Reversal of Alzheimer’s Disease with Dr. Dale Bredesen: Rational Wellness Podcast 209

Dr. Dale Bredesen speaks about the Reversal of Alzheimer’s Disease with Dr. Ben Weitz at the Functional Medicine Discussion Group meeting on May 27, 2021.

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Podcast Highlights

12:10   Traditional medicine currently has nothing effective to offer for the treatment of Alzheimer’s Disease, but yet is not open to the model that Dr. Bredesen is showing can reverse the condition.  There are over 400 failed trials with drugs to treat Alzheimer’s Disease. Dr. Bredesen has spent 30 years and he has published over 220 papers in peer review journals figuring out the fundamental nature of the neurodegenerative process to be able to design an effective treatment approach. Dr. Bredesen’s challenge to the traditional neurological community is “Look, you line up the people that you’ve made better, I’ll line up the people that we’ve made better, and let’s take a look at the lines.”  Dr. Bredesen’s group of practitioners has seen hundreds and hundreds of people improved.  Dr. Bredesen has just published a clinical trial that demonstrates the effectiveness of his approach with 25 patients treated by three different doctors.

20:37  The single drug approach has repeatedly failed for Alzheimer’s Disease and when Donanemab, which is another antibody that removes amyloid, was approved eight weeks ago, it was hailed. Yet, it doesn’t reverse or even stop the progression of Alzheimer’s Disease, but merely slows the decline and Eli Lilly stock went up 20 billion dollars. The reason for this failure is that Alzheimer’s is not a simple illness like a viral infection.  Rather Alzheimer’s is a complex, chronic disease and such a simple approach is doomed to failure unless it is possibly combined with a systems approach.

21:13  There are a number of theories about what causes Alzheimer’s Disease, including the amyloid cascade theory, which has been the target of numerous failed pharmaceuticals, including Bapineuzumab, Crenezumab, Gantenerumab, and Aducanumab and the list goes on and on. Some people say that amyloid is not important, but rather it’s tau that is the problem.  But Dr. Bredesen explained that both amyloid and tau are both mediators of a downsizing of the brain and they are both physiological responses to various insults to brain health.  Here is the full list of theories of the cause of Alzheimer’s disease that Dr. Bredesen discussed: 1. Amyloid cascade, 2. Tau, 3. Prion, 4. Type 3 diabetes, 5. Chronic herpes simplex infection, 6. Gingipain produced by P. gingivalis, 7. mercury toxicity, 8. Metal binding by amyloid, 9. Reactive oxygen species, 10. APP amplification, 11. Cortical demyelination, 12. Vascular leak. 

24:55  The amyloid hypothesis says that you have too much amyloid but it doesn’t consider why and we know now that when you remove it, you don’t get better, and some patients get worse.  The amyloid is a protective response by the brain to infections and other insults.

25:17  The problem is that if you go to a conventional Alzheimer’s center, they’ll tell you that we don’t know what the cause is, and that we’re going to give you a monotherapy, whether it be Aricept or Namenda, and it will be ineffective, and you’re going to die. 

25:51  The research findings show something completely different.  They show that there are dozens of contributors to the cause of Alzheimer’s disease and these can be broken down into subtypes.  Some patients have more of an inflammatory type of Alzheimer’s, while others have more of an atrophic type.  So we personalize the program for each person and as we treat patients we continue to optimize all the factors that can contribute to cognitive decline.  Some patients will improve and then they’ll plateau and then we find another contributor to their condition and we address that and then they improve further.

26:31  The conditions that are associated with cognitive decline include the following:

            1. Alzheimer’s disease, the most common form.  BTW, the term mild cognitive impairment, MCI, is really the third of four stages of end-stage Alzheimer’s, so this is not an accurate term to use. It is like saying mildly metastatic cancer.

            2. Lewy Body Disease. The classic version of this involves visual hallucinations but otherwise looks a lot like Alzheimer’s.  They tend to sleep late and have periods where they are very good and very bad.  They are very sensitive to drugs and can die if you give them anti-psychotics.

            3. Parkinson’s.  There are about a million patients with Parkinson’s disease in the US and it is on the greatest rise now.

            4. Vascular dementia.

            5. Normal pressure hydrocephalus. These patients usually have urinary urgency. An MRI would show enlarged ventricles and no atrophy.  

            6. Frontotemporal dementia, which a cousin of ALS.  They both involve a protein called TDP-43.

            7. LATE. Limbic-predominant age-associated TDP-43 encephalopathy.  If you have someone with a slowly progressive Alzhemier’s that didn’t start till they are over 80, esp. if they have a negative amyloid scan.

            8. Multiple Sclerosis. Patients with MS have cortical shrinkage of about a few percent per year. Dr. Terry Wahl’s protocol addresses the key points for MS.

            9. PSP. Progressive supranuclear palsy.  You can diagnose these patients by asking them to look up and then look down. They have trouble with vertical gaze.

            10. Corticobasal degeneration. This is another Parkisonian-like presentation and these patients have something called alien hand.

            11. CTE, which is chronic traumatic encephalopathy.  These patients often have the triad of depression, aggression, and dementia.

            12. TBI. Traumatic brain injury.

            13. Post-COVID-19 related encephalopathy?   Many patients report brain fog and other cognitive issues after COVID.  One feature of COVID-19-related encephalopathy is that you have multiple small vessel occlusions and there is an autoimmune aspect where patients are reacting to the virus and viral antigens.  There are some interesting parallels between Alzheimer’s and COVID-19, including that you have a mismatch between the innate immune system, which is activated, and the adaptive system, which is not able to clear the pathogens.  The adaptive immune system is supposed to take over at a certain point, but is unable to do that.  Patients with COVID-19 may have a cytokine storm and can die from it acutely, whereas patients with Alzheimer’s have a cytokine drizzle that goes on for years.

            14. CJD. Creutzfeldt-Jakob disease, which is a prion disease.  These patients tend to progress much more rapidly with patients getting worse week to week instead of over  months or years.

            15.  Subdural Hematoma.  This can be ruled out with mri.


35:46  The Stages of Alzheimer’s Disease.  There’s a pre-symptomatic stage that can progress for years and you have no symptoms but you have the pathophysiology going on. Then you progress to SCI Subjective Cognitive Impairment, which is when you have symptoms but the tests are not showing anything wrong and on average this stage lasts 10 years.  The next stage is MCI Mild Cognitive Impairment, which is when neuropsych testing is now abnormal and this tends to progress at about 10% per year.  


37:22  Dr. Bredesen’s Sub-types of Alzheimer’s Disease:

            1. Type one Inflammatory. 

            2. Type two Atrophic. 

            1.5 Type 1.5 Glycotoxic or sweet type. 

            3. Type three is Toxic.

            4. Type four is Vascular. 

            5. Type five is Traumatic.                                            

The biggest thing to note is someone presenting with an amnestic syndrome where the biggest problem, and the first problem, is really about learning new information. That’s classical Alzheimer’s and that’s typically not type three. Type three is often a little different, but that’s classical Alzheimer’s.  It’s more APOE4 positive Alzheimer’s, and it represents about two-thirds of Alzheimer’s.  You typically see a reduction in glucose utilization in the temporal region of the brain if you look at a PET scan.  But about a third of people will come in with non-amnestic presentations and they will have problems with executive function and may have primary progressive aphasia.  PCA, which is posterior cortical atrophy. So these are the people that have trouble with recognition of faces and objects.  Prosopagnosia, problems recognizing faces, executive dysfunction, dyscalculia, apraxias, agnosias, depression.  These patients will typically have a reduction of glucose utilization in the parietal region of the brain on PET scan.

39:18  Beware the patients that present with depression because they often are the ones that have exposure to toxins and these are often type three.

39:30  When we look at the molecular biology of Alzheimer’s disease, Dr. Bredesen has discovered that the neurofibrillary tangles and the senile plaques and the brain atrophy are all a result of environmental factors that promote synaptoclastic activity over synaptoblastic activity in the brain.  This results from how these things affect APP (Amyloid Precursor Protein), which sticks out of a cell and is the molecular switch that controls Alzheimer’s disease that senses whether we are in a brain growth mode or a brain shrinkage mode and this affects the way that this APP switch works. For example, estradiol binds to its receptor and enters the nucleus and turns on a bunch of genes.  Estradiol, which is a good thing, cleaves APP at one site, which leads to two peptides that are growth and maintenance. But if you have Herpese Simplex virus, which is a bad thing, or pathogens from your mouth, or Lyme disease, or leaky gut, or not getting enough sleep, or having too much stress, then APP recognizes those things and you cleave APP at three sites–at the beta, the gamma, and the caspase site and these peptides all stimulate brain shrinkage and protection mode.  Amyloid protein is being laid down to protect your brain from all these insults. Our job is to flip the switch and put your brain back into growth and synatoblastic mode and out of the shrinkage and synaptoclastic mode. The fundamental nature of Alzheimer’s is a network insufficiency of the subsystem of the brain that controls neuroplasticity.  If you have a network insufficiency of the brain that controls the stabilization of motor movements, you get Parkinson’s disease.

42:52  We know that most chronic diseases are signaling imbalances. Take osteoporosis, where you have osteoclastic activity outweighing osteoblastic activity.  With cancer you have cytoblastic activity of cancer cells outstripping the cytoclastic activity of the immune system.  With Alzheimer’s, anything that causes inflammation, whether it be leaky gut, poor oral health, chronic sinusitis, metabolic syndrome, toxins, mercury, air pollution, organics like formaldehyde, toluene, benzene, or glyphosate or biotoxins like trichothecenes or ochratoxin A.  When we talk about having too little energetics there are four major contributors: blood flow, oxygenation, mitochondrial function, and ketones, as well as sleep.  When it comes to trophic support we have growth factors like NGF and BDNF, hormones like thyroid, estradiol, testosterone, pregnenolone, and progesterone and nutrients like vitamin D and omega 3 fats.

47:47  APOE4 is the most common genetic risk factor and about 1/4 of the population has at least one copy and this confers a 30% increased lifetime risk of Alzheimer’s disease.  If you have two copies of APOE4, you have a lifetime risk of more than 50%.  Dr. Bredesen’s research shows that a critical part of your ApoE enters the nucleus and binds to 1700 different gene promoters and if you group these, they tell a story for Alzheimer’s disease.  So ApoE4 promotes inflammation and its involved with disassembling your microtubules and synapse dysfunction.  When we treat patients with Alzeimer’s, we want to resolve their inflammation. We want to know their energetic status. We want to identify if they have insulin resistance and get them sensitive again.  We want to know the status of their trophic support. We want to treat pathogens and if they have toxins to detoxify them.  It helps to provide them with some mild stimulation like infrared light or other forms. We want to improve the adaptive immune system and reduce the innate system.  After we have done the things above, then we want to remove the amyloid, but removing the amyloid at the beginning is a bad idea because it’s protecting you. And then ultimately, we want to use things like stem cells and trophic factors to promote regeneration. 

