Alzheimer’s And Pain Management With Dale Bredesen, MD

Welcome back to the Healing Pain Podcast with Dale Bredesen, MD

We’re discussing the association between Alzheimer’s and chronic pain. My expert guest is Dr. Dale Bredesen. He’s a professor at UCLA and the President of the Buck Institute for Research on Aging. His work focuses on the mechanisms leading to neurodegeneration. With his research group, he’s published over 220 scientific papers leading to the first description of the reversal of cognitive decline in patients with Alzheimer’s disease. His book, The End of Alzheimer’s, is a New York Times bestseller and is now available in 32 languages. Let’s get ready and let’s meet Dr. Dale Bredesen and learn about the link between Alzheimer’s and chronic pain.

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Alzheimer’s And Pain Management With Dale Bredesen, MD

Dr. Bredesen, welcome to the show. It’s great to have you here.

Joe, thanks for the invitation.

I’m excited to talk to you about the reversal and prevention of Alzheimer’s and cognitive decline. It’s a topic we haven’t covered on the show, but there are lots of overlaps with many types of chronic disease and chronic pain. A good way for us to start for all of our readers is for you to ease into this with what is Alzheimer’s and what are the risk factors for developing Alzheimer’s?

Alzheimer’s is the most common cause of dementia. Dementia is a global cognitive loss. About two-thirds of people will start with memory problems, but about another third of them will start with other problems such as problems with planning, word-finding, spatial recognition, navigating around areas, recognizing faces and objects or things like that. This is a progressive problem as people become demented more and more over time. When you look at what causes that, the majority is Alzheimer’s disease. That simply means that Alzheimer’s is a pathology. It shows that there are specific plaques which have a number of different proteins and peptides. The one that’s dominant is the amyloid-beta peptide or A-beta peptide. It has neurofibrillary tangles, which have this component of phospho-tau in them.

Tau is a molecule that stabilizes your microtubules and connections in the brain. These are lost in Alzheimer’s disease. This is a major issue. There are close to six million people in the US with Alzheimer’s disease, but this underestimates the problem. For example, I have two daughters. They’re too young to know that they’re going to get Alzheimer’s yet or not. If you ask the question of about 323 million Americans or so, how many of us will develop Alzheimer’s disease? The answer is about 45 million people will develop it. It’s incredibly common. As professor Kristine Yaffe has published, it is now the third leading cause of death in the United States. As we’ve been all struggling with the COVID-19 pandemic, Alzheimer’s is a much larger pandemic that’s been going on for quite some time and is on the increase rather dramatically.

You mentioned what are the risk factors. It has many of the things that have affected us for chronic illness. For example, many of the comorbidities that we hear about with COVID-19 like hypertension, Type-2 diabetes, obesity, poor immune system support, reduced vitamin D and zinc. These are all comorbidities for Alzheimer’s disease. What’s happened with COVID-19 is you’ve taken the decades-long increased risk for Alzheimer’s and you’ve compressed that into a couple of weeks. Many of the same things that are giving us ill health, metabolic syndrome and things like that are the big risk factors for Alzheimer’s. The biggest problem of all is that doctors don’t look at what’s causing the problem. They say, “It’s Alzheimer’s,” but they don’t say why. You need to look at dozens of different factors. This is the future. This is the critical piece that we have changed and that has allowed us for the first time reverse cognitive decline.

I know you talk a lot about the recontextualization of Alzheimer’s, which is important. I found that on your website. It talks to everything we speak about on the show. For certain people, is Alzheimer’s their genetic destiny or is there flexibility in our gene expression with regards to this condition?

There is tremendous flexibility. First of all, the point would be that 95% of Alzheimer’s disease is sporadic. In other words, you don’t have the genetics telling you, you are going to get this. You do have some genetics of risk just as you do for heart disease for example, but look at what people have done to prevent heart disease. The 95% of us don’t have a gene that says you are definitely going to get this. About 5% of people have mutations that are in 1 of 3 genes, APP, Presenilin-1 and Presenilin-2. Those people do inherit a very high tendency. It’s essentially 100% penetrance, so they will get Alzheimer’s. However, we are also working with some people there and it’s not so clear that you can’t impact that as well.

