seem to help cognition, we will assume that it might one day and will give it accelerated approval. It was really backward thinking. And now some more sage wisdom came in and groups from the EU and of course Medicare and the Cleveland Clinic and on said, we are not going to use this, we are not going to pay for it unless it is part of a clinical trial. I think that it put a halt to wide-scale use, large-scale use of aducanumab. And then you have, as you mentioned Lecanemab came along and of course, Donanemab is following quickly on its heels. Donanemab, being the one from Lilly. Lecanemab did slow the decline, did not make people better, did not stabilize them, but it slowed the decline by 27%. And of course, it was hailed by groups who were being paid. It was hailed as a major breakthrough. 

So my argument is, look, if Elon Musk told us that SpaceX, everybody in those rockets was exploding and dying every time. But in a major breakthrough, they die 27% later. We probably would not hail that as a major breakthrough from Elon, but that is what the argument has been. So they are still pushing for coverage with Medicare. They are pushing for full FDA approval. Again, it is just accelerated approval that is happened so far. There is a lot of lobbying, there is a lot of politics going on. So one of the things I’m interested in is based on what they published, which is 27% slowing in people who had MCI. So these were actually not even in people with dementia. It was MCI and early-stage dementia. What has actually published better results than that extra virgin olive oil alone has published better results than Lecanemab. To be fair, the study was not big, you know, it was not as large. But the fact that something like that can do better than it tells you the right thing combined with metabolic activators and these are just four different things that have basically improved energetics. And then I should have mentioned along those lines what came out of our lab. 

We could ultimately boil down to two things A D equals I A over E, in other words, Alzheimer’s disease equals immune activation over energetics. So what we want to do is determine why your innate system is active and I should say Dr. Alexei Kurakin, with whom I’ve collaborated for years, pointed out this is really mostly about innate memory. So you store your memory in these three locations, you store that in your bone marrow, you store it in your endothelial cells and you store it in your tissue Macrophages, which of course are your microglia. So energetics, that is half the equation but you also want to bring down the innate immune activation. The next thing that is done better than the Lecanemab is ketones and of course Professor Stephen Cunnane and very nice results in patients with MCI on ketones. Then, of course, the other thing has been the ReCode protocol, which has done very well. We have a published trial on that and I’m very excited about the trial that you have submitted that is undergoing review currently for your revisions, very excited to see that published and also hopefully, to come out in the upcoming book. 

I think that all of these things have led to very clearly improved results over these antibodies. And it is not surprising these antibodies are removed. It is essentially like removing one cytokine, a long-acting cytokine. You are not getting at what is causing the problem. And also, you are creating some negative effects because you are now tearing these things out there. The amyloid is sitting in the blood vessels and is also sitting in the extracellular spaces and is also intracellular. So you are ripping this stuff. It is a little bit like taking a patch off a tire and you are now, no surprise you get leakage, you get bleeding into the brain, which has been documented repeatedly. Now, where I think these would be great, but no one has proposed using them this way yet. Do the other things first, remove the insults, get the energetics up, get the inflammation down, improve people overall, and then use very low doses to gently remove the amyloid that is left. Because to be fair, it is a long half-lived molecule so you want to remove it slowly. The good news is there is a dynamic relationship between the soluble and the plaque-associated amyloid. So as long as you are removing it slowly over time, you could do a great job. But in contrast, this idea of doing nothing else and just ripping out all this stuff that has been laid down because you were under assault without changing any of the insults it is really barbaric. And it is just it does not fit the biology of the disease.

Heather Sandison, ND

It is kind of crazy. We would expect great results from that. So I want to restate it slightly differently and just to drive home this message for everyone, those medications, although they have been approved by the FDA and this kind of weird, funky way. They do not reverse the disease process. What they do is slow the very painful decline. So from my perspective, this is almost cruel. You are asking families and people to go through this torturous process longer, to experience the decline more slowly, and yes, I can understand that there is some benefit in having someone be a little better for a little bit longer. And yet there are alternatives that are available and published. There is published literature supporting them. And one of those is the ReCode protocol, a Dr. Bredesen protocol. 

