Reversing Alzheimer’s Disease with Dr. Dale Bredesen: Rational Wellness Podcast 320

Dr. Dale Bredesen discusses Reversing Alzheimer’s Disease at the Functional Medicine Discussion Group meeting on July 27, 2023 with moderator Dr. Ben Weitz.

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Podcast Highlights

5:35  Alzheimer’s disease is now optional, because Dr. Bredesen’s precision medicine approach can help to prevent and reverse Alzheimer’s and it is hoped that this approach can be extended to all of the major neurodegenerative diseases.  Dr. Bredesen and his group have published over 220 peer-reviewed papers on the underlying mechanisms of neurodegeneration.  On the conventional treatment front, so many amyloid antibody drugs have failed including bapineuzumab, solanezumab, gantenerumab, and crenezumab.  The newest drugs include aducanumab, which has a minimal effect, and lecanemab (aka, Leqembi), which does have a measurable effect.  But these new drugs do not make anyone better, but instead they lead to a slowing of the progression and they often have some negative side effects like brain bleeding and brain swelling and several patients have died. 

7:40  Homotaurine. This is currently a nutritional supplement that is currently in clinical trials. It prevents the oligomerization of A-beta, so it looks like it may be a very interesting adjunct to other parts of the Bredesen protocol.  The dosage used was either 100 mg three times per day or 150 mg twice per day. [Manzano S, Agüera L, Aguilar M, Olazarán J. A Review on Tramiprosate (Homotaurine) in Alzheimer’s Disease and Other Neurocognitive Disorders. Front Neurol. 2020 Jul 7;11:614.]   Combined metabolic activators (CMA) shows benefit in improving cognition in patients with Alzheimer’s disease. CMA dosage includes:  12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. [Yulug B, Altay O, Li X, et al. Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Transl Neurodegener. 2023 Jan 26;12(1):4. ]

8:39  Dr. Bredesen is starting a randomized controlled trial of his ReCode system with six absolutely fantastic clinicians: Craig Tanio down in Hollywood, Florida, Nate Bergman in Cleveland, David Haase in Nashville, Kristine Burke in Sacramento, Kat Toups in the East Bay, and Ann Hathaway in Marin County. 

9:25  KetoFlex.  Dr. Bredesen’s recommended dietary approach for Alzheimer’s disease, the KetoFlex and he worked with Nutrition for Longevity, a group founded by Dr. Valter Longo, to develop KetoFlex meals for home delivery, which is now available.

11:30  New lab tests for help with analyzing Alzheimer’s disease1. p-tau 181, 2. p-tau 217 is coming soon, 3. Abeta 42:40, 4. Neurofilament light, and 5. GFAP (glial fibrillary acidic protein), which will be available soon. P-tau 181 lets you know that you have the specific signaling characteristic of Alzheimer’s. The Abeta 42:40 test lets you know whether you are making Amyloid beta protein, which is typically associated with inflammation and with Alzheimer’s. Neurofilament light is not specific for Alzheimer’s, but it tells you that you do have neuronal damage.  This also goes up in frontotemporal dementia and ALS and certain other neurodegenerative conditions.  GFAP lets you know that you have reactive astrocytes in the brain, which can precede Alzheimer’s disease. 

16:00  When you compare the state of the treatments for Alzheimer’s disease, with no treatment the patient’s MOCA score will decline by about three and a half points and if you take the Lecanemab, which is the newest drug given FDA approval that costs about $40,000 per year, of which the person on average will end up paying $10,000 per year after Medicare, and it will slow the decline by 27% in men or 12% in women. Only Dr. Bredesen’s ReCode precision medicine approach will result in a gain of about 4/30 points in cognition.  


18:27  The standard of care for patients with cognitive impairment is inadequate.  If you go to a memory center of excellence, they will likely tell you that they are only going to treat you if it gets pretty significant.  There’s no attempt to identify the cause of the problem and they adhere to this outdated claim that nothing can prevent or reverse Alzheimer’s.  If you’ve got someone in a nursing home with Alzheimer’s, they don’t tell all the children that they should be on active prevention. The average patient spends an average of $350,000 before they die, with most of that on nursing homes.  The only treatment offered is mono pharmaceuticals.  Such a treatment approach is out of date.  Telling a patient that they only have mild cognitive impairment is analogous to telling them that they only have mildly metastatic cancer.  Unfortunately, once a patient has mild cognitive impairment, it is a relatively late stage of the underlying pathophysiology. 

There are four stages of Alzheimer’s:

1. Asymptomatic.  Stage one is when you are asymptomatic but you can see abnormalities on spinal fluid, PET scans, and on those blood tests that were mentioned, like p-tau 181. 

2.  Subjective Cognitive Impairment.  If you don’t do anything about it and continue to go downhill, you start to develop subjective cognitive impairment (SCI), which is stage two, when you have some changes in cognitive function, though you may still score in the normal range on a cognitive questionaire. 

3. Mild Cognitive Impairment. Stage three is mild cognitive impairment (MCI) and now your cognitive testing is abnormal, though you can still perform you activities of daily living.  Even though this is called mild, it is actually a relatively late stage of the disease.

4. Alzheimer’s disease. Each year 5-10% of those with MCI go on to stage four, or Alzheimer’s, which is the stage of dementia.  The diagnosis of Alzheimer’s is typically made 20 years after the initial biochemical changes occur. 


21:35  When you look at scans of the brains of patients with Alzheimer’s, you can see significant differences. The brain shrinks and the sulci widen and you can see differences in the ventricles.  The first area of the brain that shows damage in Alzheimer’s patients is the locus coeruleus in the brain stem, which literally means the blue spot.  Damage to this area results in people losing their way, losing their verve, losing their interaction. 

22:39  Amyloid protein and phosphorylated tau.  If you look at the brain under a microscope you can see collections of amyloid protein and you can see neurofibrillary tangles from phosphorylated tau.  There is inflammation in the brain, so you can see reactive microglia and reactive astroglia.  This is part of the model to explain Alzheimer’s, but none of this led to any approach that resulted in effective treatment.  When you simply remove the amyloid, you don’t get much of an effect in clinical trials.

23:25  There are actually a large number of risk factors for Alzheimer’s, including low vitamin D, type II diabetes, metabolic syndrome, menopause, chronic infections like herpes, and genetic risk factors like ApoE4.

25:20  Prionic nature of amyloid and tau.  Dr. Stanley Prusiner won the Nobel Prize in 1997 for his discovery of prions and Dr. Bredesen trained with him as a post-doc.  When amyloid and tau proteins get into the brain, they tend to accumulate and beget more of themselves much like prionic proteins. 

27:30  When you have infections, inflammation, and toxin exposures in your brain, your brain goes into a downsizing, protective mode and amyloid protein proliferates as a protective antimicrobial peptide, as Professors Robert Moir and Rudy Tanzi from Harvard published several years ago: Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement. 2018 Dec;14(12):1602-1614.   

29:57  Alzheimer’s disease is a chronic disease marked by a signaling imbalance much like osteoporosis. In osteoporosis, you have an imbalance between osteoclastic activity, which is greater than osteoblastic activity. In Alzheimer’s you have synaptoclastic signaling outweighing your synaptoblastic signaling.


So what that means is just as for these other illnesses, osteoporosis, right? We all know you have an imbalance between your osteoclastic activity, which is greater than your osteoblastic activity. Similarly for cancer, your sideroblastic cell signaling exceeds your cytoclastic cell signaling, so you make more cells. And we call that cancer. Well, what we found in the lab is that Alzheimer’s is no different. There’s a whole set of signals that are synaptoblastic that are going on that side of the APP that I mentioned.  There’s a whole set of things that are synaptoclastic, and Alzheimer’s is nothing more than you’ve gone to the synaptoclastic side. So what that means is it’s a network insufficiency. It’s your synaptoclastic signaling outweighing your synaptoblastic signaling. And the good news is it’s really about four major things, inflammation, toxins, energetics and trophic activity, and really the vast majority, and this is the take home lesson which will help you treat every patient with cognitive decline or risk for decline. Alzheimer’s is pretty much boiled down to just two things. The innate immune system, so ongoing inflammation and energetics. And so normally you’ve got low inflammation and plenty of energetics, good blood flow, good oxygenation, good mitochondrial function, ketone your metabolic flexibility, you can burn glucose, burn ketones all good.

                                                But of course what happens with patients over time is they started getting some inflammation from many different sites and they start going down on the energetics. They may have poor blood flow, they may have sleep apnea, they may have poor mitochondrial function, any of these things. And so now they’ve switched into this mode of downsizing. So it’s really important with all these people to look at what’s the energetic status? What is the inflammatory status? Bring the energetics up, bring the inflammation down, figure out why those two were abnormal and fix that. Do they have a chronic infection? I mentioned this patient with a posterior cortical atrophy. She’s done really well. Well, she had to be treated for herpes simplex. She had to be treated for Bartonella. It turned out she had a chronic bartonella infection she didn’t even know about.