57:27  Dr. Bredesen and his group just completed a proof of concept trial with 25 patients with MCI or early dementia with MoCA scores of 19 or above to prove that his Functional Medicine approach to Alzheimer’s Disease is effective and the first paper was published on a preprint.  Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial.  Kat ToupsAnn HathawayDeborah GordonHenrianna ChungCyrus RajiAlan BoydBenjamin D. HillSharon Hausman-CohenMouna AttarhaWon Jong ChwaMichael JarrettDale E. Bredesen.  A larger randomized clinical trial is now planned.  This trial looked at MoCA scores at the beginning, at three, six, and nine months, as well at CNS vital signs, at AQ-21, which from the patient’s partner looking at how many complaints they have, and they also did MRI with volume metrics at the beginning and at nine months and the results were striking.  They tried to achieve insulin sensitivity, mild ketosis, healing the gut, treatment of identified pathogens, detox for those who needed it, reduction of inflammation, optimization of hormones, nutrients, and trophic factors, vascular status, some degree of brain stimulation, optimization of SpO2, and then stress management, and improved heart rate variability.  76% of patients significantly improved their MoCA scores and 84% improved their Neurocognitive Index score.  Brain training scores improved in all 25 subjects.  They would have had even better results if the pandemic had not have happened during their trial.  They saw the grey matter volume of their brain went up and the hippocampal volume decline normally seen in Alzheimer’s patients improved. It is typical for someone with Alzheimer’s hippocampal volume to decline about 2.5-3.5% per year, whereas a normal individual sees a decline of about 1.7% per year, while these patients only declined by 1.29%.  So for these patients with MCI or early dementia, cognitive decline was reversed, which has never been shown in any drug trial! 

59:24  Compare Dr. Bredesen’s approach, which actually makes people better, with the announcement of this new drug for Alzhemimer’s, Aducanumab, which was just approved by the FDA and is considered the big success in drugs that are antibodies to amyloid, which did not make people better but merely slowed the decline by about 1/3.  The day this was announced the value of this company increased by $20 billion in one day. 

1:03:15  Dr. Bredesen believes that they may be able to modify this Functional Medicine approach for other neurodegenerative diseases, including Lewy body disease, Parkinson’s, Frontotemporal dementia, for ALS, for macular degeneration, etc..

1:05:07  While some anti-aging biohackers recommend taking rapamycin to inhibit mTor, which can be beneficial in promoting health, and improving biological aging and brain function, Dr. Bredesen recommends intermittent fasting and a ketogenic diet to inhibit mTor rather than taking a potentially toxic drug like rapamycin.

1:08:00  Strategies to increase oxygen to the brain, like hyperbaric oxygen, can be helpful for promoting brain healing.  Dr. Bredesen believes that hyperbaric oxygen seems to be helpful, esp. for patients who have vascular disease or head trauma as one of their contributors. He is not sure that it will help as much with patients who have glycotoxicity or just inflammation. He prefers EWOT, which is exercise with oxygen therapy to hyperbaric where you just lay in a tank. 

1:09:41  The diet that seems to work best is the KetoFLEX 12/3 that seems to drives the biochemistry towards synaptogenesis and synaptic maintenance.  The diet is very plant rich with lots of phytonutrients and fiber with fish and pastured chicken and grass fed beef and 12 to 16 hours of intermittent fasting.  You want to become insulin sensitive and get into ketosis.  If you have severe vascular disease, you might want to go vegan.

1:11:20  Statin drugs are often prescribed for patients with vascular issues and high cholesterol, but they can be problematic for brain health. They do lower inflammation, but cholesterol is important for neuronal formation and brain health and there are better ways to reduce inflammation. If you have inflammation, let’s correct the underlying cause of the inflammation, such as leaky gut or gut dysbiosis or issues with oral health.

1:14:36  Red or infrared light therapy with a frequency around 40 Hz seems to be helpful to stimulate brain healing as is 40 Hz sound.  There is Vielight and there’s magnetic stimulation or MeRT. These ways to stimulate the brain will not likely be effective until you have fixed all the issues that were keeping your brain from working well and now this type of therapy can help to stimulate neurons to fire and push your brain to heal.

1:17:56  ProLon, Dr. Valter Longo’s Fasting Mimicking Diet 5 day program, can be used to get patients to start to feel what a ketogenic diet is like, though it may not work if the patient is very thin and frail.  In such cases, you want to cycle such patients in and out of ketosis and give them a rest day, say once a week. Alzheimer’s is a disease of insufficiency, though we often get there by excess.  Patients who are very thin don’t have a lot of glucose around and may have trouble generating ketones.  We have to have that fasting period without getting them further into insufficiency.

1:21:52  Peptides like Cerbrolysin, Thymosin alpha one and beta four can be helpful when used at the appropriate time.  Intra-nasal administration may be helpful in getting them into the brain. There are also peptide fragments of nerve growth factor and BDNF.  Like pharmaceuticals, once you address all the things causing the problem, then they can be used to help the brain to regenerate, but not before.  Dr. Bredesen also believes that stem cells can be helpful, once you have corrected all the things that have been making the brain worse. If you simply apply peptides or stem cells or medications as a monotherapy, it is like trying to rebuild a house as it’s burning down. You’ve got to put out the fire first and then the conditions will be ripe for rebuilding.


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’s, and The End of Alzheimer’s Program, as well as the soon to be published, 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 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 Doctor 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. To learn more, check out my website, drweitz.com. Thanks for joining me, and let’s jump into the podcast.

                                                Welcome everyone, and thank you for joining our Functional Medicine discussion group meeting. I’m Doctor Ben Weitz, and our topic for tonight is the Prevention and Reversal of Alzheimer’s disease with our special guest Doctor Dale Bredesen. I’ll start by making some introductory remarks, including introducing the topic.

                                                The topic for tonight is Alzheimer’s disease. As most of you know, it’s a degenerative brain disease, and it accounts for between 60 and 80 percent of cases of dementia. Patients with Alzheimer’s disease develop difficulties with memory, language, problem solving, other cognitive skills that can affect a person’s ability to perform everyday tasks. The hallmark pathologies of Alzheimer’s are the progressive accumulation of beta amyloid protein in the brain that forms plaques outside neurons in the brain, and twisted strands known as tangles of tau protein inside of neurons. There are an estimated 5.7 million Americans living with Alzheimer’s disease as of 2018. Obviously, it’s higher now because it’s rapidly increasing, especially as the population of Americans 65 and older is projected to grow from 53 million in 2018 to 88 million by 2050.  According to one estimate, Alzheimer’s disease is the third leading cause of death in the U.S., according to the Alzheimer’s Association. According to the Alzheimer’s Association website, and this is a quote, “While there is no cure for Alzheimer’s disease, or a way to stop or slow its progression, there are drugs or non drug options that may help treat symptoms.” Our goal for this evening will be to prove that the Alzheimer’s Association is wrong. Now, I’d like to invite Heather Ngo [now Heather Sunshine] from Cyrex Labs, which is one of our sponsors for this evening, to give us some information about Cyrex Labs. Heather, are you here?

Heather Sunshine:         I am here. Thank you so much, Doctor Weitz. Hello, everyone. My name is Heather Sunshine, Territory Manager of Cyrex Labs. Our lab is based in Phoenix, Arizona, and our niche is environmentally induced autoimmunity. We are CLEA certified, and our innovative test provides advanced clinical tools to identify and measure immune and possible autoimmune reactivity. We have essential barrier testing evaluating the intestinal and blood brain barrier integrity. We have predictive antibody testing, identifying markers and possible precursors of autoimmune disorders. Environmental triggers, identifying reactivity to environmental triggers, which include dietary proteins, chemicals and heavy metals. We also have a mucosal immune saliva test.

                                                What I would like to share with you today, since it’s relatable to Doctor Dale Bredesen’s presentation, is our Alzheimer’s Linx panel. Alzheimer’s disease, cognitive decline, dementia, whatever name we use, the diagnosis is a heavy one. It comes with enormous financial and family burden, so ideally, you want to avoid this disorder. Environmental factors are far more influential than genes, and it if plays the larger role in Alzheimer’s disease, we have the opportunity to prevent it. We change our environment. We avoid certain foods, chemicals. We reduce stress. We make our bodies inhospitable to pathogens. We learn a new language, take dance classes, play brain games to regenerate neuronal tissues. We can protect our blood brain barriers. All of this means we are reducing inflammation. The sub clinical signs of inflammation, antibody production against triggers and tissues, can be found up to 20 years before the onset of disease. Therefore, in the more common form of environmentally induced Alzheimer’s disease, the late onset, people should be tested as early as age 40.

                                                Here’s how Cyrex is going beyond tau amyloid beta. We assess proteins, growth factors, pathogens, chemicals, enteric nervous system, enzymes, neuro peptides and foods. Alzheimer’s links can be used to identify targeted tissues, triggers and blood brain barrier integrity during the early onstage of Alzheimer’s disease when recovery is possible. Test at the first sign, especially if the patient has family history. We do have a video of Doctor Dale Bredesen with our brilliant Chief Scientist Advisor, Doctor Aristo Vojdani, along with his brilliant son, Doctor Elroy Vojdani. You can view this video on joincyrex.com. It’s under our media section. If you would like to schedule a one on one education, or have any questions, if you want me to send you a catalog of services, we do have some new bundling prices and specials, or if you just want me to send the link to the video, please email me at heather.s@cyrexlabs.com. Thank you so much, Doctor Weitz, for the opportunity to discuss Cyrex and providing us an insightful forum, as always. We are excited to listen to Doctor Dale Bredesen’s presentation tonight.



Dr. Weitz:                            Thank you, Heather. Now, my friend Steve Snyder from Integrative Therapeutics. Steve, you have the floor to tell us about Integrative Therapeutics professional line of supplements.

Steve Snyder:              That was really good. I don’t think I can do that well. One of the things I wanted to mention, Doctor Bredesen, was … By the way, I’m Steve from Integrative Therapeutics. Most of you know me already. I’m the L.A. rep for Integrative. Doctor Bredesen mentioned Gary Small over at UCLA. They actually did a nice study on our theracurmin, the high bioavailable curcumin, showing improved memory and decreased amyloid tangles and tau proteins. It wasn’t Alzheimer’s patients, it was age associated memory decline, but some pretty interesting outcomes, and they’re continuing to look at that. I don’t know where that fits into your protocols, but it was a really good study for that particular product for us.