And it shows not only does it slow decline, that is not what we are after, but what we want is an improved quality of life, improved cognition, ability to perform activities of daily living, and the maintenance of our dignity. That is what we really want. And what we see with the Bredesen protocol is that we get improvements in cognition. We would consider it a miracle if we could just maintain cognition, not slow the process, but maintain cognition, and stop the process. What we see is an even bigger miracle is that most of the time people in the same category, MCI or early Alzheimer’s, have improvements in their cognition. And so this is really exciting stuff. And it is available to you right now. You do not have to wait for a drug or approval from the FDA. You can get started today.

Dale Bredesen, MD

Exactly. And you know, I should mention one of the most important things is that the improvement is sustained. When you go after the right things, then you actually are turning off the problem. Now, let’s compare that to the drugs. There are two major classes of drugs. It is the antibodies that are removing the amyloid, and then it is the chemical approach, which is Aricept and Namenda. So Aricept and Namenda, when they looked five years after starting it, were actually doing worse than the control group. So it is a short-term solution, not a long-term solution. The antibodies, and Heather, I’m sure you saw this paper that just recently came out when they looked at brain atrophy. The atrophy was worse in people who had been on the antibodies. So unfortunately, the damage from kind of going about this the wrong way and ignoring biology is that we have the long-term effects not being so great. And again, I think that the future is definitely going to be combining these protocols and optimizing these personalized precision medicine protocols. And then you use a targeted drug here and there. You want to remove a little bit of amyloid, fine. You want to improve cholinergic transmission, fine. You want to go after a Phaspho-tau. And as a simple example, lithium is a very good way to inhibit GSK three beta, which is the major kinase. One of several P38 is another one and GSK five and things like this. But the major one that is phosphorylated tau in Alzheimer’s is GSK three beta and you can inhibit that with lithium, for example.

Heather Sandison, ND

I’m curious about the dosing rate because some people think of lithium for bipolar disorder rate, it is 100 milligrams, three grams. But I remember when I was in training actually Jonathan Wright and Alan Gabe had published some research around or they had maybe synthesized research using just like five milligrams or even 99 milligrams is another dose that you see regularly used for memory and sleep and even antiviral support. So is that more the dosing that we get brain benefits with that?

Dale Bredesen, MD

And a lot of people will use 10 to 20 milligrams of lithium orotate, which is kind of typical and I would you know, I recommend talking to Dr. Katz who is like a functional psychiatrist and part of both of our trials. She argues that you can go up to higher doses without any problem. So you want to be careful. You do not want to be going up above 300 milligrams and you want to be careful about renal function, of course. But I think it is unlikely you are going to have any trouble with 50 or 100, that sort of thing.

Heather Sandison, ND

Using it as a supplement because lithium it is a mineral can be very safe and very effective as well.

Dale Bredesen, MD

Exactly. So what is happening is we are getting a larger armamentarium. Another good example is hemotorium which it was actually tried as a monotherapy years ago and it failed. But then they noticed a small group of people who were HLA-B44, and that just represents 10% of Alzheimer’s patients and only two percent of the population there actually did seem to be some benefit. Now, what that does is interesting. Instead of trying to rip out the amyloid and adding antibodies where you now have to worry about all the things that are happening with antibodies in your brain, this is now preventing the oligomerization of the beta. So you have the less damaging monomers, but you do not have the more damaging oligomers, which is a nice idea. Now they are actually in trials with a related drug, which is a precursor for homo taurine. But I think it is an interesting one and this is again available over the counter and people are to be aware that typically in their trials they were using 300 milligrams a day in divided doses, either twice a day or three times a day. And, you know, again, this is not such a bad idea. You are as you are removing these things and you are trying to help yourself by also tweaking some of the mediators, especially in people who have large amyloid burdens or who have reasons to be all of them are rising. Their amyloid, which is basically things related to inflammation. So again, the armamentarium is huge. And knowing how to use it, when to use it, and what is in there is where I think people like you are getting such great results.