Dr. Dale Bredesen is a neurologist and an internationally recognized expert in the mechanisms of neurodegenerative diseases like Alzheimer’s Disease and the Chief Science Officer at Apollo Health. He is the author of the best selling books, The End of Alzheimer’sThe End of Alzheimer’s Program, and The First Survivors of Alzheimer’s. Dr. Dale Bredesen’s career has been guided by a simple idea: that Alzheimer’s as we know it is not just preventable, but reversible. Thanks to a dedicated pursuit of finding the science that makes this a reality, this idea has placed Dr. Bredesen at the vanguard of neurological research and led to the discoveries that today underlie the ReCODE Report.  Dr. Bredesen offers training for doctors and practitioners in his ReCODE system at his website at ApolloHealthco.com.

Dr. Ben Weitz is available for Functional Nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure and also weight loss and also athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111. Dr. Weitz is also available for video or phone consultations.



Podcast Transcript

Dr. Weitz:                            Hey, this is Dr. Ben Weitz, host of the Rational Wellness podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest in cutting edge health information. Subscribe to the Rational Wellness podcast for weekly updates and to learn more, check out my website, drweitz.com. Thanks for joining me and let’s jump into the podcast. Hello everybody, welcome to the Functional Medicine Discussion Group meeting tonight with Dr. Dale Bredesen on how to prevent and reverse Alzheimer’s disease. I’m Dr. Ben Weitz. I want this meeting to be interactive, so please participate by typing your questions into the chat box, and then I’ll either call on you or ask Dr. Bredesen your question when it’s appropriate. Thanks for joining our Functional Medicine Discussion Group monthly meeting, and I hope you consider attending some of our future events on August 24th.

                                                Dr. Tom Fabian of Diagnostic Solutions will be talking about the link between dysbiosis, mast cell activation and IBS. And on September 28th, Dr. Peter Bongiorno will be discussing an integrative approach to depression and anxiety. We also have a closed Facebook page for practitioners only, the Functional Medicine Discussion Group of Santa Monica that you should join. I’m recording this event. I’ll include it in my weekly Rational Wellness podcast, which you can subscribe to on Apple Podcast, Spotify, or YouTube. If you enjoy listening to it, please give me a five star ratings and review on Apple or Spotify. Our sponsor for this evening is Integrative Therapeutics. Steve, are you on the call?

                                                Steve said he wasn’t sure if he was going to be able to make it, but I want to tell you about a couple of Integrative products. Steve wanted me to emphasize, Integrative makes a highly absorbable form of curcumin called Theracurmin. And there was a study published in 2021 done at UCLA in which Theracurmin improved memory and mood in patients with age associated memory decline. And there’s a current study that showed that Theracurmin stabilized progression in loss of cognitive function. And so Theracurmin is a water-soluble form of Theracurmin, and the effective dose is only two capsules. It’s a highly effective product for reducing inflammation.

                                                Our speaker for this evening needs no introduction, but I am going to try to introduce him anyway, Dr. Dale Bredesen. Dr. Dale Bredesen is a neurologist and an internationally recognized expert in the mechanisms of neurodegenerative diseases like Alzheimer’s disease, and he’s the Chief Science Officer at Apollo Health. He’s the author of three bestselling books, The End of Alzheimer’s, The End of Alzheimer’s Program, and The First Survivors of Alzheimer’s. Dr. Dale Bredesen’s career has been guided by a simple idea that Alzheimer’s as we know it is not just preventable, but reversible. Thanks to a dedicated pursuit of finding the science that makes this a reality, the idea has placed Dr. Bredesen at the vanguard of neurological research and led to the discoveries that today underlie the ReCODE Report.  Dr. Bredesen offers training for doctors and practitioners in his ReCODE system at his website at Apollo Health.

I’d like to say one more thing, Dr. Bredesen before you get started. On behalf of the functional medicine community, if I may be so bold, I would like to thank you. There are many giants in the functional medicine community, including the father of functional medicine, Dr. Bland, Dr. Pizzorno, Dr. David Jones, Dr. David Perlmutter. So many others have mapped out many of the scientific bases of functional medicine. Dr. Mark Hyman has brought functional medicine into the Cleveland Clinic.  But really you, Dr. Bredesen, have really published some of the most important academic research and academic journals proving for the first time that a functional medicine approach is an effective first-line treatment for such a serious condition as Alzheimer’s disease. And this is really a landmark accomplishment. So from the functional medicine community, I thank you.

Dr. Bredesen:                    Thanks so much, Ben. Thanks very much everybody for having me. Please forgive me if I’m a little bit slow tonight. I’ve just had surgery and I’ve got a surgical drain in currently, so I’m a little bit out of it at the moment, but hopefully we’ll get through everything. But I think this is great timing. I’ll show you why. Let me just share the screen here. There’s just so much amazing stuff going on, and so I’m really thrilled. There’s just so many good things. So you can see this, okay, hopefully.

Dr. Weitz:                          Yes.

Dr. Bredesen:                    We’ve really gotten to the point that Alzheimer’s is now optional, and I’ll show you why. And what’s exciting is we hope now that we’re going to be able to extend this to all of the major neurodegenerative diseases and that these will really be, they’re going to literally we’re in a period in which we will see these transform from impossible to treat terminal life sentences, terminal illnesses, which they’ve always been. Lewy body disease, frontotemporal dementia, ALS, Alzheimer’s. These are all terminal illnesses. We’re seeing them right before our eyes transform into illnesses that are preventable and reversible. So let me show you why we believe that. We spent 30 years in the lab. We published over 220 peer-reviewed papers on the underlying mechanisms of neurodegeneration. And then back in 2011, 2012, we started to translate these into ways that you can actually make people better.

                                                And as you mentioned, we are seeing this again and again. So lots new going on. Let’s talk about that first. A lot of people have heard about lecanemab now called Leqembi as the trade name, and now donanemab, another one coming down. So what’s happened is after all of these different antibodies failed, bapineuzumab, solanezumab, gantenerumab, crenezumab, all failed, aducanumab had a minimal effect, and now lecanemab has a measurable effect. But as I’ll show you, what it does is it doesn’t make you better, it doesn’t stabilize you, but people with Alzheimer’s early on, people with MCI that what it’ll do is it is a 27% slowing, and actually if it’s a female patient it’s only 12% slowing.  So it’s a very minimal effect and unfortunately has some negative side effects like brain bleeding and brain swelling, and in a couple cases death. But there’s been so much PR around this without recognizing the fact that there are lots of things that are actually better. Homotaurine, I don’t know if anybody uses this, but it’s been very interesting. It prevents and is currently in clinical trials. It prevents the oligomerization of Abeta. So it actually looks like it may be a very interesting adjunct to other parts of the protocol. And then-

Dr. Weitz:                          Doc, is that a nutrient or is that a pharmaceutical?

Dr. Bredesen:                    Actually, it’s a supplement. So you can get Homotaurine as a supplement. Now they’re trying to do a precursor of this that will probably be sold as a drug. It’s in phase two trials right now. If this all works out, they will probably try to turn it into a drug. We’ll see. But you can use Homotaurine right now as a supplement. And they were using either 100 milligrams three times a day or 150 twice a day. Then you may have seen the paper on combined metabolic activators. Very interesting. And as you’ll see, it makes perfect sense based on the research that we published. And then we are just starting a randomized controlled trial. You can look at our proof of concept trial, which is freely available online. We published last year in the Journal of Alzheimer’s Disease. Very successful, 84% of the people actually got better.

                                                The randomized controlled trial, very excited about that. It’s with six absolutely fantastic clinicians. Craig Tanio down in Hollywood, Florida. Nate Bergman in Cleveland, David Haase in Nashville, Kristine Burke out here in Sacramento. Kat Toups, who’s over in the East Bay, and then Ann Hathaway, who’s right near here in Marin County. So very, very honored to be working with this absolutely great group of physicians. And then one of the big complaints we’ve had is, hey, it’s not that easy to get the right food, to get the right organics, to get the right plant rich ketogenic diet, make sure it has the right sourcing and so forth and so on.

So we worked with KetoFLEX, with a group from Nutrition for Longevity. This is Jennifer Maynard and her group.  This was a group founded actually by Valter Longo. It’s been months and months and months. And finally they’ve actually got this, it’s now ready for delivery. I’ve had it myself. It’s actually quite delicious. So they did a great job. So they have a KetoFLEX, 12/3 that’s available for delivery. And this is in the 48 states, so you can’t yet get it yet in Hawaii or Alaska, but you can get it everywhere else in the country.

And then you may have seen an interesting paper from a few months ago. This is the work of Professor Rick Johnson in Colorado. And David Perlmutter and I were co-authors as well as several other people. And what he showed was quite interesting, and he’s been working on fructose mechanisms for years. And what he found is that fructose, because it’s associated with massive amounts of fruit intake in the fall, it actually is getting you ready for winter. So what it does is it turns down your energetics, turns down your ATP.

                                                And as I’ll show you, the two big players in cognitive decline are energetics and the innate immune system, essentially inflammatory pathways. And so that’s the last thing you want to do, is turn this down, it makes things worse. And he has a very interesting point where he just listed all the different characteristics of Alzheimer’s and all the different characteristics of what happens to your biochemistry, your cellular biochemistry and mitochondrial biochemistry when you have large amounts of fructose, and they line up remarkably well. I think he’s onto something important. I don’t think it’s by any stretch the only cause of Alzheimer’s, but I think it’s a relatively common contributor.