                                                Then the other thing that I was just going to mention really quickly, some of you saw this on the Facebook page. There has been a lot of chatter about there about NAC, or nac, being banned. I just wanted to let people know that’s not what’s happening. The FDA sent out some warning letters last year, basically trying to say that NAC shouldn’t be considered a supplement because it was originally researched as a drug back in the early 60s. It’s not a policy change, it’s not anything out of legal change, they’re just sending out these letters. The Council for Responsible Nutrition is pushing back on it pretty hard. There’s a great letter you can Google that talks about it. It’s also on Doctor Weitz’s Facebook page.

                                                The reason people are getting excited is because Amazon pulled NAC containing products, and Whole Foods Market will probably follow that because they’re owned by Amazon. We’re not sure why they’re doing that, but we are not discontinuing any NAC containing products. We don’t think it’s going to end up coming to that. It’s business as usual. Right now Full Script has over 1500 bottles of our product. We have about 8000 bottles of our product, so it’s not in short supply. If you need it, you can get it.

                                                The other thing is, if it ever does come to that, Integrative Therapeutics will still be able to make it because we are a drug manufacturing facility even though we don’t make drugs. Not every supplement company is that, and that will affect some people, but it won’t affect us. We will continue to make NAC. We have a stand alone NAC that’s 600 milligram per cap. It’s under 20 dollars retail for 60 caps. It’s a great option. Don’t panic. Don’t believe what you’re reading, it’s not getting banned. If you have any questions you can reach me at steve.schneider@integrativepro.com. Thanks.

Dr. Weitz:                    Thanks, Steve.

Steve Snyder:              Yeah.



Dr. Weitz:                            Our speaker for tonight, who really needs no introduction, is Dr. Dale Bredesen. Dr. Bredesen is an internationally recognized expert in the mechanisms of neuro degenerative diseases like Alzheimer’s disease. He’s the author of the best selling books, The End of Alzheimer’s and The End of Alzheimer’s Program, as well as the soon to be published, the first Survivors of Alzheimer’s.  Also wanted to let everyone know that Dr. Bredesen, Dr. Kat Toups, and associates, have just published a paper documenting their trial with 25 patients showing the effectiveness of his protocol for Alzheimer’s disease. The paper is entitled “Precision Medicine Approach to Alzheimer’s Disease, Successful Proof of Concept Trial”. Doctor Toups posted it on the Facebook page, so you can get a full copy of it there.

                                                I’d like to tell you one more quick anecdotal story. I’ve been organizing these Functional Medicine meetings for about five years, and about four years ago I decided I wanted to discuss Alzheimer’s disease. I tried to get in touch with Doctor Bredesen because I had heard him a few years earlier on Doctor Bland’s Functional Medicine Update audio show, to see if he could join us. I was not successful, so I sent out a copy of Doctor Bredesen’s 2014 paper to our members to use as a basis for our discussion. Then I contacted the UCLA Alzheimer’s program that Doctor Bredesen was associated with to see if perhaps another neurologist might want to join us. When I called, the woman who is the administrator of the program said that she would ask around the neurologists there, but she let me know right up front that they don’t agree with anything that Doctor Bredesen talks about.

                                          Doctor Bredesen, thank you so much for joining us tonight.

Dr. Bredesen:                    Okay. Thanks for the invitation here. Let me go ahead and share my screen here. Okay, there we go, share that. Can everyone see that okay, hopefully? Okay, there we go. It is interesting to me, having trained as a neurologist, and very classically training, Cal Tech and MIT, and Duke, and Harvard, and all this, where we have nothing. Classical medicine has nothing to offer Alzheimer’s disease, and as you indicated earlier, the Alzheimer’s Association is basically saying, “There is nothing to offer, but maybe we can have a symptomatic effect.”   As I’ll show you today, that is completely wrong, and in fact, we need to be looking at what actually moves the needle. We’ve spent 30 years, we’ve published over 220 papers in peer review journals, and the whole point of the laboratory research was to understand the fundamental nature of the neuro degenerative process well enough that we can begin to fashion the first effective treatments. As you know, this has been the area of greatest biomedical therapeutic failure. As they say, “Everyone knows a cancer survivor, no one knows an Alzheimer’s survivor.” There are some interesting parallels with what’s happened with Covid-19, as well, and we’ll get into that.   The bottom line is, it continues to amaze me that people who have absolutely nothing to offer are complaining when there’s something to offer. When people say this sort of stuff to me, I always say the same thing, “Look, you line up the people that you’ve made better, I’ll line up the people that we’ve made better, and let’s take a look at the lines.” We’ve had hundreds and hundreds and hundreds of people improved. As you’ll see from the trial, very exciting results with the trial.

                                                This is essentially a pandemic without a vaccine. Just for some perspective, and let me just minimize this here so I can see all the slides a little better. Covid-19 has killed now, we just passed 600,000 people in the United States. Alzheimer’s will lead to the death of nearly a hundred times that many. If you look at all the currently living Americans, about 45 million will die. As Ben mentioned earlier, about 5.7 million are already recognized. Of course, younger people, we don’t know. We have two daughters who are 29 and 31, we don’t know if they’re going to get it or not. If you take everyone who’s currently living, statistically, about 45 million will die of Alzheimer’s. This is a huge, huge pandemic.

                                                The problem is a fundamental one, and we don’t hear enough about this. We’re always told, “Well, it’s something about the plaques and the tangles, and we’re trying to figure that out, and maybe the next drug is going to work.”, and of course, there are over 400 failed trials per drugs. The fundamental problem is not talked about enough. The fundamental problem is, for example, Covid-19 is a simple disease, we know what causes it. We even have sequence from the virus. We have sequence from the mutants. All these things, we know what to do for prevention. We have vaccines developed, some people like them, some people don’t. At least we understand the disease itself. That is not the case for Alzheimer’s. It is a chronic, complex disease of unknown etiology. People keep on, as I’ll show you, they keep on thinking it’s going to be one thing, “We’re going to figure out what causes it, and boom, we’ll be able to do something about it.” That’s not the way this disease works, and it’s important for us to understand that.

                                                No surprise, billions of dollars, over 400 failed clinical trials. We really need to take a completely different look. What I ask you to do today is, forget what you know, forget what you’ve heard about Alzheimer’s for just a few minutes, and we’re going to look at this from the ground up, and look at what actually this disease represents, which is what our research had been all about. We want to develop a model that is consistent with all the papers published. There are over a 150 thousand published papers about Alzheimer’s. None of them has led to any successful treatments. We want to reconsider this, and look at what we can do. Can we develop a model that is predictive, that tells us what’s going to work, and tells us what’s not going to work? That would be such a helpful model. As you may have heard, if you look at something like Aducanumab where there’s been very little help trying to get rid of amyloids. If you could simply have a model that would tell you what’s going to work and what’s not going to work it would be exceedingly valuable.

                                                The day that Donanemab, which is another antibody that removes amyloid, it just came out about eight weeks ago. What they showed was, it doesn’t make people better. It doesn’t stabilize people, but it slows the decline. In the trial it slowed the decline by about one third. The day that came out, the stock in its company, Eli Lilly, went up by 20 billion dollars in total company value. To be able to say, “We understand this disease. We know what’s going to work. We know what’s not going to work, and we know when to use it.”, would be a very, very important thing. Let’s talk about that.

                                                I think everybody here, anyone who’s interested in functional medicine, and I have to say I really appreciate Jeffery Bland’s contributions over the years to this whole idea, everyone understand that there’s a fundamental difference between simple illnesses and complex chronic illnesses. Here’s simple illness, which we all dealt with in medical school. You got someone with pneumococcal pneumonia? Yes. If they’ve got alcohol onboard they’re at increased risk. If they have diabetes melitis they’re at increased risk. If they have abnormal B cells, for example, people with multiple myeloma do poorly with pneumococcal pneumonia. There are lots and lots of other contributors. We, as physicians, have gotten away, over the years, with because of the fact that the pneumococcus itself is so much more important than any of these other variables, we’ve gotten away with writing prescriptions for penicillin, amoxicillin, cephalosporins, what have you. That’s been good enough, even though it doesn’t address all the contributors.

                                                That’s great for a simple illness. However, here’s the problem, in the 21st Century we are virtually all dying of complex chronic illnesses. Alzheimer’s, and cancer, and cardiovascular disease, and Lewy Body and Parkinson’s, all these sorts of things. Therefore, when you look at those, they are fundamentally different than these simple illnesses. Let’s look at Alzheimer’s for a minute. Insulin resistance is one critical risk factor. Various pathogens, everything from Borrelia to Bartonella and Babesia, to Herpes Simplex from the lip, to P. gingivalis from the oral microbiome, these are all things identified by the neuro pathologists in the brains of Alzheimer’s disease patients. These are critical. NfkB, which is simply activated in your cell when there is ongoing inflammation, turns out to be important, and I’ll show you why.

                                                Mercury, inorganic and organic mercury, turns out to be important in your risk. Various micro toxins turn out to be important. Various organic toxins, high homocysteine, poor methylation, and we could go on and on. There are dozens and dozens of contributors. The good news is, it appears there are not thousands. There are dozens and dozens, somewhere probably fewer than 100, but it’s not one or two. As you can see here, the big difference between pneumococcal pneumonia and Alzheimer’s disease is that there is no one of these that outstrips the others the way the pneumococcus did for pneumococcal pneumonia. Therefore, we can’t simply write a prescription that says, “Here’s a prescription to treat your homocysteine.” It’s not that simple. Therefore, we need to flip the script. We need to look at all the different contributors in each person, and then address those with a systems medicine, or precision medicine, approach.

                                                Therefore, no surprise, you can go at trial, after trial, after trial that has failed. As an example, here in the middle, Semagacestat. That was from Eli Lilly. They spent over 500 million dollars developing Semagacestat.  Not only did it not help, it actually made the disease worse.  Donanemab, here you can see, they didn’t believe it when it failed the first time. They did another trial, this time with Aricept, it failed again. There’s something fundamentally wrong about the way we’re going about this, when you’re seeing such failure time, after time, after time.

                                                Here are theories of Alzheimer’s, and there are others. These are many of them, but not all of them. There are ones, bottom line is, none of them has led to an effective treatment for Alzheimer’s. What the heck is wrong? We have to understand that. The dominant theory over the last 25 years has been the amyloid cascade theory. That came about basically for two reasons. There are people who have mutations in the amyloid precursor protein, and they develop familial Alzheimer’s. That’s rare, fewer than one in a thousand has the APP mutation that is associated. There are several of the mutations that are associated with this. It’s literally, it’s about just over 100 families worldwide, so it’s not a common cause. The idea was, “Okay, this amyloid is bad stuff, and we’re going to get rid of the amyloid, and you’re going to be all better.” Then, this has been tried time and time again with various pharmaceuticals. Bapineuzumab, Crenezumab, Gantenerumab, Aducanumab, Donanemab, the list goes on and on and on. Nothing. They have not had success.