Heather Sandison, ND

You have this analogy of thinking of your brain like a country. I use this every single day. I repeat it is that if your brain is and you say My brain is done right, if you think of your country and your brain is in the fight and defend mode. Yes, these amyloid plaques and this tau, these misfolded proteins they are essentially part of that defense. They are part of that attack and defend mode. They are telling us that there is something there to attack and defend and if we rip them out, we have kind of gotten rid of part of our attack and defense. And it is too early for us to be switching towards a regeneration rate. If we are fighting a war, we do not need to be building schools and roads or synapses and new neurons, but what we want to really be doing is resolving those things that led us to war. And so that is what I hear you describe it as. There are lots of things we can measure that will tell us if we are or not. And then let’s allow that to trigger this move in the direction of identifying and treating those really causal level pieces of which this entire summit is about that. So if you have any questions about that, they will all be answered this week.

Dale Bredesen, MD

Yeah, the point now.

Heather Sandison, ND

Switching to that regenerative mode, but let’s lay down those tracks. Let’s build something new. But we do not usually have the resources to do both at the same time. And although we want to be of course supporting nutrients and there is some nuance to this and it is really important to work with the states and train providers. There is so much we can do from a lifestyle perspective. And certainly, my work has been about making this as pragmatic and practical, and easy to implement as possible.

Dale Bredesen, MD

Yeah, and you have done a fantastic job with that. So yes, if you are in my brain and the World Trade Center is going down and you are saying, what the heck is going on? Then, as you indicated, you have got to start by asking where this is coming from. And it just kills me that in clinics today, people are not asking that enough. If you go to a neurology clinic and you say, yeah, I’m having trouble with my memory, and they say to you, Oh, well, you have Alzheimer’s disease. Well, yeah. What caused it? Well, no one knows what causes it. Well, actually, we have a lot of information on what causes it. And it is literally a network insufficiency. So what happens? You get that IA over, you get the innate activation and you get the energetic reduction, and that then is putting you into a mode in which your network is insufficient. So you are literally downsizing this. And you are now using your resources not to build and maintain synapses, but rather to fight the various inflammatory ends and pathogens and toxins and things like that so that you are now redistributing your resources. And unfortunately, you are living with a smaller brain. I think one of the things that, again, that is just come out recently was some wonderful work from the University of Colorado and from Rick Johnson, showing that when you are essentially triggering fructose metabolism, either because your glucose is very high or because you have got a lot of high fructose corn syrup, and it is typically not so much just from eating fruit because there is plenty of fiber in fruit and things like that. But because of inflammation, stress, it is one of these stress responses that go along with high uric acid things, all these sorts of things. 

Then one of the things that does is reduce your ATP. So you literally are going into a lower energetic state. Physiologically it is because you think winter’s coming. So you are like, Okay, I’m going to now go into my cave and I’m going to have a few months here and I’m going to conserve resources. That is not a good thing. When you are trying to keep your brain functional, it is pulling you back. Your ATP levels are actually declining so all of these things lead to this protective pullback that now decreases your synaptic count. And you can look and you can tell you a lot about why people get this when they get it. You have to lose a certain number of synapses. So no matter how bad things are when you are younger. The second thing to know is you can lose synapses anatomically or chemically. When you are losing them chemically, you can bring them back more quickly. When you are losing them anatomically, it is more difficult. So you kind of have to keep count on both methods, are you losing more anatomically or chemically when you hit that threshold then you start having symptoms. So we want to get there before the threshold, which is where these new tests are going to be very helpful. And as you indicated, we remove the problems, we optimize what is there, and then we get into a regenerative mode. And that is where things like intranasal trophic factors and stem cells and hormone optimization, all these things are so helpful. We should be able to do better as we apply these things appropriately to people. And there are more things in the armamentarium that are so helpful.