That’s ongoing research and we’ll see over time, but for 95% of us who are going to get Alzheimer’s, we can absolutely do something to prevent it. We’re seeing also reversals time and time again. The common risk factor gene is APOE or Apolipoprotein E. It’s one of the fat carrying proteins. We think of this as your butcher. Our studies years ago showed that not only is this your butcher carrying around the fat, but it’s also your senator making the laws of the land. It’s changing the programming of yourselves and it’s changing them into a more proinflammatory and protective state. What we think about with Alzheimer’s is this whole idea of recontextualization. If you look at what Alzheimer’s is, unfortunately, people have had it backwards for many years.

When I say that, what I mean is they wait for you to get symptomatic. They don’t do any prevention. They look at a very small data set or they look at a couple of things, your thyroid, your B12 and say, “We don’t see a problem, Joe. You’ve got Alzheimer’s, there’s nothing we can do.” They put you on a drug that doesn’t help. They tell you that there’s nothing that can be done. All of that is completely backwards. Twenty-first-century medicine is about why. This is true for other chronic conditions, not just Alzheimer’s. Twentieth-century medicine was about what it is. We all learned in medical school to make a diagnosis. Is it measles? Is it a broken leg? Is it Alzheimer’s? What is it? Twenty-first-century medicine is about why instead of about what. It’s not just making the diagnosis, it’s saying, “Why do you have this?”

This refers to people with chronic pain. As you pointed out, they are at increased risk for cognitive decline. They should be getting checked with what we call a cognoscopy and getting on prevention. The idea here in 21st-century medicine, we look at 150 different variables that all contribute. We want to know if you have specific pathogens. For example, there’s a leak between recurrent herpes simplex that’s an untreated and cognitive decline and Alzheimer’s. There is a link between P. gingivalis, one of the oral bacteria that is associated with plaque in your mouth. If you have bad teeth, you are at increased risk.

We want to know what could be the cause so it can be treated. If you have increased homocysteine, reduced vitamin D. If you have pathogens, toxins, all of these things are contributors. The idea that there’s one cause is biologically naive. You want to identify the contributors. Typically, we find between 10 and 25 different contributors when someone has cognitive decline, and then we address all of those with a precision medicine personalized protocol. That’s the whole idea.

In essence, what you’re saying with this recontextualization of treating Alzheimer’s is instead of looking, there’s potentially a gene that turns on. The only way to reverse or “cure” this disease is to turn off that gene. That’s the old news. The new information is how do we look at the entire context of someone’s health span in their life and how that influences not only their genes but also all the different cellular mechanisms and in essence, how their systems biology influences their entire expression of this condition. I’d like you to talk a little bit about APOE 4 and APP or amyloid precursor protein. I was reading some of your research and you did a nice job at comparing Alzheimer’s to osteoporosis, and this synaptoblastic versus synaptoclastic imbalance.

HPP 196 | Alzheimer's Disease
Alzheimer’s is the most common cause of dementia.


Let’s start with APOE 4. As with other genes, we have two copies of the APOE gene. It comes in three different alleles, essentially 2, 3, and 4. You inherit one from your mother and one from your father. For example, the most common is APOE 33. I checked myself. I’m a 33, for example. That’s the vanilla. That’s the typical one. The APOE 4 is the one that gives you increased risk. If you have zero copies of APOE 4, which three-quarters of us have, your risk for Alzheimer’s over your lifetime is about 9%. It’s not zero, but it’s not terribly high. If you have a single copy, which 75 million Americans do and most don’t know it, this is again why we recommend to check it out and get on prevention. Let’s make this a rare disease, which we can now do.