                                                Tau, and other people just say, “Okay, amyloid is not important, but tau is important.” Well, yes. They’re both mediators of what I’ll show you is happening that is a mediator of a downsizing of the brain. It’s actually a physiological response to various insults. Then, of course, prions, and actually, my mentor, Professor Stan Prusiner, discovered prions and was awarded the Nobel Prize in 1997 for his discovery of prions. Again, these are mediators of the disease, but in general are not getting this because they’re catching prions. We believe that this is actually part of the downstream signaling. Type three diabetes, we hear that term all the time, and there’s no question, most… Type three diabetes, we hear that term all the time. And there’s no question most of the people with Alzheimer’s do have insulin resistance. But you don’t have to have that to get Alzheimer’s and you don’t have to have diabetes to get Alzheimer’s. You don’t have to have Alzheimer’s to get diabetes. So, the bottom line is it’s neither necessary nor sufficient. But yes, it’s an important overall player.

                                                Chronic herpes simplex, nice studies out of Taiwan, showing that people who actually treated their chronic, their recurrent herpes simplex oral, labial here, they actually had a reduced risk for Alzheimer’s.

                                                Gingipain. So there’s a whole company that is arranged around the idea that we’ve got these P gingivalis, which are associated with poor oral health. So they get into the brain and they’re producing a protease called gingipain. And that’s what’s doing the damage. Likely that’s part of it, unlikely that that’s the whole story.

                                                Mercury toxicity. Again, treating mercury has turned out to be helpful for a number of people. Metal binding by amyloid. This goes on and on. Reactive oxygen species, APP amplification. That’s some nice work out of UC San Diego. Cortical demyelination, vascular leak. It just goes on and on. None of these has led to a successful treatment for Alzheimer’s, and that’s really ultimately the asset test.

Dr. Weitz:                          Doc

Dr. Bredesen:                    So here’s the problem. Sorry, Ben. What’s that?

Dr. Weitz:                          Yeah. Can I just make a comment about the amyloid?

Dr. Bredesen:                    Sure.

Dr. Weitz:                          I think the amyloid, nobody’s asking, why is there amyloid there in the first place?  And you just mentioned the amyloid binding to the metal. And we’ve learned that amyloid is a way to protect the brain against infections and inflammation. And that’s really the key, is asking the additional question, what’s the root cause?  Why is the amyloid there in the first place?

Dr. Bredesen:                    Yep, absolutely. I think it’s critical to understand that. And the amyloid hypothesis just says you have too much amyloid for some reason, and that’s why you get Alzheimer’s, and it really doesn’t give you any insight. And we know now, if you remove that, you don’t get better. And in fact, what we found a number of people actually get worse when they remove the amyloid. Because again, as you said, it is a protective response to these various insults.   So here’s the problem. If you go to an Alzheimer’s center or an Alzheimer’s center of quote “excellence” today, what they’ll tell you is that there’s a cause, we don’t know what it is. There’s some cause that’s unknown. This is a disease called Alzheimer’s. There is a treatment. It’s a monotherapy, Aricept or Namenda, you can also use Exelon. It’s the same idea. It’s one phase. We’re going to give you the same thing each time. We’re going to stick with it and it’s going to be ineffective and you’re going to die.  And it’s just a horrible, horrible state of affairs. I have to say, it’s pretty barbaric right now.

                                           The research findings on the other hand, show us something completely different. What they say is there are dozens of contributors. As I mentioned earlier, we initially identified 36. There are a few more, low forties, but it’s not thousands. Therefore, no surprise, there are subtypes. You see people who have more of an inflammatory type of Alzheimer’s, people who have more of an atrophic type, and we’ll get into the subtypes in just a minute. And therefore, no surprise, there are many personalized programs and you’ve got to keep optimizing for the person.   We have people who will improve and then they’ll plateau and then find another contributor. And then we address that, they improve still further. This happens all the time. So some of the causes. When you do see people with cognitive decline. And since I assume that most people here are seeing some people with cognitive decline, let’s talk for a minute about what causes cognitive decline. As Ben said earlier, the majority, the most common Alzheimer’s disease. And let me just take a moment. This idea about mild cognitive impairment, this is the third of four stages to end-stage Alzheimer’s. So we really need to find new nomenclature for this idea of mild cognitive impairment.

                                                This is just like saying mildly metastatic cancer. Yeah. Okay. Well it’s already metastatic cancer. That’s a very late stage of cancer. And it’s the same thing with Alzheimer’s. MCI is a late stage of the problem. You go about 10 years of SCI before you ever get to MCI. Now Lewy body disease, about a million people in the country. Parkinson’s also about a million people in the United States, and actually Parkinson’s is the disease in neurological degenerative diseases that is on the greatest rise right now.   It seems to be linked to various toxins. So these things are critical. Lewy body, of course, the classic is people with visual hallucinations. Otherwise, it looks a lot like Alzheimer’s in many respects, they have a few other features. They tend to sleep late. They tend to have something that’s called showtime where they get really good and they get really bad. They’re very sensitive to drugs. They can, if you give them classical anti-psychotics, they can actually die. So you have to be very careful about those people. Keep an eye out for those. Vascular dementia, of course, very common as well. And especially if you have people who have sudden stroke-like changes, something to look at. An MRI can be very helpful at picking up that.

                                                Normal pressure hydrocephalus. It’s been claimed that one out of 10 patients with dementia has normal pressure hydrocephalus. I myself think that’s too high. I would argue more like a couple out of 100 maybe. Not common, but you will see it at some point. You don’t want to miss it because it’s very treatable with a shunt. And the classic, the thing to ask and the thing to look for, if these people don’t have the triad of gait apraxia, urinary incontinence, and dementia, simply they must have some degree of urinary urgency. If they don’t have urinary incontinence or urinary urgency, very unlikely.

                                                Again, if you get an MRI that shows that you’ve really got these blown up ventricles and no atrophy, it’s something to think about. So you don’t want to miss that one. Frontotemporal dementia, interestingly, is a cousin of ALS. These things often run together. They both involve a protein called TDP-43. It’s a tough one. It’s only about one-twentieth as common as Alzheimer’s. So not terribly common, but again, something to keep an eye out for.

                                                And then there’s a new one that was just described about a year ago, called late limbic-predominant age-related TDP-43 encephalopathy. That’s a mouthful, but essentially it is like frontotemporal dementia, but it’s in people who are over 80. So this is the one, it affects the limbic system and it affects the temporal lobes. So different place than frontotemporal dementia, but same pathology with a TDP-43, which is present in ALS and frontotemporal dementia and LATE.

                                                So if you see someone who has slowly progressive Alzheimer’s, that didn’t start until they were over 80, good chance that that’s LATE, especially if they have a negative amyloid scan. Then of course, multiple sclerosis. Interestingly, people with multiple sclerosis have actually cortical shrinkage of about a few percent per year. So they actually do, over time, often develop some degree of cognitive decline. And that’s why things like Terry Wahl’s protocol, I think is fantastic. Really addresses the key points for MS.

                                                And then PSP, progressive supranuclear palsy. Another thing that can present with cognitive decline. These people, the classic, have them look up, have them look down. These people have trouble with vertical gaze. And then corticobasal degeneration. This is another Parkinsonian-like presentation. These people often have something called alien hand. So these are less common things, but something to keep your eye out for.

                                                And then CTE and TBI. So trauma. Huge, huge player. NFL players, people who’ve been in the war, blasts, traffic accidents, even repetitive, mild head injuries. People who head soccer balls, all these sorts of things can give you chronic traumatic encephalopathy. The triad to think about for that, so if you hear this triad, so it’s depression, aggression, and dementia. So what happens to the football players? They beat up their families and then they commit suicide. They have both aggression and depression, as well as the dementia.

                                                COVID-19 related. This is something for all of us to keep our eyes out for. A lot of people with COVID report some brain fog, even after the COVID. And so there’s concern of many coroners, are we going to see more and more cognitive decline as a post-COVID effect? We just don’t know yet. Of course everyone’s concerned thinking back to post-encephalitic Parkinson’s of 100 ago, and we’ll see what happens with COVID-19, but it certainly, again, behooves everyone to get on appropriate prevention.

Dr. Weitz:                          Hey, Doc.

Dr. Bredesen:                    Yeah?

Dr. Weitz:                          Just a second. What would you speculate would be the mechanism if we see brain related issues related to COVID? Do you think it might be related to decreased oxygen getting to the brain? Do you think there’s an autoimmune attack on the brain? What do you think might be the mechanism?

Dr. Bredesen:                    Yeah, so there’ve been multiple neuropathological studies already published on COVID-19-related encephalopathy, and it actually has several features. So just what you said. One is you do see multiple small vessel occlusions. So there is some degree it’s not major vessels typically. Now sometimes it is major vessels, but more commonly it’s small vessels. There was an interesting publication from … what’s that?

Dr. Weitz:                          This is the clotting and the vascular component of COVID?

Dr. Bredesen:                    Yeah, this is one of the contributors. Then the second thing is there is an autoimmune effect. So there’s a little bit of an MS-like phenomenon. So you’ve got people reacting to virus and virus antigens, and then you’ve also got the previous damage where you had from hypoxemia, depending on how severely, were they on a respirator? Were they not on respirator? Those sorts of things. So there are multiple mechanisms.    And I do think this is something where everyone who’s had COVID-19 should be on active prevention. And certainly if they develop more than just brain fog especially, then you really want to jump on them early and evaluate them and do everything possible to optimize, to give them the appropriate immune status.

                                                Interestingly, there are some very interesting parallels, as I mentioned earlier, between Alzheimer’s and COVID-19. And one of the more interesting ones is that, one of the problems with the disease is that, both in COVID and in Alzheimer’s, you have a mismatch between the innate immune system, which is activated, and the adaptive system, which is not able to clear the pathogens. In one case, we know what the pathogen is, in the other case, it can be all sorts of different pathogens with Alzheimer’s. But it’s been known for years that Alzheimer’s people aren’t particularly good at phagocytosis. They are not particularly good at antigen presentation. So part of the job of the adaptive system is to turn down the innate system and say, okay, I’m going to take it from here, but it doesn’t succeed in doing that. So what happens, as we know, people with COVID-19 have cytokine storm and can die from that. People with Alzheimer’s have cytokine drizzle, it’s not an active cytokine storm, it’s years and years of this.   And by the way, the amyloid we associate with Alzheimer’s is part of the innate immune system. That’s the whole point. So as long as your innate immune system is chronically activated, you’re going to continue to make that amyloid. You are protecting yourself against an insult. So it’s our job to find out what these insults are and go after them and target them.