Heather Sandison, ND

As you well know, in 2017. And then again in 2020, The Lancet published a kind of comprehensive report on Alzheimer’s and dementia. And they list the factors that are basically that we can manage, that we can do something about. So there are risk factors like age and gender that we can not do anything about. The whole list of now 1517 modifiable risk factors that we can change. And they suggest that 40% of dementia could be prevented or even completely do not have to happen at all. Right. And this is from The Lancet, which is a highly reputable journal in the U.K. Now, why is it that knowing that if that literature is out there, that it is in a highly respected journal, why do people still go into a neurologist? And are they still told there is not much we can do to prevent or reverse this disease?

Dale Bredesen, MD

One of the points I made in the paper we just submitted was that we must retire. The phrase, the assertion that has been used year in, year out which is that there is nothing that will prevent, reverse or delay Alzheimer’s disease. It is just been proven incorrect by the finger study, by our clinical trial, by your clinical trial, and by others. So it is kind of at this point, it is kind of silly to say that. And yet you hear it all the time.

Heather Sandison, ND

You state it is heartbreaking because people are suffering. That is people that is the refrain. And people are still hearing it, even though it is so outdated. Now.

Dale Bredesen, MD

I agree with you, this is a real problem. And then the other one that always kills me is they say we do not know what causes this disease. We know a lot about what causes the disease. Now, you mentioned The Lancet, and I think that is great. You know, what they tell you is do not smoke. You know, get your blood pressure taken care of, some basics. This idea that you could prevent 40%, I think is a huge underestimate. We should be able to prevent the vast majority. You know, as I mentioned, when you and I were talking earlier, I have talked to so many doctors to say, have you seen anyone who’s gone out, has gone on active prevention, done the right things, been compliant, and yet still developed dementia? I’ve never heard about a single case, so, in fact, we are quite good at preventing dementia and reversing it, especially in the SCI phase and especially in the MCI phase, 84% people of people improved in our trial, and even in some cases, as you have indicated from Marama, people with very low MoCA scores who have end-stage dementia and are still improving. Now they are not improving all the way back to normal. That is the sign. That is our goal as scientists, we need to understand what will take someone from a MoCa of zero to a MoCA of 30. And along those lines, we are also now extending what we are doing to other degenerative diseases. I think that we should have a place where people from all over the world can come and have treatment, especially early on, in any neurodegenerative condition.

Heather Sandison, ND

I wanted to share a little bit more about the research because you and I are both very involved in that. So we have talked about some of these other trials that have been going on. And then you referred to this 84% number. So would you just describe the clinical trial design of that and the follow-up to that?

Dale Bredesen, MD

This was a trial that we published, just last year, 2022, and in that, it was a proof of concept trial with historical controls. We took 25 people who all had to meet the criteria for mild cognitive impairment, MCI, which is really the third of four phases, or early dementia, which is the fourth of the four major phases. And these people had MOCA scores of 19 or above. They had to have abnormal CNS, vital signs, and scores, and they had to have complaints. So they are a huge 21, which is where their partners will say, are there problems? They had to score over five and anything over four is considered MCI and over 14 is considered dementia typically or correlates with dementia. So they all had to have over five to get into the study. Then they were treated for nine months with a precision medicine protocol. So we looked very extensively at their genetics, looked at whether they had no hyper coaxial ability, and actually worked with Intelex DNA. And Sharon Houseman Cohen, who did a great job at looking at the genetics of these people. Then we also looked at their biochemistry and looked at what they were doing. We then also looked at their MRI with volume metrics to see whether they had atrophy. And then over time, we would also look back at their MOCA scores and their CNS vital science scores. They were treated with the protocol we developed. So we looked, we subtype them, and then we looked at what are their inflammatory things going on. If so, what is it? We addressed the inflammation, we addressed the glycol toxicity. We addressed the low hormones and the energetic failure. 