                                               And then interestingly as you may have seen, there is a whole new set of blood tests. People in the past have had to do spinal taps or PET scans to determine where you stand with your Alzheimer’s disease and do you really have it or not?   Now you can do blood tests. P-Tau 181 is already available. I believe it’s now available from LabCorp. P-Tau 217 is not yet available, but it’s coming soon. Both of them very helpful. What they’re really telling you is that you have the type of signaling that is associated with Alzheimer’s disease, so you don’t have to do the spinal taps, you don’t have to do the expensive PET scans. Abeta 42 to 40 ratio also helpful, and that’s available from a couple different groups. And then interestingly, Neurofilament light, also online is available. And then GFAP, not yet available, but is coming. Now, they each tell you something different. So the pTau is telling you that you have the associated signaling of Alzheimer’s. It’s relatively specific. Same thing for 217.  Abeta 42 to 40 is telling you whether you have a condition where you are making Abeta, which is typically associated with inflammation and Alzheimer’s. Neurofilament light, not specific for Alzheimer’s, but it is telling you you actually have neuronal damage from whatever. It goes up in frontotemporal dementia, it goes up in ALS, things like that. And then GFAP again is complimentary, is different. It’s not as specific at all. It’s just telling you you have reactive astrocytes, but it’s very sensitive. So you see changes first in GFAP. So my feeling is anyone who’s 40 or over should find out their GFAP, and it’s going to be available presumably within the next few months, because you can get an idea, am I heading toward anything? The future is going to be, none of us is going to wait to have dementia.

                                                Frankly, it’s just so silly the way medicine is currently practiced where people wait and wait and wait and wait and wait, and then finally say, oh yeah, you got dementia. There’s nothing we can do. You can see this coming years and years ahead of time. And we’ll talk about the four major stages. And then it’s interesting you mentioned Santa Monica, Ben. We are just going to open later this year, the first precision medicine program for neurodegenerative disease in the world. So we’ll allow people to send people from all over the world who have various neurodegenerative diseases, be they Alzheimer’s, frontotemporal dementia, ALS, Lewy body, what have you, and have real hope.      And this is going to be at the Pacific Neuroscience Institute, PNI, within one of its centers called the Pacific Brain Health Center. So very enthusiastic about that. And I’ve been working with-

Dr. Weitz:                          Is that affiliated with Providence Hospital?

Dr. Bredesen:                    Yes, yes. Will be affiliated with Providence. Yes. And you probably know Dan Kelly, who’s the neurosurgeon who runs PNI and David Merrill, actually one of the guys who took our training early on has been doing a great job and founded the PVHC. And so I’ll be working with David and his team and we’ll be now adding new features there. So very enthusiastic about that.

Dr. Weitz:                          That’s great.

Dr. Bredesen:                    So as I said earlier, we are literally witnessing the transformation of neurodegenerative diseases. For my whole career and for my whole time in the lab, there’s nothing you could do about these things. And we’re seeing them go from hopeless to preventable, reversible, and ultimately optional. We’re far ahead on Alzheimer’s. We’ve got some good results with Lewy body. We’re beginning to see some good results with dry macular degeneration. But I hope that we’re going to now see the same sorts of things with ALS, with frontotemporal dementia. We’ve got an interesting case, for example, with Dr. Craig Tanio down in Florida, and he’s had some wonderful results with a person recently who has corticobasal degeneration, which is a death sentence.  This person had already been told, get your affairs in order. There’s absolutely nothing to do. And Craig has had wonderful results. Similarly, posterior cortical atrophy, which is one of the presentations of Alzheimer’s, which Kerry Mills Rutland, you may know from New York, has a patient with PCA, just beautiful results, doing very, very well. It’s so wonderful to see these things which were simply never possible before.

So as I mentioned earlier, it’s important to compare what actually happens with these drugs and the one that’s just been given FDA approval and the reason that for all of us who are paying Medicare, we’re all going to be paying more because this is a multi-billion dollar drug, it will cost the patient about $40,000 a year. Medicare will be picking up 80% of that. The person will still end up paying close to $10,000 a year.   So here’s lecanemab. What it does is if you have no treatment and you have MCI or Alzheimer’s, you go downhill about three and a half points on a 30 point scale per year. Lecanemab slows that up by 27%. As I said, if you’re a woman, it’s 12%. In our trial that we’ve published, you can see here, we actually made people get better, didn’t simply slow their decline. So huge difference.

Dr. Weitz:                          Essentially Dale, what they’re saying with that drug is that your mother is going to spend a longer period of time in the memory care center. The goal is to get her out of it and not spend more time there.

Dr. Bredesen:                    It’s really impressive to me. The PR for this, it just keeps saying, well, there’s nothing else you can do. Well, there’s published results that say the opposite of that, but they just literally just ignore published results. So it’s interesting to me, this has really been many, many, many millions of dollars paying consultants to write good things about this drug, which is really not such a great drug. I think as we’re all aware, we are seeing the kind of medicine that I learned many, many years ago back in the 70s and 80s, literally the Titanic of mainstream medicine is going down right in front of us, sunk by the iceberg of chronic illnesses. You talk about Alzheimer’s or vascular disease or ALS, you just go right down the list.   And we saw this with our own daughter years ago who developed early lupus, and we took her to two world experts on lupus who said, yeah, she’s got early lupus, nothing you can do. When she gets worse we’ll give her some steroids. And we said, well, why did she get this? And they said, we don’t know. Nobody knows. So we then took her to a functional medicine physician who said, yeah, I know exactly why she got this and I can do something about it. And she’s had virtually no problems in the last 10 years. And it really shows that the new era is about why did you get these problems?

                                               But as you know today if you go to a standard of care doctor, you go to a memory center of excellence, what they tell you is it is probably not Alzheimer’s. We’re only going to treat you if it gets pretty significant.  They get small data sets. There’s no attempt to identify what’s actually driving the problem. They adhere to this outdated claim that there’s nothing will prevent or reverse or delay Alzheimer’s. If you’ve got someone in a nursing home, they don’t tell all the children, hey, wait a minute, all of you should be on active prevention. Why are they not doing that? And the statistics show that the patients spend an average of $350,000 before they die. Most of it on nursing homes of course. And of course this insistence on treating with mono pharmaceuticals, this stuff is really, really out of date unfortunately. One of the big problems is people say, you only have mild cognitive impairment. This is a analogous to telling someone, don’t worry, you’ve only got mildly metastatic cancer. This is a relatively late stage of the underlying pathophysiology.

                                                So you go through four stages when you get Alzheimer’s disease. Phase one, you’re asymptomatic but you can already see abnormalities on spinal fluid and PET scans. And the good news, you can now see the abnormalities on those blood tests that I just mentioned. So just as everybody, we all want to know our blood pressure, our HRV, our lipid panel, we should also want to know our Alzheimer’s panel. Really good idea. If you don’t find that out and you continue downhill, you start to develop some, what’s called SCI, subjective cognitive impairment. And by definition, this means that you’ve got some changes where you notice there’s something that’s not quite right. Often your spouse and coworkers may notice that something’s not quite right, but you’re still capable of scoring in the normal range.

                                                The good news, SCI lasts about 10 years on average, and it’s 100% reversible. We see these people reverse all the time. So if we could get everybody to come in for active prevention, I.e phase one, or even before phase one or phase two with SCI, there would be virtually no dementia. Now if you don’t do something about this, this you then progress to mild cognitive impairment, which as you can see is a relatively late stage of the disease. So it’s too bad they called it mild cognitive impairment. By definition now your cognitive testing is abnormal, but you can still perform your ADLs. Five to 10% of those people convert each year to stage four, with phase four, which is Alzheimer’s. And by definition, that’s really the dementia phase of Alzheimer’s. It’s all Alzheimer’s, but this is the dementia phase.  And so that means your activities of daily living are affected. And so what that means is the diagnosis of Alzheimer related dementia is typically made about 20 years after the beginning, biochemical changes. And that’s well documented. So we can do so much better if people simply won’t wait.

                                                And I don’t know how many people have looked at the brains of Alzheimer’s patients, but you can see striking differences. One thing you can see, for example, here are your SCI here, and you can see here that they widen. You can see right here versus here. And then interestingly, of course the brain shrinks. You can see the huge difference in the ventricles here, here versus here.  And then interestingly, the very first area that is damaged even before the entorhinal cortex, which is often said to be the first area, happens to be this locus coeruleus, which is in the brainstem right here, which literally means the blue spot. And this is the site where there is noradrenergic projection to your cortex. And so no surprise, one of the things you see early on is people lose their way, they lose their verve, they lose their interaction. And one of the things we hear commonly when people are starting to get better, is that their spouse will say, wow, they’re just more engaged. They’re really more with it.

                                                And then of course, if you look under the microscope, we’ve all heard about amyloids. You can see here collections of amyloid. This is largely from a peptide called amyloid beta. We’ll talk about that in just a second. You can see here these neurofibrillary tangles, and this is where you find the phosphorylated tau. So these are two different pieces here, the amyloid and the tau, and then of course there’s inflammation. So you see reactive microglia, and you also see reactive astroglia as well. So these are all part of this. So if we want to ask, well, what is this thing? And this is basically what we spent all these years in the lab looking at, because all these models that had been generated, none of them led to any approach that actually gave you good treatment. So we have to explain a lot of things to explain this disease.