                                                And then CJD, Creutzfeldt-Jakob disease, which is a prion disease. Typically, that is much more rapid. So you see people getting worse week to week instead of months and months and year to year. And then of course, don’t miss the subdural hematoma. Of course your MRI should help you with that. But these people tend to wax and wane and they can have, or they can present with something that can look like Alzheimer’s disease.

                                                So what about stages, subtypes, and presentations. Four stages. So there’s a pre-symptomatic stage. You already have the pathophysiology going on, and that can last for several years, but at the time you don’t notice any symptoms. Then you progress to SCI, which on average lasts 10 years. So again, I would argue that we should start calling this pre just like pre-diabetes, this is pre-Alzheimer’s and SCI is early Alzheimer’s. Because everything has been focused on the end stage of this, which really makes no sense. So SCI is subjective cognitive impairment. By definition, that means you know there’s something wrong, but the tests are not showing it yet.

                                                That progresses to MCI, so-called mild cognitive impairment. But as one of the patients said, it’s anything but mild. This means that you’ve progressed far enough that you’re neuropsych testing is now abnormal. And so you are relatively late in the process and you really want to jump in and get treated optimally.   And then that progresses at the rate of about 10% per year. The MCI patients will progress to full-on Alzheimer’s, which is really end-stage Alzheimer’s, which is, by definition, when you begin to lose activities of daily living. Well, as you know, when you’re losing activities of daily living, you are very, very late in this process. So we recommend everyone, please either get on active prevention when you turn 45, or think about, the very earliest when you have symptoms, please get on treatment.

                                                So, as I mentioned earlier, there are subtypes. Type one is inflammatory, type two is atrophic, type 1.5 is glycotoxic or sweet, type three is toxic. And as I’ll show you, it often presents very differently. Vascular type four, and then traumatic type five. And so, depending on what type you have or what combination of types you have, you need to treat them differently. No surprise.  The biggest thing to note is someone presenting with an amnestic syndrome where the biggest problem, and the first problem, is really about learning new information. That’s classical Alzheimer’s and that’s typically not type three. Type three is often a little different, but that’s classical Alzheimer’s. It’s more apoE4 positive Alzheimer’s, which represents about two-thirds of Alzheimer’s.

                                                But about a third of people will come in with non-amnestic presentations. So they have problems with executive function. So here, non-amnestic. So for example, the primary progressive aphasia, that’s a relatively common one. PCA, which is posterior cortical atrophy. So these are the people that have trouble with recognition, recognition of faces, recognition of objects, things like that. Prosopagnosia, problems recognizing faces, executive dysfunction, dyscalculia, apraxias, agnosias, depression. So these are all things typically that are parietal.  If you look at a PET scan, you see a temporal and parietal reduction in glucose utilization. Classical Alzheimer’s is more of a temporal heavy. It’s memory. The non-classical, the non-amnestic is really more of a parietal presentation. Those are the PCAs and the apraxias and the dyscalculias and things like that. And beware the ones that present with depression, because they are often telling you, “I’ve got exposure to toxins,” and that’s a common presentation of the ones that are going to turn out to have type three.

                                                So let’s now go back to the molecular biology. We’re going to go all the way back to the beginning and look at what this thing actually is. And that’s our research over the years was could we understand the fundamental nature of this disease? How do we explain the neurofibrillary tangles and the senile plaques and the atrophy and all this sort of stuff? And the genetics and all the other things in these 150,000 papers.   And the intriguing thing here is the amyloid precursor protein, which sticks out of a cell, so this is a cell membrane I’m showing you here in this diagram. Here’s the extracellular space. Here’s the intracellular space. And amyloid precursor protein turns out to be a fascinating protein. It is a little bit like the president of your country. So let’s say that you’re living in Mybrainostan and you’ve got a president, President APP, and the president is looking at, are things good? Are we going to build roads and build bridges and do all these sorts of things? Obviously things that our current president and our last president were thinking about. What do we do? There’s a pandemic on the one hand, but we got to keep things going. Are we going to go into a recession? That’s the same sort of thing.   And by the way, this, again, is a good analogy. What happened with COVID-19?  We were all told there is SARS-CoV-2, there’s an insult.  So we’re going to shelter in place.  We’re going to downsize.  And of course we had a recession. That’s exactly what your brain is doing with Alzheimer’s. It’s saying there are insults around, I’m going to switch from growth mode to protection mode. So interestingly, APP senses both of those.  So you can literally trace the molecular pathways.  So when things are good, whether it’s in your country or your brain, if it’s in your brain, APP senses things are good.

                                                And again, as an example, estradiol binds to its receptor, enters the nucleus, turns on a whole bunch of genes. And one of the genes that turns on is the one that cuts right here. So it’s saying, okay, we’re going to cleave APP at one site. It leads to two peptides that are growth and maintenance. These are saying, go ahead, times are good, make new memories, grow, keep your brain doing well.  Now, this same thing, when it’s exposed to all the things we talked about, to herpes simplex and to pathogens from your mouth, to borrelia, to leaky gut, to staying up too late, to too much stress. You can go on and on and on. When it recognizes those things, it has a completely different outcomes. So it’s now, just like your president, saying, we’re going to protect ourselves and we’re going to downsize.  And again, you can trace a direct molecular pathway. So you then cleave APP at three sites. This is the beta site right here, the gamma site, and the caspase site. And these four peptides all say, pull back, pull back, protect yourself and pull back. And so that’s the fundamental difference. Everybody with Alzheimer’s has got too much on this side and too little on this side. So it’s our job to figure out what’s driving that and to increase the things on this side and decrease the things on that side. And that’s what actually works to make people better.

                                                Okay. So what we realized over the years of research is that chronic illnesses are typically signaling imbalances. As everyone knows, if you’ve got osteoporosis, your osteoblastic activity is being outstripped by your osteoclastic activity. If you have cancer, your somatic mutations typically are giving you more cytoblastic effect because you’ve got oncogene activation and you’ve got tumor suppressor gene mutation. You’ve lost that function. Therefore, cytoblastic outstrips cytoclastic, and you make too many cells.   What we found in the lab, Alzheimer’s no different. There are all sorts of things that contribute to synaptoblastic signaling, and that is being outstripped by synaptoclastic signaling from exactly what I just showed you with APP. That’s recognizing this.  So the point here is that the fundamental nature of this disease that we call Alzheimer’s is actually a network insufficiency. So you have subsystems of your brain. You have a subsystem that is there for stabilization of motor movements. When that goes awry, you get Parkinson’s. You have a subsystem that is very good with neuroplasticity. When that goes awry, you get Alzheimer’s. And so each of these has its own supply requirements and its own demand requirements. In all of these diseases, you’re outstripping. The supply is not meeting the demand.

                                                In the case of Alzheimer’s, there is a set of things, as I mentioned, synaptoclastic. So let’s just quickly go through this. Your probability of Alzheimer’s is proportional to, over time, you’re integrating a whole sum of things that are, and I’m going to talk about what they are here, synaptoclastic signaling over synaptoblastic signaling. So that tells you a lot about what Alzheimer’s actually is.   That’s why your brain shrinks when you get Alzheimer’s disease. That’s why it acts like it’s trying to protect itself. Now the good news is, although we can’t send a lab test for this one, I don’t think that there’s any sort of tests we can do. I know Dr. Vojdani may be at work on something like this. He’s made some great tests, but the reality is we can measure these things. So this is approximately equal to four different things.   So the things that are on the bad side here, and then here are the things that lower the risk. But, when you have too little of them, you’re in trouble. So anything that’s causing inflammation is going to increase your risk for Alzheimer’s. So whether, again, whether it’s leaky gut, whether it’s poor oral, whether it’s poor dentition, whether it’s chronic sinusitis, whether it’s a metabolic syndrome, just go on and on. Any toxins, and these come in three general types, the inorganics, things like mercury, and air pollution, air pollution is a huge one. And then things like organics, things like formaldehyde and toluene, benzene, glyphosate. And then of course the biotoxins, things like trichothecenes and ochratoxin A, and things like that.

                                                Now, too little energetics, that’s the third of the four things, and the energetics are basically four major contributors: blood flow, oxygenation, mitochondrial function, and the actual ketones that are actually going to be burned as a substrate. So that’s one thing we want to optimize as well, so anything that reduces that, people who have sleep apnea, people who have some degree of vascular disease, people who have poor mitochondrial function, people who are incapable of getting into ketosis, all those things. And then finally, trophic support, and that’s, again, three things. That is growth factors, NGF, BDNF, things like that. Hormones, estradiol, testosterone, pregnenolone, progesterone, all that stuff. Then nutrients, things like vitamin D. Those are the big four. Each one has groups and you can literally go through and figure out what each person has that’s giving them this problem.

                                                What that means is, the perfect Alzheimer’s drug… And we spent years screening for Alzheimer’s drugs. The perfect drug would have to do this, which makes it really difficult to get a single drug. And I do think the drugs are going to be very helpful in the long run, as part on the backbone, basically, of a functional medicine or systems medicine sort of approach. We always tell the patients, imagine you have a roof with 36 holes, you’ve got to patch many of them before you’re going to see any real effect. And of course, we have to train a new kind of position who understands both systems biology, the basic, the traditional Chinese medicine sort of approach, as well as DNA, RNA, larger data sets, all of the modern things, and so we really need to get… This is obviously… This group is very well aware of that.

                                                So I’m just going to spend a couple of minutes here on ApoE4 because it is the most common genetic risk factor. What the heck? Why would this give you Alzheimer’s? It’s so incredibly common. Even though about a quarter of the population has it, it represents, because of this increased risk, about two thirds of all Alzheimer’s patients. So if you have zero copies of ApoE4, and that’s three quarters of our population, you have about a 9% risk. It’s not zero, but it is relatively low. If you have one copy, that’s 75 million Americans, the vast majority don’t know it. They have a chance about 30% during their lifetime, and if you have two copies, your chance during your lifetime is well over 50%. That’s 7 million Americans. Most likely you will develop it.

                                                So we recommend please, everybody, check out where you stand. People used to say, “Doesn’t affect me.” The standard claim today from the experts, “Don’t bother to check it because there’s nothing you can do.” Which is just… It just drives me crazy. There’s a tremendous amount you can do. Please, everybody find out where you stand, get on active prevention. So-

Dr. Weitz:                          Hey doc, do you have an opinion about ApoE2 versus ApoE3?