We addressed the vascular changes, we addressed the toxicity, and we addressed any sort of thing that we could do in terms of preventing trauma or healing previous trauma with things like BDNF and that. And they were treated that way. So this was different for each person. We had an appropriate diet, exercise, sleep, stress, and brain training. The usual basic seven things. And they did very, very well. 84% of them improved their scores on CNS vital signs 76% improved their MOCA scores. And then interestingly, their MRIs also improved their gray matter, which declines a little over 2% per year in people with MCI and Alzheimer’s actually went up instead of down. And their hippocampal volume, which did shrink slightly, shrank less than normal aging and far less than someone with MCI or Alzheimer’s. So with all these different parameters, they did better. And by the way, they also did better with their insulin resistance. They did better with their vitamin D, they did better with their homocysteine, and they did better with their hs-CRP. So all of these things improved in accord with their cognitive improvement.

Heather Sandison, ND

And so exciting. And so this was over nine months. And independently I was running a very similar trial. We looked at slightly different things but had 23 participants. Although our participants were a little more advanced in their cognitive decline. So we took participants with MOCA scores of 12 to 23, and instead of seeing their vital signs, we looked at Cambridge Brain Sciences, which is another battery of tests that test cognition a little more, more specifically and with basically a more scientific way than our clinical MOCA score. And we did this over six months, so it was a little bit more compressed, it was a little quicker. And we got almost identical results to what you guys got. We saw that 74.9% of the time or maybe it was 73.9% of the time we had our participants improving their MOCA scores, and the Cambridge Brain Sciences had the same participants improving their cognition in that way of looking at it as well. And so very similar study design and very similar results. Other years were published a year ago and July of 2022 in the Journal of Alzheimer’s Disease right now, minus in peer review and hope. We are hoping for publication this summer. These are things that are advancing the research so that more and more people can have faith that this is something that will work for them. Now, one of the criticisms that is totally normal and make plenty of sense is that these are not controlled trials. And so that is what is next, that is on the horizon. And you are currently recruiting for a follow-up trial. So both of our trials were feasibility trials, right? And we were just looking to see, you know, this is a complex approach. This is a very complex protocol. It is a lot to ask someone with cognitive decline. So we wanted to know, is it feasible? Can we do this? And sure enough, not only did we show that we can do it, we showed that we get really phenomenal outcomes, miraculous outcomes. 

And so now the next step to do is to have these controlled trials. And I want to just make sure everyone understands that when you hear that there is not enough research around this. That is true. It is true. We get it. Yes. And we are working as fast as we can to get the research out there. I have personally had funding for a trial since 2019, maybe the end of 2018. And here we are starting in May of 2023 and it has not been published yet. And part of this is COVID but part of it is just the snail’s pace of research. And Dr. Reticent, if you would, maybe share about your follow-up trial, the controlled trial, and then also share a little bit about why it was so hard and inserted this paradigm of research that we exist in, that it was so hard to do a multifactorial intervention. And even though you had funding, you were not able to start those trials immediately.

Dale Bredesen, MD

It is such a good point. When you are changing the standard of care, it is very difficult, as they say. You know, and this goes back to Machiavelli, who said the hardest thing to change is the status quo because the people who are doing well with the status quo are not going to budge. And the people who would do better with the new are kind of waiting to see what happens. So it is going to be tough to change it. And as you indicated, we tried to do this trial back in 2011 and were turned down in 2011 because it is not your typical trial. They wanted something with a single variable. And I think we all understand it is easier to do the math. It is a simpler and more obvious approach when you change a single variable. But the problem is to say, we are going to do this in a more scientific way but with poorer outcomes, that is a horrible tradeoff. We want to start with what are the best outcomes and then and then form the trial around that. The research is showing laboratory research is showing this is a multiple-contributor disease. This is not a simple disease like pneumococcal pneumonia, where you can just target one pathogen and everything’s great. You are now targeting a network, a system. And so to do that, you have got to tweak it at multiple points. It is a different way to do medicine. And I hope that five or ten years from now it will be the norm. But it takes a while to convince people.