                                                We have to explain why it is hugely different risk factors, whether it’s a change in your oral microbiome with P. gingivalis or type 2 diabetes or metabolic syndrome or menopause, low vitamin D, herpes simplex, mycoplasma, APOE4, which is the common genetic risk, down syndrome, just on and on and on. These risk factors are so different. So whatever we come up with has to explain those. There are about 100 risk associated genes, as I mentioned, APOE4 being the common one, but there are many, many. Why is that? What does that mean? The fact that amyloid is in the brains, it’s been implicated repeatedly, and yet when you remove it, you don’t get much of an effect in clinical trials. Why is that? The age associated risk, this dramatic increase as you get over 65.

                                                And by the way, we’re seeing a lot of people in their 40s and 50s now get diagnosed with Alzheimer’s. When I was training, we never saw people in their 40s or 50s with Alzheimer’s. And in fact, the epidemiologists have pointed out that this is what’s been on the rise more than anything else in Alzheimer’s. It’s the 40 somethings and the 50 somethings that are really increasing. And then there’s a very interesting mouse that has in its genome the instructions for a monoclonal two nerve growth factor. So what it does is it reduces the nerve growth factor, not to zero, but it reduces it. And interestingly that mouse develops Alzheimer’s pathophysiology. Why? Again, we got to explain that. And then all these aggregated proteins, so many people just say, Alzheimer’s, all it is aggregated proteins. Well, there are lots of aggregated proteins in the disease, but it doesn’t tell you what the disease is.

                                                And then of course, the remarkable failure, greater than 400 clinical trials, the prionic nature of Abeta and tau. So I trained as a postdoc with Stanley Prusiner, who won the Nobel Prize in 1997 for his discovery of prions. And it turns out that Abeta and tau both have this phenomenon where they are proteins that beget more of themselves. And then the high incidence and prevalence, about 15% of the population will die of Alzheimer’s. We’ve had over a million people now die of COVID-19 in the United States. But if you look at the in country as a whole of the currently living Americans, about 45 million of us will die of Alzheimer’s if we don’t have a better treatment and prevention. So this is a huge area.

Dr. Weitz:                          Hey doc, could you just clarify what you mean by the prionic nature of amyloid and tau?

Dr. Bredesen:                    Yes, absolutely. So what this means is if you put these into a brain, they will beget more of themselves. So they act like infectious particles, even though they have no DNA or RNA. That was the big finding that won Stan the Nobel Prize. He pointed out that these are infectious agents. In this case it was a prion protein, PrP, which he discovered, cloned, characterized, et cetera. And he showed that this begets more of itself. So if you put this into a brain that has PrPC, the normal isoform, you will get this abnormal isoform. And the same thing happens with Abeta and tau. You put enough of it in a brain, it will beget more of itself. Now the good news is if you don’t have too much, you can actually damp it down and you will then lose. You won’t go on to have this prionic effect.  So that’s one of the things we want to do. We want to remove all the things that are driving it, and then we also want to remove the prions themselves. So the point here is that any model that you come up with has to be predictive. It has to say, okay, this clinical trial’s going to work and that clinical trial is not going to work, and it has to be consistent. These other models that just say, well, this works for this group, but it doesn’t work for that group, that really doesn’t help us.

                                          Okay, so what we want to look at is under the hood, let’s look at what actually happens here. This is amyloid precursor protein. This is just now a diagram here of a single cell. So we’re looking at one neuron and we’re looking at the membrane here.  This is a protein that’s in neurons and other cells, but mostly neurons and mostly at the synapses. And this is the parent of the amyloid that you’re going to make. Now, what happens is really interesting. This stuff acts like a switch. This molecule sits, and you can see most of it is outside the cell, a little bit of it is inside the cell. It’s literally crossing the membrane. Now, when things are good, this thing literally recognizes that and is cut at a single site to give you two peptides, sAPP alpha and alpha CTF, and these things tell your nervous system things are good, grow, maintain, make new synapses, et cetera. Very much like what happens in our country, when things are good, the stock market is good, people are paying their taxes, et cetera. Then you build new bridges, you build new interactions with other countries, et cetera.

                                                On the other hand, when things are bad, for example, with the pandemic, we were told, hey, we’ve got an insult. In that case, SARS-CoV-2, we’re going to pull back and put our resources into protection. People aren’t going to go to work, they’re going to stay home, they’re going to socially distance, et cetera. And of course what happens, we go into a recession. And that’s the same thing that happens in your brain when you’ve got infections, inflammation, toxin exposure, all these sorts of things, your brain changes into this very interesting downsizing protective mode. So this amyloid, here it is right here. The amyloid peptide, which has been vilified in Alzheimer’s, is really a protective antimicrobial peptide. And Professor Robert Moir and Rudy Tanzi from Harvard published this several years ago, showing that this is actually a protective antimicrobial peptide.   It’s very different. This thing will literally switch from one mode to the other, and that this is the one on this side that’s associated with Alzheimer’s. And so now we understand what this is all about. This is not just trying to give you Alzheimer’s, it’s trying to protect you from these various insults. Okay.

                                                 So what that means is just as for these other illnesses, osteoporosis, right? We all know you have an imbalance between your osteoclastic activity, which is greater than your osteoblastic activity. Similarly for cancer, your sideroblastic cell signaling exceeds your cytoclastic cell signaling, so you make more cells. And we call that cancer. Well, what we found in the lab is that Alzheimer’s is no different. There’s a whole set of signals that are synaptoblastic that are going on that side of the APP that I mentioned.  There’s a whole set of things that are synaptoclastic, and Alzheimer’s is nothing more than you’ve gone to the synaptoclastic side. So what that means is it’s a network insufficiency. It’s your synaptoclastic signaling outweighing your synaptoblastic signaling. And the good news is it’s really about four major things, inflammation, toxins, energetics and trophic activity, and really the vast majority, and this is the take home lesson which will help you treat every patient with cognitive decline or risk for decline. Alzheimer’s is pretty much boiled down to just two things. The innate immune system, so ongoing inflammation and energetics. And so normally you’ve got low inflammation and plenty of energetics, good blood flow, good oxygenation, good mitochondrial function, ketone your metabolic flexibility, you can burn glucose, burn ketones all good.

                                                But of course what happens with patients over time is they started getting some inflammation from many different sites and they start going down on the energetics. They may have poor blood flow, they may have sleep apnea, they may have poor mitochondrial function, any of these things. And so now they’ve switched into this mode of downsizing. So it’s really important with all these people to look at what’s the energetic status? What is the inflammatory status? Bring the energetics up, bring the inflammation down, figure out why those two were abnormal and fix that. Do they have a chronic infection? I mentioned this patient with a posterior cortical atrophy. She’s done really well. Well, she had to be treated for herpes simplex. She had to be treated for Bartonella. It turned out she had a chronic bartonella infection she didn’t even know about.

                                                She had to be treated for mycotoxins. And then interestingly she started really improving when she did EWOT exercise with oxygen therapy. So as with so many other patients, she had multiple contributors when they were addressed, voila, she starts getting better and she’s continued. And her MoCA has gone from 21 to 29. Her symptoms have gotten much better. By the way, her MRI just spectacular improvements. Her parietal lobe went from less than first percentile to the 23rd percentile. So just dramatic improvements, because Kerry was actually able to find out what was driving this. And what that means is, yes, if we’re going to develop a perfect Alzheimer’s drug, that’s fine, but it’s going to have to do all these things.

                                                But what we really want to do is combine one or a few targeted drugs with a functional medicine or precision medicine approach. That’s clearly the way to deal with this complex chronic illness. So we’ve been telling people for years, imagine you have a roof with 36 holes that came from the early research that showed there were 36 different mechanisms. We know of a few more now, but it’s not thousands, it’s dozens. So we can address those, we can identify those. And of course, as I mentioned, the most common risk factor genetically is APOE4. And for years people didn’t know why that was. About two thirds of Alzheimer’s patients have APOE4. In fact, if you have zero copies, which is three quarters of our population, your lifetime risk is about 9%.

                                                If you’ve got one copy and that’s 75 million Americans, your lifetime risk is about 30%. And if you’ve got two copies and that’s seven million Americans, unfortunately most don’t know it, your lifetime risk is about 70%. Most likely you will get Alzheimer’s disease. And there’s a wonderful website, which is called apoe4.info, started by a woman whose APOE4 herself, had symptoms, has done beautifully. She’s been on the program for now over 10 years. She’s gone from 35th percentile to 98th percentile in her cognitive testing. She’s just amazing. She actually wrote a part of the second book, and her story actually appears in The First Survivors of Alzheimer’s. And so she’s got a wonderful website where people share information who are APOE4 positive. I think they have now something like 7,500 people on that site.

                                                So the problem had been how does this work? Why does this thing that simply carries fat? It’s like your butcher. It’s the guy who carries the fat around. How the heck does that give you Alzheimer’s? And so we launched a project, now it’s over 10 years ago in the lab. And all we found is really fascinating. And this is a thing that turns out to have to do with our evolution as hominids. And so up until five to seven million years ago, of course there were simians, but there were no hominids. And the first hominids appeared about five to seven million years ago. And what’s interesting is our DNA is very similar to the simians. There aren’t that many changes. It’s over 98% similar genes. And interestingly, the genes that did change between the simians and the hominids, many of them, outsized proportion of them were related to being pro-inflammatory, including APOE4.