Dr. Bredesen:                    Yeah. So ApoE2 actually reduces risk. It’s relatively uncommon. ApoE3 is the most common, and that one, the risk is going to… That’s the one that’s set as the standard. And so yes, if you’re a e2/3, you do have a slightly lower risk, the 9%. However, if you’re a e2/3, be careful. You are also susceptible to some of the toxins. More than the ApoE4 people are. So the ApoE4 tend to get a more vascular and inflammatory and glycotoxic type of disease. The ApoE3s and 2s, in general, they tend to get a more toxic, sometimes vascular as well, but they tend to be more on the toxic side.   So what had been known is that ApoE4, some sort of risk factor, not clear how that works. ApoE is a little bit like your butcher. It’s the guy that carries around the fats. And so what the heck does that have to do with Alzheimer’s? And so we started in the lab over a decade ago looking at “How do you turn ApoE4 into Alzheimer’s disease? Why is this association?” And it had been claimed in the past, “It’s simply because you clear your amyloid less well,” and yeah, you do clear less well, but that’s not the only reason by far, as you’ll see here. It turns out to be a fascinating story. So what happens is, this ApoE4 was the primordial ApoE. So when the hominids appeared from the simians between five and seven million years ago, there actually aren’t that many differences, as you probably know, between the simians and the hominids. The DNA is over 95% similar.

                                                And so, as I told my wife, “My DNA is actually more similar to a male chimp than it is to yours.” And she said, “Well duh, of course, you guys both like ESPN. You both like The Three Stooges.” We get it, okay. So the bottom line is, yes, there are a lot of similarities between the simians and the hominids. And of course God touched us all with DNA, made a small number of changes, and lo and behold, we became what we are today. And we all had, for 96% of human evolution, everybody was ApoE4/4. And so these are interesting. ApoE3 just appeared 220,000 years ago, so relatively late in hominid evolution. Nobody knows why it appeared then. One of the interesting possibilities is that ApoE4 is a very pro-inflammatory gene, so it’s great for if you’re eating raw meat and things like that. And that as people became able to be eating cooked meat and things like that with fire, they didn’t need that, and so they ended up with ApoE3, which is now the more common one.

                                                So you can see here what happened, ApoE4 looks like columns on a house, and that’s because this arginine 61, which is positively charged, interacts with glutamate 255, which is negatively charged. And interestingly, this arginine 61 is not present in the chimp ApoE. Now what happens is, 220,000 years ago, cystine 112 appeared right here and swiped right on the arg 61, and you can see here, these two guys interact now. So this now swings free, and so now it looks much more like a nutcracker than it does like these columns. So very different look, and as I mentioned, this is just a relatively late change. ApoE3 just appeared late in our evolution, ApoE2 just 80,000 years ago.   And here’s the big surprise. People had known that it binds to receptors, several different receptors, actually, but what we discovered was really fascinating. It actually interacts with part of NF-kappa B, RelA, and enters the nucleus. The reason that hadn’t been picked up before is, it’s not all of it that enters the nucleus. It’s a subpart, it’s about 10%, but it’s a critical part of your ApoE that enters the nucleus and it binds to 1,700 different gene promoters. And if you group these, you could not tell a better story for Alzheimer’s disease. So it’s involved with inflammation, it’s involved with disassembling your microtubules. So it has this interesting pro inflammatory effect. And so okay, we can find out who has it. We can actually make an impact on this.

                                                So the bottom line here is, when we treat people, we want to understand what’s causing the problem. We want to know what their energetic status is. We want to identify whether they have insulin resistance and get them to be sensitive again. We want to know the status of their trophic support. We want to resolve inflammation, treat pathogens. If they’ve got toxins on board, we want to detoxify them. We found that people do better if they have some mild stimulation, whether it’s light, whether you like to use magnetic, defocused laser. Any of these things. We want to improve the adaptive immune system and reduce the innate system. That’s one of their problems. And then we can remove the amyloid. Removing the amyloid at the beginning is a bad idea because it’s protecting you. So address the things, it’s root cause medicine, no surprise. And then ultimately we want to think about regeneration, things like stem cells and trophic factors.

                                                So here’s an example of a guy. Did very well. You can see these dramatic improvements in his neuropsych testing. He actually started back in December of 2013, so he’s done very well for a long time. And that’s the most important thing. People have stayed very good. This is a guy… Classical Alzheimer’s, ApoE4 positive, both parents died, and you can see, as a functional medicine physician, you can see the problems this guy has. Now he himself is a very smart doctor, and I was trying to explain to him, “Look, this is why you have Alzheimer’s.” And he said, “Well, addressing these things, none of these things is a cure for Alzheimer’s.” No, not by themselves, but you have to look at the overall system.   And by the way, he did absolutely great. Responded metabolically, cognitively, volumetrically, and his neurologist said he’s now normal. You can see his hippocampal volume… Just dramatic improvements, and you can also see, he’s not perfect with his metabolism. His fasting insulin is much better, it’s not perfect. His hs-CRP, much better, it’s not perfect. His homocysteine, pretty good. His vitamin D, pretty good. So he was improved and you can see here his gray matter actually increased by 23%. What’s that?

Dr. Weitz:                          I’m sorry. What would be your goals for the fasting insulin and those other parameters?

Dr. Bredesen:                    Yeah, fasting insulin… we usually go with what Mark Hyman has always suggested. We want to be in that kind of four to five range. I worry when I see people down at one, unless they’re doing really well. If they’re at one and their hemoglobin A1C is at six, they’re just not able to make enough insulin. And by the way, they often get better as they start being treated, and they’re now able to make more again, but yeah, four or five. I like to see their HOMA-IR right around 1.0 and his HOMA-IR was something like 13, or something. It was just way off scale. So we published a number of papers on this, and of course, everybody pushed back and said, “Yeah, these are anecdotal. You got to do a trial.”   So we actually tried to do a trial back in 2011. It was turned down because it was multi-variable. We got turned down again in 2018. We finally got approved in 2019, and we just finished the trial, and I’ll show you the results from that. Published a couple of books about this to document some of these. And so, as you know, functional medicine has improved outcomes for many illnesses. It’s really been striking. And of course, this is not taught in medical schools, typically. One leader of one of the medical schools, a very well-known medical school in the United States, said, “We’d like to teach this new kind of medicine, but we can’t do that until all physicians accept it.” Well, of course all physicians won’t accept it until you teach it, so it’s a really very backwards approach. So clearly, if we’re all going to make functional medicine the standard of care, it’s going to be important to perform clinical trials to prove efficacy.

                                                So therefore, we proposed a proof-of-concept trial, which as I mentioned, I just finished up, and we just published the first piece on one of these preprint servers called medRxiv. And I’m really honored to have done this with Dr. Ann Hathaway, Dr. Kat Toups, and Dr. Deborah Gordon. I’m sure a number of you know them. They’re absolutely fantastic physicians. And we all worked on this together, along with the Four Winds Foundation that funded the trial, a question, which a CRO. Dr. Cyrus Raji, who was the neuroradiologist and Alan Boyd, who is the neuropsychology guy that provided the CNS vital signs. So it’s the first trial in which we flip the script and say, okay, let’s find out what causes I mentioned. It was denied a few times. It’s a small proof-of-concept trial, 25 patients with MCI or early dementia, MoCA scores of 19 or above, compares a personalized precision medicine approach to historical outcomes. Now we’re following this up with a larger, randomized controlled clinical trial.  So we look at MoCA zero, three, six, and nine months. We look at CNS vital signs because it’s more sensitive. We look at AQ-21, which is from the patient’s partner looking at how many complaints they have. We look at AQ-20, which is basically the partner saying, “Did they improve? Did they not improve?” in 20 different areas. A little improvement, a lot of improvement, none, or were they actually worse? And then we did MRI with volume metrics at zero and nine months, and really striking results. So we tried to achieve insulin sensitivity, mild ketosis, healing the gut, treatment of identified pathogens, detox for those who needed it, reduction of inflammation, optimization of hormones, nutrients, and trophic factors, vascular status, some degree of brain stimulation, optimization of SpO2, and then stress management, and improved heart rate variability.

                                                And I just want to say a word about the semantics of success. We hear this almost every day, “Oh, someone did a trial, someone made a mouse better, or someone slowed up the decline.” So here’s an example, Aducanumab, which is the big success in the antibodies of the drugs. What it did was, it didn’t make people better, it didn’t stop the decline, it slowed the decline by about one third, a little less than a third, actually. And so you can see here, here’s no treatment… Yes, you go downhill. With this big success, and this thing, by the way, the day this was announced, the value of this company increased by $20 billion in one day. So here you can see, it slowed it by a third. Whereas, in our trial, we didn’t just slow the decline, we made people better. And here’s an example on the Neurocognitive Index, you can see where they were baseline- what’s that?

Dr. Weitz:                          What was the change in the market value of Dr. Dale Bredesen as a result of the trial?

Dr. Bredesen:                    I think three more arrows in my back. That’s what happened. That was the result of that one. So yeah, there’s no market value here.

                                          So here’s just from the NCI data and the significance of this P<.001. So everything I’m showing you here, it turned out to be significant statistically. So here you can see. MoCA, <.001, 76% of patients improved. Neurocognitive Index, <0.001, 84% of the patients improved by their NCI. Cognitive subtests, verbal memory improved, executive function, psychomotor speed, cognitive flexibility, and others. Interestingly, the partners said the same thing. Yes, they said these people have improved. Again, a P value for that <.005. Brain training scores improved in all 25 of them. No question, the pandemic affected this. We had seven people who had already improved by six months, the pandemic hit, and then they actually went down a little bit at the end. But the good news is, the other ones improved so much that it was still statistically significant as a group, but there’s no question. They would have done better as a group if the pandemic hadn’t intervened.

                                                Now, here’s what’s interesting. The MRIs improved. So if you look at the overall MRIs, they improved both with respect to gray matter volume, and with respect to hippocampal volume… There we go. Hippocampal volume itself… So hippocampal volume in someone with Alzheimer’s goes down about 2.5%-3.5% per year. If you’re a normal individual, it still goes down about 1.7% per year. The hippocampal volume actually did go down a little, 1.29% per year. So these people actually did better than the normal controls with their hippocampal volume change. And interestingly, their gray matter volume actually went up by 0.3%. So implications, cognitive decline is reversible for most people with MCI or early dementia.

                                                Now we’re very interested in looking at later dementia. What about people who have MoCA scores of zero to 18? We’ve seen anecdotal evidence of improving them, but it may take more to get them to improve. We’ll see. For those with cognitive decline, likely contributors should be obvious. One of the interesting things that came out of this was, there are only three who didn’t improve who declined. We should be able to tell why. And we could see one of them, for example, lived in a very moldy house with lots of mycotoxins and just said, I’m not leaving. Okay. This person continued to decline. So the good news is, we could tell with these people what was actually wrong, and the other ones that did the right things actually improved. So one of the issues here is how feasible is this to do with everyone? So we need to continue to work on the practical nature on this. The good news is, the results really strongly support doing a larger trial, which is what we’re setting up now.