Heather Sandison, ND

I think there is a moral imperative that every neurologist is aware of this and has some basic understanding of how to deliver this to patients or refer them to somebody who does get it. Yeah.

Dale Bredesen, MD

These are not.

Heather Sandison, ND

Suffering tissue. Tell us about your new trial. And I’m sure there are people who are listening who are interested in understanding if they could potentially be involved.

Dale Bredesen, MD

Thanks so much for mentioning that. And so, yes, the next step now is a randomized controlled trial and this will be the control group. You have to be fair to them. They are still looking for something. So what we do is we simply delay their treatment for nine months so everybody will get the treatment. And if you are delaying, you are just doing it. You are doing standard care. You are still going to get what is the standard of care for nine months, and then you are going to go on the protocol, if you want, at the end of that. And this is going to be done with Dr. Craig Tannehill, who is down in Hollywood, Florida, and Dr. Nate Bergman up in Cleveland. Dr. David Horsey, who’s in Nashville, Dr. Christine Burke, who is in Sacramento or actually Folsom just outside of Sacramento with Dr. Anne Hathaway here in Marin in San Rafael, and then Dr. Kattouf, who’s out in the East Bay.

Heather Sandison, ND

What an all-star team. I just love it.

Dale Bredesen, MD

Fantastic. And all six of these people have seen this with their own eyes, who have produced that have had tremendous, tremendous results over time. I never tired of hearing of great results from physicians who are doing this well, as all six of these are. And so I’m really honored to work with them. We are also honored to have Diana Merriam and the Four Winds Foundation which had fund that funded the first trial. And they are actually now funding this second trial again. So we are very excited about that. And the great thing is there are a lot of new tests, as we talked about. Now we will be able to look at epigenetics for brain aging, for biological age. We will be able to look at some cases we will have some electrophysiology as well. Not all of the sites, but some of the sites will be able to look at FOS. FLATOW. We will be able to look at GFP. We will be able to get a great look at whether what we are doing is driving this in the right way. And because we can look at it along the way, we can actually make some tweaks to see if, okay, it is coming down part, but it has not come down as much as we’d like. Let’s now make changes or let’s look at what we might have been missing, or we could optimize and see if we can get even better results in nine months. So we are very excited about that.

Heather Sandison, ND

That is so exciting. So I’m just waiting for my paper to be published and then we are going to go on our follow-up trial on our randomized controlled trial. And I will be picking your brain and Kat’s brain and anybody who will talk to me about how to design that based on what you guys are learning. It is time to move all of this forward and make sure that we are answering those questions about getting enough research out there that shows that this really is something that will benefit so many families who are faced with the potential of going down the scary, dark path of Alzheimer’s.

Dale Bredesen, MD

If there is one thing that we could change, it would be to move people earlier. I just today got the data that if you look at the peak of when people are going on the prevention that we develop versus when they are going on the reversal we developed, the peak for the prevention is in the sixties and the peak for the reversal is in the seventies. If we could move those two decades earlier and even if we could move them one decade earlier, but ultimately I’d like to see them in their forties and fifties. There would be very little dementia. You really could make a huge impact.

Heather Sandison, ND

So if you are the child of someone, but.

Dale Bredesen, MD

Get everybody in the family evaluated and get on active prevention. That is the best thing you can do for your family. In the future, everyone’s 40th birthday should include a presentation on the prevention of cognitive decline, and as you have indicated before, it also improves the cognition you have. There is just so much more that can be done and it is just a matter of changing the Zeitgeist. Everyone’s so used to hearing, There is nothing you can do, so just wait. And we hear about this all the time. I hear about celebrities who have waited until it is very late. We need to get people to come in earlier, recognizing there is so much that can be done.