                                                APOE4 appeared and was the primordial gene for the hominids, and it is a pro-inflammatory gene. And interestingly, why would that be? Well, as Professor Tuck Finch from USC pointed out, it allowed us as hominids to come down out of the trees to walk around the Savannah, to puncture our feet, to get infected, to eat infected meat full of microbes, to fight with our brethren, to fight with our food. We’re very good when we’re APOE4 positive, at healing, very good at dealing with infections because of this pro-inflammatory state. But it also because of the ongoing inflammation is associated with heart disease and with Alzheimer’s later in life. So just recently then, so you can see here, God came down, changed a few genes, and of course we ended up as amazing hominids.

                                                So if you look at the original APOE4, you can see here, it looks like columns on a house. And that’s because this arginine 61 and the glutamate 255 interact, the arginine has a positive charge, the glutamate has a negative charge, and they interact here. And this was actually shown by the discoverer of APOE. And then on the other hand, just 220,000 years ago, APOE3 appeared. And now what happens? Cysteine 112 appeared as a mutation, interacts with arginine 61. So now this swings free. And Dr. Mey Lee, the discoverer of this, called this domain interaction. So you can see they’re quite different. So for 96% of our evolution, everybody’s been APOE4 4. Just in the last 220,000 years, APOE3 appeared. And then just in the last 80,000 years, APOE2 appeared.

                                                So to make a very long story short, what we found is APOE4 does something really interesting. It had been known, it binds to a number of receptors like LRP, for example, on your cell, enters the cell. But what we found is that it interacts with a pro-inflammatory molecule called Rel. This is part of NF-kappa B, and it enters the nucleus and it interacts with 1700 different gene promoters. And if you map those out, you could not tell a better story for Alzheimer’s disease. So it has to do with synaptic changes, it has to do with CT, for example. It has to do with inflammation. It has to do with glucose homeostasis. So it’s really changing. So it’s not just your butcher that’s carrying around the fat, it’s also your senator that’s making the laws land.

                                                Literally APOE4 reprograms your cells toward a more pro-inflammatory state. So when we look for these different things, we now start looking at them, identifying them, and actually addressing them. We see some remarkable examples. So let me just give you a couple examples here. Here’s a 68 year old woman presented with cognitive decline. Her first thing was she started making paraphasic errors. She also had some depression, struggled with computer work. She couldn’t complete a gingerbread man. She confused clock hands, forgot to pick up her granddaughters, which really scared her. She went in, she had an amyloid PET was positive. She was APOE4 single copy, had a MoCA of 24, so already well into MCI, that third of four phases. Hippocampal volume was already down. This is a professor. Hippocampal volume was already down to the 14th percentile. So her diagnosis was MCI due to Alzheimer’s disease.

                                                She actually went on a clinical trial for an anti-amyloid drug. And interestingly, as we’ve seen with some other people, she got worse with each injection instead of getting better. So after eight treatments, she said, I am not doing this anymore. She quit the trial and she actually contacted me at that time. So we looked further. I worked with her physician actually. She failed her visual contrast sensitivity. Her C4a was high, her TGFβ-1 was high, MMP-9 was high. Her urinary mycotoxins were increased. She was MARCoNS positive. Her hsCRP was a little bit up 1.1. Triglycerides were very low as we often see with people who have mycotoxin related cognitive decline. Her zinc was also very low, another thing we see. So she began on the ReCODE protocol. She did great. She’s actually now seven years into this. Her symptoms resolved. She could speak again, tell time, build a gingerbread man, no longer problems with her granddaughters.

                                                And by the way, she’s actually part of a documentary that’s called Memories for Life: Reversing Alzheimer’s. It’s come out from the Japanese NHK that’s making its rounds around the country. It was just at the Manhattan Film Festival a couple of weeks ago. Her MoCA score became a perfect 30. Hippocampal volume went up to the 28th percentile. She’s remained stable. As I said, she’s now in her 7th year, so she’s done absolutely great. Here’s a 66-year-old man family history. Both parents died with Alzheimer’s. Single copy APOE4, amyloid PET markedly positive. So classic case of a guy with Alzheimer’s disease. You can see why his homocysteine is high. His hsCRP is very high, vitamin D is low. His testosterone’s low, his free T3 is low. He responded metabolically, cognitively, volumetrically to ReCODE. His neurologist said he’s now normal. He’s done very well.

                                                You can see here his MRI hippocampal volume went from 17th percentile to 75th percentile. So he’s done very, very well. And you can see his hsCRP is still not perfect. His fasting insulin is still not perfect, but it’s so much better than it was. And we see this commonly. His gray matter volume went up by 23%. So just say a little bit about the trial that we published last year. You can read the details in the Journal of Alzheimer’s Disease. So instead of predetermining a treatment, we just flipped the script here. As you know with all these trials, people say ahead of time, we’re going to treat with X. We said, instead of telling you ahead of time what we’re going to treat with, we’re going to look to see what’s causing it, and then we’ll address those things.

                                                You can see it on clinicaltrials.gov. We were denied for this trial in 2011, again, in 2018. We finally got approved in 2019. Small proof of concept trial with 25 patients. We compared personalized precision medicine approach for nine months to historical controls. And looked, again, just a standard a functional medicine approach. Looking at what’s actually driving this. We used MoCA scores. We used CNS Vital Signs because it’s more sensitive. So we got a good dynamic range. The MoCA scores were better for people who were farther along. And the CNS Vital Signs were better for people who weren’t so far along. People had MRI with volumetrics, they improved their neurocognitive index. You can see here, actually the pandemic started right here. So we had a few people who actually stopped doing things and were not doing as well. But actually they still showed improvement overall.

                                                And these are highly statistically significant. You could see improvements in hsCRP, hemoglobin A1C, the HOMA-IR a little improvement, but we didn’t have enough data on that. And so it didn’t reach statistical significance. Triglyceride HDL ratios, homocysteine, vitamin D, all of these were statistically significant in their improvements. So all of these things, MoCA, 76% improved. Neurocognitive index, 84% improved. Improvement on subtests, improvement in a change scale where you ask the spouses if they’d improved or not. That was statistically significant as well. All of them improved on their brain training. Their MRIs, interestingly their gray matter, which even in normal aging slowly shrinks and with Alzheimer’s rapidly shrinks, these people actually increased their gray matter size. And then their hippocampal volume had a minimal decline.

                                                But again, it was actually less than normal aging and far less than Alzheimer’s. So lots of improvements in these people. And interestingly when you look at patients as a whole, the ones who tend to do the best are the ones that come in a little bit early. As I mentioned, SCI, they all improve. People with MoCA scores of 18 or above are easier to improve. We had a couple people in the trial who went from MoCA scores of 18 to perfect 30, clearly addressable metabolic abnormalities. That tends to be easier when you can actually find what’s causing the problem. If you find a chronic infection, if you find specific toxins. The ones who had supportive families and work with health coaches, the ones who had a positive attitude and actually were compliant, the one who just continued, they didn’t give up, okay, you make them a little better, now You keep looking at how can we make this better and better. So keep tweaking, keep optimizing, and they do better.

                                                The ones who did get into ketosis, whether endogenous or exogenous, tended to do better. The ones who didn’t have massive amounts of toxicity tended to do better. And the ones who had symptoms for less than five years. So again, we encourage people, please, please don’t wait. Come in early if you can. And then the ones where we did see improvement in their metabolic markers. And on the other hand features associated with continued decline, poor compliance, lack of interest, so we had one person in the trial, one of the few in the trial who didn’t get better, was someone who turned out to have massive mycotoxin exposure in their house and just said, I’m not leaving and I’m not remediating. I’m just going to sit here. And no surprise, she did not improve.

                                                Severe toxicity, continued exposure. MoCA scores less than 10. They’re tougher. We have had people with scores of zero who do improve, but they don’t go all the way back to 30. We’ve seen them go from zero to nine, and we’ve seen them go from 18 to 30. My goal is can we ultimately get someone to go from zero to 30? Haven’t done it yet. It’ll be interesting to see what does it take to do that? Does it take stem cells? Does it take intranasal peptides? We don’t know yet. Many years of decline also tougher. Lack of support from family and health coach. I see this almost every day. I just got an email today from a woman who said, in fact, actually she posted this on Facebook. That’s right. There is a woman who said, I’m trying to help my mother, but the rest of the family just says, forget it. There’s nothing you can do.

                                                She’s gone through the whole protocol and said, let’s do the right things. And everyone says, no, no, no, no, no. Let’s just give her some hot fudge sundaes and let her go. So yeah, when you don’t have support, that doesn’t work as well. I do think health coaches are really important and really helpful. And then finally, failure to identify key contributors. Many times we’ve had someone who improved and then after a few years started to have a little bit of sliding and we say, wait, what’s been missed here? And then you find something new and now they go right back again. And that’s really important. So don’t give up. And again, some surprising responses people, I got an interesting email from a guy a couple years ago whose wife had a MoCA score of zero, and he said she’s in a nursing home, but she’s responded beautifully.