                                                I’m excited about the idea that we may be able to modify this for Lewy body, modify it for Parkinson’s, modify it for frontotemporal. Each one has its own subsystem with its own neurochemistry, so we should be able to modify this, and we’re already doing this. In fact, I just had a meeting today on the three-month followup of the first couple of patients with macular degeneration, and it’s the same story. They have their own separate neurochemistry, and we can now begin to look at improving them by combining the appropriate things. So the good news is, if you combine the results of this trial with what’s already been known, that there’s a decades long pre-symptomatic and early symptomatic period, the fact of the matter is Alzheimer’s is now something that is optional. It’s not that anybody has to get it.

                                                So please, get on prevention or early reversal. You don’t need to get this disease. Just as for leprosy and polio, which were scourges in their time, Alzheimer’s disease shall become a former scourge. And one of my favorite sayings is actually from a rabbi who said, “You’re not expected to complete your life’s work during your lifetime. Neither are you excused from it.” And I recognize that this is going to be going on… I’m just about to turn 70, this is going to be going on long after I’m gone. But my hope is that we’ll keep making this better and better, and we really will reduce the global burden of dementia. So let me stop the sharing there, and happy to go to any questions that anyone would like to ask and thanks again to Ben for the invitation.

Dr. Weitz:                            So the first question I’d like to ask is, I found a paper that you wrote about rapamycin and its potential for inhibiting mTor and playing a role in prevention and treatment of Alzheimer’s. Can you talk about that?

Dr. Bredesen:                    Yeah, mTOR is one of the several, as you know, sensors. So these are all about nutrition and energy. And when you are eating, when you’ve got a lot of protein around especially, mTOR is active, and so you want to inhibit this, and that’s what you’re doing by fasting. Rapamycin has been touted by some as, “Here’s the way of the future. Let’s all take rapamycin and inhibit mTOR, and we’ll age less rapidly.” And I should mention there’s a great paper that just came out recently from Kara Fitzgerald, another integrative physician who used a similar sort of approach to what we do, but instead of asking the question, “What happened to cognition?,” Said, “What happened to aging parameters based on the methylome?”   And what she showed, that these people aged backwards by essentially by 3.26 years. So I think we’re all trying to have that impact to improve brain function, to improve biological aging. I don’t think you need to take a drug like rapamycin that has side effects to get that. You’re getting it by doing things like fasting appropriately. Look, if you want to try the fasting mimicking diet, that’s what it’s for. If you know, doing exercise, getting appropriate sleep, minimizing your stress, having a mildly ketogenic plant rich high fiber diet with plenty of phytonutrients. These are all ways to get at mTOR without taking a toxic drug.

Dr. Weitz:                          Kara mentioned in her article about this test to measure biological aging based on methylation. I’m sure you’re familiar with that. Is there a correlation between the outcome of that test and the risk of Alzheimer’s?

Dr. Bredesen:                    Great question. We don’t know yet. We’re actually going to be working with Kara. Just been talking to her the last few days. We’re going to be working with her on this next trial to see what happens, as I think it’s highly likely that we will see reduced biological age given everything that we’ve seen so far with cognition and what she measured in her trial. So I’ll be very interested to see what happens with that. But again, this is a biomarker of biological aging. We don’t yet know if it’s going … hey, if we impact that and we reverse it, are there going to be… Presumably they’re going to be some good things that happen, but are there also going to be some negative? We don’t know yet.

Dr. Weitz:                          What about strategies to increase oxygen to the brain? Like hyperbaric oxygen, ozone, there’s several others.

Dr. Bredesen:                    Yeah. You know, there’s a group in Israel that is claiming that they’re getting some very good results with hyperbaric. You know, I think for the appropriate people, it seems to be very helpful for people who have vascular disease as one of their key contributors, or for people who have head trauma as one of their contributors. Whether it’s the best thing for the people who have glycotoxicity or just inflammation, I don’t know yet.   I actually like EWOT a little bit better, the exercise with oxygen therapy, because you’re now active, as opposed to HPOT, where you’re inactive. But yes, I think for the appropriate people and especially in those two groups I mentioned, I think it’s fine. As you know, it’s expensive. And so, we’re looking at how do we get this to the greatest number of people. And by the way, Aducanumab, which failed was turned down by the FDA, but now has been pushed by Biogen for the FDA to reconsider it, and they’re going to issue a response by June 7th. Even though it failed in trials, one dose in one trial, it seems like it might have slowed a little. Again, it didn’t make people better, just slowing the decline. It will cost people a minimum of $30,000 per year. So again, we can do far, far better. And by the way, the average person with Alzheimer’s will spend $350,000 before death. Mostly to things like nursing homes and medical care and things like this. So for a tiny fraction of that, we can do much, much better.

Dr. Weitz:                            Several questions came in about some of the particulars of the nutrition program and parameters related to the type of intermittent fasting that you’re recommending.

Dr. Bredesen:                    Yeah. Great point. And so we use… And I wrote about it in the books; KetoFLEX 12/3. So again, we’re agnostic about what to use. It’s how do we drive your biochemistry and neurochemistry toward the best places for synaptogenesis and for synaptic maintenance? That’s the key. And, so far the diet that seems to be working best is… you would say high, or plant rich, no surprise. And again, for people who have truly severe vascular disease, maybe you consider going vegan. For people who don’t have a significant amount of vascular disease, you want to do more fish and some pastured chicken maybe, and maybe some grass fed beef, but not as major parts. So, it’s a plant rich, high phytonutrient, lots of non starchy vegetables, high fiber diet. You want to optimize microbiome, no surprise, and have appropriate prebiotics.   Make sure you don’t have dysbiosis. That’s one of the most common contributors to systemic inflammation in Alzheimer’s disease. And then as you indicated, some fasting 12 to 16 hours we recommend. And then it’s key. I see this again and again and again, if you can get in… become insulin sensitive and get yourself into mild ketosis, you do better than if you are insulin resistant and you don’t get yourself into ketosis. So, that is an important part of the overall approach.

Dr. Weitz:                          I know vascular issues is one of the categories that could affect decreased blood flow, et cetera, blockages.

Dr. Bredesen:                    Yeah.

Dr. Weitz:                          On the other hand, is there a danger with some of the medications like statin drugs? And is there a danger lowering the cholesterol too much, given the importance of cholesterol for neuronal formation?

Dr. Bredesen:                    Yeah, absolutely. And I worry about this all the time. And the problem is that in studies… that the studies were done to try to show that the statins are going to save us from Alzheimer’s. And of course, no surprise, they showed the opposite. However, they didn’t show much in either direction. And I believe that is because they do have an effect on a reduction of some degree, of reduction of inflammation. Well, we can do much better. We don’t need statins to reduce inflammation. So again, we want to use what is most natural, what is most physiological. You can reduce inflammation. Let’s find out why you have inflammation, and let’s remove that. Is it leaky gut? You know, is it oral…dentition oral microbiome? Whatever it is, let’s fix that and then you won’t need those sorts of things.  Lowering your cholesterol is horrible and everyone wants to lower their cholesterol to zero. And it’s just crazy. We’d like to see, if you’re concerned about that, please check your LDL particle number or your sdLDL or your oxidized LDL, whatever you like.   We also like to look just simply at a TG:HDL ratio, your triglyceride HDL ratio, another good marker. Not total cholesterol.   And yeah, I really dislike the use of statins because they have negative impact. You can get the positives… And by the way, many of the people who’ve gone on this… And the three physicians who were seeing the patients notice the same thing. People came off their anti-hypertensives, they came off their antidiabetic drugs and they came off their statins because they no longer needed these things.

Dr. Weitz:                          So, all the neurologists who were pissed off at you, now you got the cardiologists upset.

Dr. Bredesen:                    Yeah. Well, yeah. I… So it’s interesting, but I was just, we were just talking about a patient earlier today, and that very thing came up. This person had significant vascular disease. And I said, okay, well, are they seeing cardiologists? Yes. They’re seeing a cardiologist. Okay. What did the cardiologists do?  The answer was statins and hydroclorothiazide.   I mean, nothing about diet, nothing about exercise, nothing about stress, nothing about sleep. This person could have had sleep apnea for all the cardiologists know. It’s… I’ll tell you, it gets to the point where it is criminal negligence.  It’s unbelievable.  So my argument is, we need to now form new departments in each medical school called the Department of Modern Neurology.  That’s really what we need to do because there are so many departments that are just stuck in the 20th century.

Dr. Weitz:                          Well, we mentioned earlier, before we started that it takes approximately 17 years for a new idea to get incorporated into medical practice.

Dr. Bredesen:                    Yeah. Absolutely.

Dr. Weitz:                          What do you think about some of the ways to increase using red or infrared laser to stimulate the brain?

Dr. Bredesen:                    Yeah, absolutely.  So there’s a lot of research going on as you know, on this.  And what comes up again and again, is frequency around 40 Hertz stimulation seems to be helpful.  Now, unfortunately, some of this stuff, what they’re trying to do is see if they can simply remove amyloid.  And once you understand what the disease is all about, it’s not about removing amyloid.  It’s about removing what’s causing the amyloid, then getting rid of the amyloid.  But it is true, even interestingly 40 Hz sound seems to be helpful and 40 Hz light.  And so that’s the birth of violight, for example. There’s also magnetic stimulation that seems to be helpful. Things like MeRT, and Dr. Jeralyn Brossfield over in Palm Springs has done some really nice work with that as others have. And then of course, Dr. Robert Hedaya has done some really nice work with laser.  So yes, there does seem to be an advantage when you’re now getting… you’re doing all these appropriate things. You’re now saying to the brain, okay, we’ve now fixed all the issues that were stopping you. Now let’s start kind of pushing you back into work again, let’s get your Brain-derived neurotrophic factor firing again, let’s get your neurons firing again. Again, you don’t want to do it at the beginning because you’ve got to get things fixed, but once you do that, it’s no different than, an athlete who’s been out for six months with a broken leg. After it’s fixed, so get them start-up slowly get them back on the track again, that sort of thing. So yeah, that’s… This is the sort of thing that is again and again, proving to be helpful or get, him or her back on the track again. So this is, again, the way our brains work, is it any surprise that it’s not just one molecule? Really? Are we really surprised by that?

Dr. Weitz:                          Is it an appropriate analogy to compare amyloid with cholesterol?  The reason why cholesterol, just like, it’s often not asked why is cholesterol there?  Let’s just find some way to reduce it.  You know, when we really look at it from a root cause standpoint, we realize that cholesterol is there to coat the artery wall to prevent damage from inflammation, from oxidation.  You know, the body doesn’t just do harmful things for no reason. And is it an inappropriate analogy that the amyloid is being laid down in the brain to protect the brain, much the way cholesterol is being laid down in the artery to protect the artery?