Heather Sandison, ND

This is not just about Alzheimer’s for you. You are a neurologist and you are. Some people may be obsessed with the pathophysiology and the science of how this is all happening. And what you found with your research is that this does not just apply to Alzheimer’s, that there is actually a more general application for these concepts in these interventions. Can you talk about some of the other diagnoses that have demonstrated benefit?

Dale Bredesen, MD

That is such a good point. So what I’m doing right now is actually writing a paper on the Unified Theory of Neurodegeneration so that what our research suggests is very different from what has been in the literature over the years. The literature over the years has said it is about reactive oxygen species, it is about metal toxicity, it is about misfolded proteins, it is about aggregated proteins, it is about prions, again, yes there are prions there is no question about that. That tremendous work shows that these things do have this prion-like effect, but they do not seem necessarily to be causative. This is, again, a response to these various insults. It is one of the mediators. So all these different ideas, what our research suggested is that all of these are network insufficiencies. So you have a supply and you have a demand for every network. So you have a network that serves motor control. That is what goes awry in Parkinson’s. You have a network that is neuro plastic, which is what goes awry in Alzheimer’s, you have a network that supports your macula, which is in macular degeneration, which is not supported enough. So what we can see is that in all these diseases, the supply is too low and the demand is too high in a chronic or repeated way. And it can be because of pathogens or toxins or what have you.  The cool thing is each of these has its own network with its own Achilles heel. We know that in Parkinson’s, for example, the Achilles heel is a complex one of the mitochondria. Anything you do to inhibit that, whether it is Paraquat, whether it is MPTP, whether it is TCE, Trichloroethylene, which unfortunately people are getting exposed to all the time and they do not realize it until they get Parkinson’s. It is horrible. If any of these things, you are going to change that network support. You are going to start dropping in. Of course, your supply is dropping because of all sorts of different things in macular degeneration. The biggest one is actually smoking. And in Alzheimer’s, you could argue that the biggest one really is insulin resistance and metabolic abnormalities that are so common in our country. But of course, there is a huge role for things like Mycotoxins as well, because.

Heather Sandison, ND

Sleep apnea.

Dale Bredesen, MD

Proinflammatory and sleep apnea and so on. The good news is with each one of these now, we can start listing all the things that can contribute. We can check them, we can now change this. And we have seen improvements for example, in people with Lewy Body Disease, which is really exciting to see. We have seen improvements in people with vascular dementia and we have seen some improvement, some initial improvements in people with dry macular degeneration and again with dry macular degeneration. If anything, that is a simpler disease than Alzheimer’s disease. There are 11 million people with macular degeneration more than Alzheimer’s in the United States. And the current approach is essentially to wait for it to become wet, which is where you are now actively bleeding into your eye, and then give injections into the eye. This is barbaric. And what do you do with these injections? t goes just the opposite of physiology.

What is it doing? It is preventing you from allowing your blood vessels to grow with your macula, crying out for support. And this is saying, no, we are not going to let you do that. So what do you do? It increases your risk for geographic atrophy, which is an end-stage form of dry macular degeneration. Let’s get in at the beginning, the optometrists and ophthalmologists are seeing this all the time in these early dry stages and typically use an approach called A Reds Two, which does not actually decrease your long-term risk so unfortunately, it really does not work very well at all. What we want to do is actually improve where your stand and we want to prevent you from ever getting too wet. Macular degeneration is just done by doing appropriate physiological things, getting the oxygenation, getting the supply, getting the blood flow, reducing the toxin load, and improving the inflammation. All these things are critical. So there is overlap as you, but each one has its own sub-network that has its own Achilles heel.