                                                She’s part of the family again. She talks to us, she dresses herself again. She’s doing so much better, but she’s still in the nursing home. She still has dementia, but she’s much more interactive. So can we now make this optional? We got to encourage people to come in earlier. We encourage everyone, please get a cognoscopy at the age of 40, just like you’re going to get a colonoscopy at 50, and identify factors and get on active prevention, those people who then fall through the cracks. Okay, it’s a multi-tiered approach now, if you now start developing symptoms, get in with at SCI. And ten if the people continue to fall through the cracks, you want to do a more and more extensive evaluation so that we can really make a big impact on a whole population.

                                                And then ultimately over time, AI will help us to identify what are those things that are making the biggest difference and what are the things that are making the least? And I mentioned the KetoFLEX. So we want, here’s the critical paradox, and this is something that many people don’t recognize. So it’s important to know this. The disease is a network insufficiency, so something is not enough. You don’t have enough support, blood flow, oxygenation, whatever it is. On the other hand, it started often by excess because you had lots of carbs and you developed insulin resistance. So you’ve lost the ability to burn the glucose and you’ve lost the ability to make and burn ketones. So we want to get both of those back to normal. So we want to be careful.

                                                If we starve people to get them to be insulin sensitive, that often makes them worse. So which is why I usually say just start, give them some ketones at the beginning. Give them some exogenous ketones for a couple of months. And during that time, you can restore their insulin sensitivity. Now they’re doing better. Be careful for the people who are frail. This is a common problem. If they don’t have fat to burn, to make ketones, help them out, give them some ketones. So that’s the important paradox. And this is why we work with Nutrition for Longevity, to make it so that they made appropriate meals, appropriate sourcing, appropriate organics, appropriate ability to get into ketosis, all the appropriate things to get the best outcomes, appropriate caloric income, et cetera.

                                                So we want insulin sensitivity and ketosis, I.e metabolic flexibility. We want to plant rich, mildly ketogenic diet with fasting periods 12 to 16 hours. You want to be careful, you go too long, you’re getting back again into insufficiency. High fiber, high phytonutrients, anti-inflammatory, et cetera. High fat, intermediate protein, low carb, no simple carbs. And many people like to cycle off once per week or twice per week. That’s fine. No problems. Grains and dairy, we stay away from. Wild cat fish, great pastured eggs, great pastured chicken, grass-fed beef, all of those are fine. As I mentioned, this says coming soon, but it’s actually here. So as you know, a couple of books on this that are available. And just to finish up here, the ARC project, very excited about this.

                                                And so the idea here is to take people with different neurodegenerative diseases, and we’ll be doing this at this new group at Pacific Neuroscience Institute as well. And then to do deep dive looking at genomes, looking at epigenomes, looking at all the things that are driving these in just a couple of people, hence ARC, like two by two by two, so that we can actually look to see what is driving the problem in each of these diseases, and then address those things. I’m very enthusiastic that we should be able to prevent and reverse many different neurodegenerative diseases in the near future. I recognize, I’ve been doing this for a long, long time, I’m an old guy now, I’m now 71. So as they say, you’re not expected to complete your life’s work during your lifetime. Neither are you excused from it.

                                                I recognize it’s you guys that are going to be doing this. It’s you guys that are going to be taking this forward and making it better long after I’m gone. And I really hope that we will see a world with far less neurodegenerative disease, because it’s been a huge problem. I’ll end there. Happy to take some questions. How are we doing on time here?

Dr. Weitz:                          We’re doing fine. We have as much time as you want. I wanted to ask-

Dr. Bredesen:                    Would love to answer questions, and I think we’ll stop sharing there.

Dr. Weitz:                          I wanted to ask a question about the use of statins and about cholesterol in general. We know statins have been a huge benefit for reducing cardiovascular risk and we know that blood flow is really important for brain function. And this is important also because recently in the medical community, it’s been a big push to really try to drive cholesterol levels down as low as possible. There’s a prominent practitioner who has a very popular podcast, and he said that we should drive LDL down below 40 and we’ll eliminate all heart disease. And he also said that we don’t have to worry about these drugs that reduce cholesterol affecting the brain, because the cholesterol in the brain is made in the brain.  And yet we know that at least 25% of the cholesterol in the body exists in the brain. And I’ve looked at some of the studies, and there’s at least, there was a study a couple of years ago that showed that PET scans showed that there was a decrease of blood flow to the parts of the brain that are associated with Alzheimer’s in those particularly who took lipophilic statins.

Dr. Bredesen:                    Yeah, no question. There’s a nice study from UCLA that showed that lipophilic statins were associated with brain atrophy and with a greater likelihood of developing dementia. I assume you’re referring to Peter Attia who’s pushing.

Dr. Weitz:                          Yes.

Dr. Bredesen:                    I get it. He’s very concerned about heart disease. Fine. Of course, Dr. Esselstyn, Caldwell Esselstyn has done a great job with showing that, hey, if you don’t have any fat around, you can’t make those plaques. Unfortunately you can make dementia. That is the problem. So if you look at the literature, you’ll see half the papers saying that statins reduce your risk of dementia, and half the papers saying that it increases your risk for dementia. How can that be? And the reason is because they have both a positive and a negative effect. So sometimes one wins out, sometimes the other wins out. So for example, they have an anti-inflammatory effect, great, but they also reduce your cholesterol so much that you can increase your risk for dementia.

                                                My argument is why don’t you get the best of both worlds, use other anti-inflammatories, use appropriate diet and exercise and lifestyle approaches to get your cholesterol lined up. And if you need a little help, then there are other things you can do. There are other ways to go about this. You can even try with these PCSK9 inhibitors like Repatha. That’s another way to consider, probably better for you. But here’s the problem, when we’re seeing people coming in with cognitive decline, we see that they’ve been overtreated with these statins, and they come in with total cholesterols of 105, 110. Anything below 150 is associated with brain atrophy. And in fact, interestingly, you may know Dayan Goodenowe, who’s an excellent biochemist. He’s the one that developed the plasmalogens and initially found that people with Alzheimer’s disassociated with people with low plasmalogen levels.

                                                And he pointed out the healthiest profiles he sees are when people end up with total cholesterols 220, 225 that’s kind of typical. So you’re right, we want to look at the critical ones like LDL particle number, small dense LDL, oxidized LDL. ApoB now has become probably the most common one. And actually something that my wife, Dr. Lasheen taught me about months ago, and saying, hey, ApoB is really the way to go. So, okay, fair enough. I’m agnostic, whatever helps people to get better outcomes. And I totally understand we don’t want to have myocardial infarctions, so we recommend that people get calcium scores or get CT angios. So you make sure you’re okay. But if you’re looking good, if your score is zero and you’re developing some cognitive decline, you should be thinking way more about your brain than your heart. You’re probably going to do fine with your heart.

                                                There’s a lot you can do for your heart. So again, this is why I like to, if possible, avoid statins or at least minimize the statins and do the things that are good for you for the statins. Things like anti-inflammatory, you can do that with lots of other things. Curcumin is one of many. Cat’s claw is another one. What’s really interesting to me as someone interested in cell biology, is that the amyloid that we make in our brains is part of your innate immune system. It is part of your body saying, oh, I’ve been invaded, something is not quite right here. So it actually it makes perfect sense. And interestingly, if you look at what part of the innate immune system it is, it is part of your innate system’s memory, and your memory lives in three places. It used to be thought your innate system didn’t have a memory, your adaptive system had the memory.  But it turns out your innate system has a memory as well, and it lives in three sites. It lives in your bone marrow, it lives in your endothelial cells, which is why these people unfortunately get increased thrombosis and poor blood flow. And it also lives in your tissue macrophages, which is why you end up having this in your microglia as well as your neurons.

Dr. Weitz:                          Interesting.

Dr. Bredesen:                    So it’s very interesting system, and when you understand Alzheimer’s in this way, that it is a physiological response to these insults, suddenly everything makes sense. You can see how to prevent it. You can see how to treat it and reverse it, and all these crazy ideas. One of the standard things they say is amyloid is the thing that causes Alzheimer’s. Then they found out that it’s an antimicrobial. They said, well, sometimes it’s good and sometimes it’s bad. It just like it is hand waving. Whatever you come up with has to make sense in all situations. And this model does.

Dr. Weitz:                          Lynn asked, why are we seeing an increase in dementia in 40 to 50 year olds, in younger patients?

Dr. Bredesen:                    A great question. The answer is nobody knows for sure. No one’s proven it. But the leading contenders are the changes with ultra processed food. The fact that everybody’s, so many people now have metabolic syndrome. We have something like 80 million Americans with metabolic syndrome, that dramatically increases your risk for Alzheimer’s disease. And interestingly, the ones I see in their 40s and 50s are usually associated with toxin exposure. It’s this overwhelming toxin exposure. It’s the mycotoxins, it’s the air pollution, it’s the mercury, it’s the organics. When you look at these toxins that are associated with cognitive decline, they come in three groups. Inorganics like air pollution and mercury and heavy metals. Organics like glyphosate, toluene, benzene, formaldehyde. And then thirdly, biotoxins.  So many people without knowing about it, as you know, they either live in or work in an area that is just filled with mycotoxins and they don’t know it until they start having cognitive decline. And when you start detoxing them from those mycotoxins, they start to get better.

Dr. Weitz:                            And when you mentioned metabolic problems, we now know there was just recently a study published showing that statins increase your risk of diabetes.