Dr. Bredesen:                    I think that the work that came out several years ago from Dr. Robert Moyer, the late Dr. Robert Moyer, and Dr. Rudy Tanzi that showed that the amyloid is an anti-microbial peptide.  I think that’s really interesting and really important and fits perfectly with what we’ve been saying here.  You are responding to these various insults, the insults of modern life.  And so, as long as you’ve got those insults there, you’re going to be making this stuff.  And so we want to remove the insults before we remove the response to it.

Dr. Weitz:                          Somebody asked about using ProLon for Fasting Mimicking as a version of intermittent fasting.

Dr. Bredesen:                    Yeah.  And I think it’s fine.  Some people prefer to go on a more kind of standard ketogenic diet, which is fine.  Some people like to start out with, a few days, several days of ProLon.  Be careful, some people just hate the taste of that stuff, or they just don’t find it very palatable. Others are fine with it.  So, absolutely it’s a reasonable thing to do. Now be careful, what we find is that people who are very thin have a very low BMI, they sometimes do poorly when you try to get them on a fasting mimicking diet. In fact, Valter himself, Valter Longo says be careful if you’re elderly or if you’re frail, or if you’re too thin, be careful about this. So, what you want to do then is cycle people, give them a rest day and then cycle them in and out of ketosis about once a week. And then the rest of the time, keep them on ketosis. Because we do have people who will actually do more poorly with their cognition when they start trying to do this kind of a ketogenic diet. Because… you have to remember, this is an insufficiency, this is a disease fundamentally of an insufficiency of a plasticity network.   So therefore, if you’ve got someone who’s very thin and can’t generate the ketones and doesn’t have much glucose around, et cetera, you’re now really hurting them. So you’ve got to be careful. So that’s the paradox, it’s a disease of insufficiency. And yet we got it often by excess. And so we’ve got to now bring these together, and we’ve got to have that fasting period without getting people to get farther into an insufficiency.

Dr. Weitz:                          Do you ever include acupuncture in your protocols?

Dr. Bredesen:                    That’s a great point. You know, we haven’t, we didn’t use it in the trial, but absolutely, appropriate things that we use, other approaches for things like stress reduction and things like that. But yeah, it’s certainly reasonable. And there are many things as a scientist in a scientific position, I never believed. I thought all this stuff was crazy 15 years ago, but I can’t argue with the data. There’s no question. You have things like TM, which actually clearly helped neuroplasticity, clearly helped blood pressure clearly helps stress.  We had a patient only, just a couple of weeks ago. I was talking to the husband of one of the patients and we’ve been through, she had a lot of tremendous mycotoxicity. She’s slowly getting better, and then she started to go downhill again. I’m like, what the heck? We’re looking at all the different parameters, and it turned out the biggest issue with her, she was under a tremendous amount of new stress. And just addressing that, she then started getting better again. So there’s no question, these things have very clear impacts on our cognitive function.

Dr. Weitz:                          Yeah. So trying to get into more of a parasympathetic state is beneficial.

Dr. Bredesen:                    Yeah.

Dr. Weitz:                          Yeah, you might look into, there’s a number of devices… I’m wearing something called the Apollo, which uses vibrations to put you into a parasympathetic state.

Dr. Bredesen:                    Interesting.

Dr. Weitz:                          I mean, not very effective for some of my patients.

Dr. Bredesen:                    Well, so let me ask you a question then, because one of the things I always worry about, people say, well we’re going to put you into this state or put you into that state. Well, if it’s not the right state for me, I’m not sure I want to be put into that state. So, you want to be habit appropriate. In other words, you don’t want to be put into a parasympathetic state in the middle of shooting a gun at something, you’re in Iraq or something.

Dr. Weitz:                          Absolutely. So this device, they give you an app on your phone. There’s a wake up mode, there’s one for concentration and focus, there’s one to relax. So-

Dr. Bredesen:                    Oh nice.

Dr. Weitz:                          Different frequencies and intensity of vibration has a different effect. What do you think about peptides for reducing, preventing Alzheimer’s. There’s a number of peptides-

Dr. Bredesen:                    Yeah.

Dr. Weitz:                          Cerebrolysin, selank-

Dr. Bredesen:                    Cerbrolysin, sure.

Dr. Weitz:                          What do you-

Dr. Bredesen:                    Thymosin Alpha one, beta four, all that sort of stuff. But I know Jill Carnahan has been very big about using these and she’s done a great job. So yeah, I actually think they’re going to be one of the most important things going forward. And I think that especially intra-nasal administration where you’re really getting things into the brain, things like ADNP.   There was a trial of a fragment of ADNP called davunetide a few years ago. And unfortunately they did the trial as a monotherapy, nothing else. And no surprise, it was a negative trial, didn’t work. I think that’s one particular peptide… it’s a tremendously neurotrophic peptide. Doing that in the right setting, I think is going to be tremendously helpful. Same for nerve growth factor, same for BDNF, same for peptide fragments of these, same for things like cerebrolysin and Thymosin alpha one and beta four. So I think that these things can be very helpful. And I would put these very much, as I said earlier, pharmaceuticals are going to be helpful when used in an appropriate setting. But please remember to address the things that are actually causing the problem. That’s the place to start.

Dr. Weitz:                          What about stem cells?

Dr. Bredesen:                    Yeah. And so I actually just talked to a guy today who just had given stem cells to someone yesterday and we’ll see how they do. Here’s the thing about stem cells. And as you know, there are trials-

Dr. Weitz:                          What type of stem cells and how did he administer them?

Dr. Bredesen:                    These are the ADRC’s, and this is with blood-brain barrier opening, and this was actually done in LA.   So, here’s the thing. The issue with giving these, again, as a monotherapy, it’s like trying to rebuild a house as it’s burning down, it doesn’t make sense. So please stop the fire first, get all the appropriate things. Then I think for rebuilding the synapses that have been lost… Because let’s face it by the time you have a diagnosis, you’ve lost a lot of synapsis and you need now. Now, initially these synapsis become non-functional but they’re still anatomically present. But then you lose them and then ultimately you lose the neurons themselves. So my argument would be… Great, stem cells should be very helpful at the appropriate time and, with the appropriate treatment and, the appropriate protocol. So we’ll see, I think the data will tell us over the next several years.

Dr. Weitz:                          So what is the best imaging for understanding where the neurons in the brain is growing or shrinking?

Dr. Bredesen:                    Yeah. Great point. So there are several different ways to go. PET scanning has been the most helpful for telling you if you actually have Alzheimer’s because there’s a signature on FDG PET. And then of course there’s amyloid, and now there’s now Tau PET as well. So it’s a very neurochemically oriented approach, and so that’s helpful for diagnosis. However, for following and what we did in the trial was to use MRI with volumetrics. So you want to have, whether you like NeuroQuant or you like Neuroreader, you want to have a computer-based algorithm to look at do you have hippocampal atrophy? Do you have parietal lobe atrophy? Do you have frontal lobe atrophy? Temporal lobe? These sorts of things. Various regions of the brain, do you have normal pressure hydrocephalus? Do you have big ventricles and no atrophy, that sort of thing.   So that’s helpful, but that doesn’t tell you if you have Alzheimer’s or not. You can infer that you probably have it. And I think some people have argued, we should quit talking about Alzheimer’s just talk about cognitive decline, it’s all going to be related. And so you could argue that… I think I like having an idea of, is this Lewy body? Is this Alzheimer’s? Because that simply tells you where you should focus more attention. If you have Lewy body, most likely you have toxin exposure. So you really want to focus more on that. If you have Alzheimer’s, you’re likely to have insulin resistance, you better focus on that. You know, all the things we talked about for that, each one is a little different. But again, you could look at just cognitive decline. So that’s the second kind of imaging.

                                                Then of course, there’s this group Darmyian, which is trying to look at, can we essentially infer a histology from looking at different regions of the brain? And that’s going to be interesting we’ll see. That’s early days, very little published about it. And so, lots of claims, not much in the way of publications yet. So I think it’ll be very interesting to see, they may be correct. And maybe we’ll see in the next few years, some very striking outcomes with that where we really can infer underlying pathology, which would be fantastic.

Dr. Weitz:                            I knew you prefer the Montreal Cognitive Assessment tool for assessing patients with Alzheimer’s among other questionnaires. Is there a good questionnaire when patients have subjective cognitive impairment?

Dr. Bredesen:                    Yeah. You know, this is such a good point because you can use SLUMS, which is the St. Louis one, which is similar to the MoCA in terms of sensitivity. MMSE is another one that’s been used over the years, but that one is not very sensitive at all. So that’s really… each one has its own dynamic range. When you have someone who’s got relatively severe dementia, you want the MMSE. The MoCA was developed specifically for MCI. But as you indicated, as we talked about earlier, you really want something that’s hypersensitive for SCI so that you can really catch people early and see if you can improve them. And I should mention parenthetically, we do have people coming in saying I’m here for prevention. And they score 23 on the MoCA. They already have fairly significant MCI. And they’re thinking they’re there because it comes on so slowly.   And so these people typically get right back to 30 when they do the right things. So I happen to like CNS Vital Signs, but there are others there’s, Cogstate, there’s Cambridge. We have used the CNS Vital Signs because you can do it over the internet, it only takes about 35 minutes or so. It’s pretty easy, in fact, we even have a shorter version called CQ, which is easy to do. And it can really give you a pretty sensitive… much more so than the MoCA scores, pretty sensitive indicator of where you stand cognitively. And also it does multiple domains.

Dr. Weitz:                          Great. Awesome. Thank you so much, Dr. Bredesen and we all thank you. Excellent presentation, we learned a lot. It was incredible.

Dr. Bredesen:                    Yeah. Thanks for the invitation. Appreciate it. And I look forward to hearing more great things. I hope everybody out there will help to prevent and reverse cognitive decline. That’s I think, this is the way that everything’s headed. So thanks very much.

Dr. Weitz:                          Yeah, we’re all on that mission with you. Thank you everybody and we’ll see you next month.


Thank you listeners for making it all the way through this episode of the Rational Wellness podcast. Please take a few minutes and go to apple podcasts and give us a five-star ratings and review, that would really help us so more people can find us in their listing of health podcasts. I’d also like to let everybody know that I now have a few openings for new clients for nutritional consultations. If you’re interested, please call my office in Santa Monica at (310) 395-3111 that’s (310) 395-3111. And take one a day, a few openings we have now for a individual consultation for nutrition, with Dr. Ben Weitz. Thank you and see you next week.

PART 4 OF 4 ENDS [01:30:04]



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