Heather Sandison, ND

This is such a hopeful message and so exciting for those who are suffering or know someone who has suffered. You have in your work with Apollo made this thing accessible and now there is a new partnership with Nutrition for Longevity where there are even meal delivery services. I want to make sure that our audience understands what support is out there because as you know, we have been talking about this can feel overwhelming for people. It is a lot to do and it does require work and some resources and yet it is so worth it. And there are tools out there to help you to implement this at home. So would you share a little bit about Apollo?

Dale Bredesen, MD

Yeah. So glad you brought that up. So Apollo is a software company that has basically created a community so that we can begin to get people to, first of all, understand what is driving the problem and then ultimately to do the right things about it and the idea here was that as physicians. There is only so much we can do. We can not look at a piece of paper and say, here is your 3.33 billion base pair genome, and here are the changes. So you need computers to read these things. You need to have them. And ultimately, there is a lot that people do today. But for the future, you will want that little helper, which is software that says, okay, do not forget, these things are those things, and here are things. Here are the things that can be helpful. And as you mentioned, probably the most important recent change is through nutrition for longevity. And I’m really thrilled because people have said to me over the years, look, starting with diet is the thing to start with. Everyone should get on a plant-rich, mildly ketogenic diet. 

But you are telling me I got to go to the store? I got to think about this. I got to go home and cook things. I got to think about it. Everyone said, Look, can not you just send me some meals? So finally, the answer is yes. And they are actually relatively inexpensive. I really like what they have done for them. I sampled them several months ago and I was actually shocked at how good they were, so I was really impressed. Nutrition for longevity really did a fantastic job and we are grateful to them. These now can be shipped anywhere in the US and soon, hopefully outside the US, but certainly at the moment anywhere in the U.S. you can get these very easily. And for the future, the goal is that these would ultimately be covered by Medicare because they will be part of what is improving cognition. But they are not terribly expensive. You are going to be paying for something somewhere to eat anyway. So they have done a really great job with this. And this is a plant-rich, mildly ketogenic diet. When I did it myself, I checked in. Yes, my ketones went up on these things. So I really appreciated it and they are delicious. They have got all sorts of things and there is a pescatarian one that you can choose or in other ones, you can choose as well. So this was on. I should mention that Julie G and my wife, I eat a lashing by this doctor. Dr. Aida Lasheen did a great job with putting these together and working with nutrition for longevity.

Heather Sandison, ND

I know there are going to be people listening to it a little happy dance at home right now that there is finally an option that is read. It is approved and working through Apollo and this is just going to make it so much easier to get those outcomes that people got in the trial. And there was another trial. We have just a couple of minutes left, but I just want to mention Rob Rouse. He was a great author on a trial that showed this was it. 55% of people who were enrolled in Apollo had improved cognition. And I bet that that number is going to jump a ton when there is access to this meal delivery.

Dale Bredesen, MD

You know, I’m glad you mentioned that, because this is very complimentary. So the idea was, instead of these trials where we are controlling certain things, we are bringing people in and we are saying we are working with them one by one. The complimentary piece that you really want to know is what is going on out in the community. If you have trained physicians who are seeing people and treating them, but they are doing their own thing, sometimes they may be changing things. They may not have the same follow-up. It is not really a trial. It is a pragmatic, essential observation of what is going on. Right around 50%, just a little over half the people. It wasn’t as good an outcome as it was in the trial, and yet it was far better than any of the drug approaches. So we are continuing to optimize this. We are continuing to get better ways. And you have done a great job with simplifying, helping to simplify things. We want to make this as simple as feasible as possible for everyone, to avoid cognitive decline and reverse cognitive decline.

Heather Sandison, ND

Dr. Bredesen, I could not be more grateful to you for your mentorship, for your kindness, for your support, and for your time, especially today, sharing with our audience. Thank you.

Dale Bredesen, MD

Thank you so much, Heather. Here is to great outcomes for all of us.

Heather Sandison, ND

Cheers.