Dr. Bredesen:                    Absolutely. And that’s another big issue. And of course diabetes just gives you increased risk for cognitive decline.

Dr. Weitz:                          Let’s see, you mentioned exercise with oxygen. Can you explain what that is?

Dr. Bredesen:                    Yeah, that’s one of my favorite things now because we’ve had such good responses to this. So again, as we get a little older, we are perfusing areas of our brain less perfectly than we did. We’re getting a little less blood flow, a little less oxygenation. Some of us developed some sleep apnea or some upper airway resistance syndrome. We’re just not quite firing on all cylinders and we may notice it. What does EWOT do? Well, you’re now combining exercise with oxygenation. So you get this wonderful benefit where you’re perfusing areas of your brain and you’re providing oxygenation. And people have done very, very well with that. Now, some people like to use HBOT instead. Great.  But HBOT, it’s expensive and it’s not active. It’s a passive form. So you’re not getting that exercise to help with the circulation. Yes you are getting more oxygenation, no question. You now got it under increased pressure, but the two have somewhat similar effects, but one of them is a more active and one of them is more passive.

Dr. Weitz:                          What exactly is the device? And this is something that you’re turning up and down as you’re exercising.

Dr. Bredesen:                    So the device is, and you can get it from different groups like MaxO2 or LiveO2 or things like that. So this is basically, it’s basically an oxygen concentrator. So you basically do 20 minutes of exercise with this pure oxygen. And some people like to do it with stationary bikes. Some people like to do it with cross country. Any sort of exercise that you do. Now, to be fair, it’s missing one thing. It’s better to do your exercise outdoors than indoors, unless you live in a place that’s heavily polluted, you want to get out of those mycotoxins in the house. So that’s the one negative. But yeah, hey, you could put it out on your balcony if you want to do something like that. But getting that oxygen with the exercise, again about 20 minutes and then it will run out, is actually quite helpful.

Dr. Weitz:                            Somebody asked, would you be willing to share your slides with us?

Dr. Bredesen:                    Oh yeah, sure. You can have a copy of the slides. Can I send them to you as a PDF? Is that okay?

Dr. Weitz:                          Sure, yeah.

Dr. Bredesen:                    I’ll send you a PDF of the slides.

Dr. Weitz:                          Okay. Great. Somebody asked that, Dr. Sherry Viensech said that she’s a certified ReCODE practitioner and she’d like to connect with other ReCODE practitioners. Do you have a Facebook page or something like that just for ReCODE practitioners?

Dr. Bredesen:                    Yeah, just go on the forums. We have the forums at Apollo Health. Just go on the forums, there are other practitioners there, so you’ll connect with them there.

Dr. Weitz:                          Somebody asked about book suggestions. Well Dr.Bredesen has three of them.

Dr. Bredesen:                    Someone asked for book suggestions? The first one was really about how we came to this conclusion. That was The End of Alzheimer’s and that’s in 33 languages. Then the second one we got, people said, we’d like more day-to-day specifics. Where do I buy the food? Where do I do this? Where do I go? And so I actually worked with the woman I mentioned earlier, who’s Julie G, and my wife, Dr. Aida Lasheen Bredesen. And they wrote a whole section of essentially a handbook. And this was called The End of Alzheimer’s Program. So now this was the program for that. That’s the second book. Came out in 2020. And then the third one is The First Survivors of Alzheimer’s. And these seven different people talk about their own stories.

                                                And then there’s going to be a book coming out by Dr. Heather Sanderson. And by the way, she just did a trial, which came to very similar conclusions, used the same approach. She was one of the first trainees when we first started training people back in 2016. And so she’s now done a trial, as I said, reached very similar conclusions. She did take people all the way down to MoCAs of 12. Although to be fair, what she found was the ones below 16 didn’t do as well as the ones above 16. So that’s something we really need to work on to understand how do we do better for people who are in those later stages. And hers is also freely available online also in the Journal of Alzheimer’s Disease, as you’ll see.

Dr. Weitz:                            And check my podcast, last week I had a wonderful interview with her.

Dr. Bredesen:                    Great, great. I should also mention Marama. So she opened an assisted living facility in San Diego and it’s been fantastic, because people in the assisted living facility for the first time, they’re not getting worse. Some of them are getting better, some of them are very stable, but nobody’s getting worse, and it’s really striking. That’s just unheard of in assisted living.

Dr. Weitz:                          I don’t know if you might want to comment on this, but I just got an email a couple of days ago from a group called the Alzheimer’s Centers of America, and it’s run by a guy who ran Pizza Hutt.

Dr. Bredesen:                    I know the group well.

Dr. Weitz:                          It looks to me like this is part of what I have seen is I think a poor trend or dangerous trend, which is financial firms buying or starting medical centers with the wrong incentives in place, and it looked very much like that sort of place.

Dr. Bredesen:                    You know what, this comes up a lot. People say, I’ve got something that’s really great. Okay, show us your peer-reviewed published data and all these business things just shrink right back. And they say, well, we’re going to publish it someday. We’re going to do this. When you do it, please contact us.

Dr. Weitz:                            Okay, great. Sarah asked, how do we get the testing? Sarah, are you talking about getting it for you or are you talking about for your patients? Are you there, Sarah?

Sarah:                                 Yes, I am. For myself, yes, and also for my patients.

Dr. Bredesen:                    Easy. So just go to mycognoscopy.com and you can actually do this over the internet and you don’t even have to go to a specific physician. You can get a report. And again, happy to go over the report with anyone. But that also shows you where the trained ReCODE practitioners are. So you can see that. The health, the coach network, all that stuff is online. And by the way, one of the most valuable things I think is over a hundred guides that have been written, again by Julie and my wife. Really, really helpful to look at what are the things that actually work the best. So those are also available online through Apollo Health.

Sarah:                                   Wow, thank you so much. And also had another question. Do lesions and or ischemic changes on an MRI represent potential for future AD, Alzheimer’s?

Dr. Bredesen:                    That’s a really good point. It depends on what kind of lesions, and this is again why I think all these things like the blood tests are going to be very complimentary. If you’ve got a couple of lesions, but your GFAP is normal, your phospho tau is normal. Your 42 to 40 ratio is normal. Your NFL is normal. These are probably inconsequential lesions as far as any cognitive change. If you’ve got lesions on the other hand and these things are starting to change, you’re moving the needle there, then there are things that you should address further. So as you know, you kind of alluded to there, these can be ischemic, these can be white matter changes, these can be autoimmune, these can be beginning of MS, there all sorts of different things that can be seen.

                                                And as you know, one of the most common findings on MRIs is so-called unidentified bright objects, UBOs, you see them on a lot of these MRIs. And we’re starting to understand better this white matter disease is often part of Alzheimer’s disease, often part of cognitive change. So great idea to know and to quantitate that. So you should have the radiologist give you a physica score, which is zero, one, two, three, or four, that tells you how significant the white matter lesions are.

Sarah:                                   So helpful. Thank you.

Dr. Weitz:                            Sherry, you want to jump on? You have a question here about Dr. Ray Dorsey, substantia nigra in Parkinson’s disease due to poor myelination of highly branched amino acids, juicy damage of the substantia nigra with the toxic type of Alzheimer’s.

Dr. Bredesen:                    Great point. I know Ray and I love his book, A Prescription for Action, which is all about ending Alzheimer’s. In fact, he told me that they wrote that book about ending Parkinson’s based on what I’d published on ending Alzheimer’s disease. So love that. I’d love to see less Parkinson’s. There are about a million Parkinson’s patients in the United States. There are about a million Lewy body patients in the United States. Of course with Lewy body, you have parts Alzheimer’s and part Parkinson’s, essentially. Typically you don’t see damage. But again, what we’re finding, what we’ve separated as, okay, this is Alzheimer’s and this is Parkinson’s. With the classic presentations, you don’t see damage to the substantia nigra in Alzheimer’s.

                                                You do see it in Parkinson’s. But here’s where things get a little bit tricky. It’s been shown now that when you look at alpha-synuclein, so this is Lewy bodies, which are the hallmark of Parkinson’s. You see Lewy bodies in over half of Alzheimer’s cases now. They’re not in the substantia nigra though, but they’re around the brain. So Lewy body disease, which essentially sits in between Alzheimer’s and Parkinson’s, is often a toxin driven type of cognitive decline. And in that case, you do see changes and you do see sometimes changes in the substantia nigra. So these things, it depends. And we’re starting to be able to look at these. You have to remember, all of these have been defined based on pathology.

                                                This all comes from the 19th century pathologists. People like Charcot who are saying, okay, this is what we’re going to call this diseases, we’re going to call that disease. Okay, great. But now we’re looking much more at metabolics, metabolic profiles, epigenetics, genomes. So we’re going to get I think, a reclassification of these diseases. And as you alluded to, what we see is that a toxic form of Alzheimer’s type three often looks more like Lewy body disease and a little bit less like classical Alzheimer’s disease.

Dr. Weitz:                            David Trader asked about Parkinson’s disease. I wanted to point out, we had Dr. Karen Duncan at our meeting several months ago, and you can see the recording on the YouTube channel or listen to it. And she’s talked about how she’s using a functional medicine similar approach for Parkinson’s disease with really good results.

Dr. Bredesen:                    Fantastic. I have to say, there’s nothing better than hearing about someone who has a neurodegenerative condition, which typically you’re told there’s nothing that can be done, and now they actually are getting better. It’s just so fantastic to see. Now, in the ARC project we’re looking at all neurodegenerative diseases, so that will include Parkinson’s. However, it wasn’t one of the early ones we approached for the simple reason that all the others have nothing to offer from classical medicine. So there is nothing to do, even for age-related macular degeneration, dry macular degeneration, it’s AREDS 2, which has virtually no impact on it. For Lewy body, nothing. For frontotemporal, nothing. For ALS, nothing. But for Parkinson’s, that’s the one where you actually have a pretty good pharmacological armamentarium.

                                                You can make people better. You don’t change the disease outcome, you still are losing your substantia nigrostriatal pathway, but you at least have some positive impact. And even things like glutathione can be very, very helpful. So that wasn’t one of the earlier ones that we did, because there’s an alternative, but we will include that with this new center that I mentioned earlier.

Dr. Weitz:                            Let’s see, Shadi, any idea of certain types of dementia like frontotemporal or primary progressive aphasia are more challenging to reverse?

Dr. Bredesen:                    I should mention this other part about how long did it take people in the study to see improvements? We saw statistically significant improvements within three months. We saw better improvements at six months and still better improvements for the ones who stayed on the program at nine months. And we’ve had people where even after two or three years, they’re continuing to get better, tweaking, tweaking, getting better and better outcomes. Now, as far as others, primary progressive aphasia, as you know, is interesting. That can be due to frontotemporal dementia or it can be due to Alzheimer’s and sometimes neither. But those are the two common ones. We definitely see improvements with PPA, primary progressive aphasia in Alzheimer’s, and with PCA in Alzheimer’s as I mentioned earlier, posterior cortical atrophy.

                                                With frontotemporal dementia we have very little outcome data yet. It’s much less common than Alzheimer’s disease. And so we just don’t have the data yet. My hope is as we study it further and as we understand better what’s actually driving the process, we’ll begin to see some improvements, but we just don’t have the data yet. So if it’s PPA associated with FTD, don’t know yet. If it’s PPA associated with Alzheimer’s, yes, we’ve seen some good improvements.

Dr. Weitz:                            David asked about a test from LabCorp. David, what test are you talking about?

Dr. Bredesen:                    Maybe Phospho Tau 181. That’s a new LabCorp test. One of the ones-

David:                                   Yeah, that’s the one that you mentioned.

Dr. Bredesen:                    Yes. And we’re using that on everybody now. And we are seeing what you’d expect. People where we thought it was probably not Alzheimer’s tend to be as low, I think the upper limit of normal in that particular test is 0.95. We see people up above two who clearly have an Alzheimer’s associated dementia. Now, what we’re really interested in seeing is that the reason that your tau gets phosphorylated, is because you are telling your tau, I want to pull back my neurites. I’m under stress, I’m under assault, so I am now going to phosphorylate my tau. The tau is what holds the microtubules steady. Basically it supports them. So just like if you want to tear down a part of your house and you’ve got all these rafters, you got to take off the bolts. And so when you phosphorylate the tau, it pops it off the microtubules, which can then collapse.

                                                So what you’re really seeing with that increase in tau, is you’re seeing your brain tell itself, pull back, pull back. Now what we’d like to see is as we treat people, it goes down. And interestingly, I just got an interesting email from a woman who did go on our program partway. Unfortunately she didn’t go on the whole thing a few years ago, and so she’s now looking to do more. But what happened was she had a high phospho tau, when she went back after being on the program it was much lower. We’d like to get it completely down to completely normal if we could, time will tell. So our current trial that we’re doing is looking at phospho tau throughout the trial to see whether we can bring that back down. It takes about six months to show some improvement. It doesn’t happen overnight. But you’re looking at that change in the brain signaling to tell you, is your brain signaling synaptoclastically or is it signaling synaptoblastically?

Dr. Weitz:                            David, what are you asking about phosphorylated tau from LC?

Dr. Bredesen:                    LabCorp, yeah, that’s the one. So they have Phospho Tau 181. I suspect they’ll come out with 217 at some point, but I don’t think it’s available yet.

David:                                   Okay, cool. I just want to know which lab test it was from LabCorp.

Dr. Bredesen:                    PTau181.

David:                                   Awesome. Thank you.

Dr. Weitz:                            And Karen wanted to know, have you had success helping to reverse tremors so that patient’s writing improves?

Dr. Bredesen:                    That’s interesting. With this corticobasal person recently, Craig Tanio has some wonderful results where one of the things that improved the alien hand that they have. Tremors in general, of course they are different. Are you talking about a sustention tremor, an intention tremor, or a Parkinsonian tremor?

Dr. Weitz:                          Karen, are you there? You want to unmute yourself?

Karen:                               Yeah, I am here. It’s an intention tremor, when they go to write, when go to eat, any purposeful movement.

Dr. Bredesen:                    Those are not typically part of Alzheimer’s disease. But yeah, there are multiple things you can use. People use everything from primidone to propranolol to clonazepam, to all sorts of things you can use for those sorts of tremors. You want to make sure it’s not a resting tremor obviously, because that’s associated with Parkinson’s disease. But those tremors tend to respond pretty well. It can be of course benign essential tremor. You can hear it in their speech typically. You can see it sometimes in their heads as well as their hands. And those tend to respond to simple pharmaceuticals like those.

Dr. Weitz:                          What peptides have you been using on patients? Have you?

Dr. Bredesen:                    Good point. And it just depends, again, on what we believe is driving the problem. But people have used thymosin alpha 1 and thymosin beta 4. Epitalon has turned out to be quite interesting. And so again, as you know, there are hundreds of these things. So it’s going to be what do you think is driving the problem? I’m interested, is Cerebrolysin going to be turning out to be something really good? One of the ones I’m most excited about failed in its trial, and that’s davunetide, which is an ADNP derivative. So ADNP activity derived activity dependent neurotrophic peptide is extremely potent in the brain, really helpful. And yet, I think because they used it as a monotherapy, it just didn’t move the needle. And so I’m hoping it’s going to make a comeback at some point because I think it could be very useful.

                                                And then of course there’s intranasal insulin. There’s also non peptide synapsin, which is another nice intranasal approach. Intranasal glutathione, there’s so much that can be done with intranasal treatments because you get such good brain penetration. I’m hoping at some point that someone will come out with a derivative of Netrin-1. We actually worked on that in the lab for a while and developed a little peptide that works like netrin, full length netrin, no penetration, just doesn’t work. It’s just too big. Does not get into the brain if you use it intranasally. Of course there’s intranasal insulin as well, but you have to be careful about insulin resistance. So those are just some of the many that people are using and I think are going to be very valuable.

Dr. Weitz:                            Lynn is raising her hand. Go ahead Lynn.

Lynn:                                     I was just interested, talking about central tremor and the tremors. What do you feel about deep brain stimulation?

Dr. Bredesen:                    I think for people who are literally incapacitated due to severe uncontrollable dystonia or tremors or hemiballismus or severe Parkinson’s, things like that, that’s where deep brain stimulation really works well. For people with Alzheimer’s, yes, there’s been a report. I don’t think you need to go there for most. I think there’s so many other things that are better that I wouldn’t go there unless everything else had failed in someone with cognitive decline. So far it’s better for movement disorder, severe uncontrollable movement disorders.

Dr. Weitz:                            What about some of the other forms of brain stimulation, like different colored lights and similar type approaches?

Dr. Bredesen:                    Absolutely. So one of the things, again, going back to this is about energetics and this is about inflammation. And one of the ways to do both. That you can reduce some of the inflammation with red light, for example, and you can enhance support. So absolutely, we have a whole section on brain stimulation, and it includes everything just from brain training, which was developed by Professor Mike Mesnick, has been very helpful. We use it in our trials to MeRT, Magnetic e-Resonance, which works very well. Transcranial magnetic stimulation, microcurrent, all of these things have their place and people are getting good results with them.

Dr. Weitz:                          Thank you so much for your time, Dr. Bredesen. This has been awesome.

Dr. Bredesen:                    Great to talk to you guys. And Ben, give you some followup. I’ll send you the slides and let me know if anything else comes up. Okay?

Dr. Weitz:                          Great. And we’ll see everybody next month. Thank you.

Dr. Bredesen:                    All right, take care guys. Bye-bye.



Dr. Weitz:                            Thank you for making it all the way through this episode of the Rational Wellness podcast. For those of you who enjoy listening to the Rational Wellness podcast, I would certainly appreciate it if you could go to Apple Podcasts or Spotify and give us a five star ratings and review. That way more people will discover the Rational Wellness podcast. And I wanted to let everybody know that I do have some openings for new patients so I can see you for a functional medicine consultation for specific health issues like gut problems, autoimmune diseases, cardiometabolic conditions, or for an executive health screen and to help you promote longevity and take a deeper dive into some of those factors that can lead to chronic diseases along the way.  That usually means we’re going to do some more detailed lab work, stool testing, sometimes urine testing. And we’re going to look at a lot more details to get a better picture of your overall health from a preventative functional medicine perspective. So if you’re interested, please call my Santa Monica Weitz Sports Chiropractic and Nutrition office at (310) 395-3111, and we can set you up for a new consultation for functional medicine. I’ll talk to everybody next week.


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