If you’ve got a single copy, 75 million Americans, your risk is about 30% during your lifetime. If you have two copies, which about seven million Americans do, then your risk during your lifetime is well over 50%. Most likely you will develop Alzheimer’s during your lifetime unless you get on appropriate prevention. If you don’t do that, please get treated as you notice the earliest changes. It turns out APOE is something that is protective but gives you a pro-inflammatory state. As you know, pro-inflammatory state is associated with aging, cardiovascular disease and many other things including Alzheimer’s disease. You mentioned APP and I’m glad you did because it’s the way these things play out. APP is a protein that sits in the membranes of your cells, especially in your neurons and near the synapses where the neurons are connecting.

You have nearly one quadrillion connections in your brain. We have a tremendous supercomputer inside our skulls, which has about 100 billion neurons. On average, it’s nearly 10,000 connections per neuron. You have close to quadrillion connections. It’s truly an amazing brain inside our skulls. What happens is there’s a whole set of things that essentially give you a synaptoblastic signal. In other words, when things are good, your brain is saying, “I can make new synapses. I can build and maintain it.” When you’ve had good sleep and things are going well, you learn very well. When you’re under a lot of stress, you haven’t had any sleep, poor nutrition, you’ve got an ongoing inflammation, and all sorts of problems, you learn and remember less well. When we started to look many years ago at what is Alzheimer’s, that was the whole question. Could we understand the fundamental nature of this problem enough that we could begin to fashion the first effective preventions and treatments?

What we found is that APP, this thing sitting in this membrane, functions as a molecular switch. It’s striking. Let’s imagine that you’re the president of a country called Mybrainostan. When things are good, you as the president say, “We’re going to make new structures, build new bridges, and interact with new countries.” That’s what your brain does. In that case, APP is cut at a single site and produces two peptides, sAPP-alpha and alpha-CTF that do that. They signal and say, “Things are good. Let’s make connections. Let’s remember things.” When things are bad, let’s say in your second term as president of Mybrainostan and you’ve got pollution, people invading you, and you’ve got all sorts of problems. You don’t have any money in the coffers anymore in the national treasury, then what do you do? You say, “I can’t build. I have to downsize. I have to protect myself,” especially if you’ve got invaders coming across the borders.

Your brain does the same thing. Your APP recognizes this. It’s integrating signals from all sorts of different things. Your hormone levels, your nutrient levels, your trophic factor levels, your level of inflammation, all these things. What it does is saying, “Time to protect ourselves and pull back.” If you’re a president of Mybrainostan, you say, “We’re going to kill the invaders. We’re going to use napalm,” which now means we have less arable soil. You’re making your country a little smaller because you’ve got a war zone. That’s exactly what’s happening in your brain.

The first part when things are good is synaptoblastic signaling. It’s making and keeping synapses. Just like with osteoporosis, as we age, if we don’t have the right nutrients, hormones, etc., we can’t make new bone. We start losing our bone and we start developing osteoporosis. Alzheimer’s disease is synaptoporosis. When you don’t have the right support, when you’ve got invasion from mouth organisms or systemic organisms, you are protecting yourself against those. You’re trying to kill them. In so doing, you are now retreating. It’s a brain in retreat. That is synaptoclastic signaling. Everybody with Alzheimer’s has too little synaptoblastic signaling and too much synaptoclastic signaling. What we’ve done to translate this research into the clinic is to look at each person and ask, “What are the things that are contributing? Why are you on the wrong side of that balance?”

What we want to do is increase the synaptoblastic signaling and decrease the synaptoclastic signaling. That has given us unprecedented improvements in people with cognitive decline. We published the first examples of reversal of cognitive decline back in 2014. We published a book on this in 2017. It’s now in 32 languages and was on The New York Times bestseller list for five months. We’re now seeing this reproducibly. Thousands of people are now on this protocol. Not every single person responds but many do. The critical piece is to identify what’s driving that decline.

For the practitioners, I was reading through some of Dr. Bredesen’s work. I encourage you to go on PubMed and check out his studies. For everyone, you can check out The End of Alzheimer’s, which is his New York Times bestselling book, which is available on Amazon and other places. I want to go back to that idea of a molecular switch that we’ve discovered. The molecular switch, in essence, maintains the synaptic cleft. In essence, maintains healthy nerve function. It has the ability to repair that cleft or that nerve function. Can it remodel? Repair and model is similar but not exactly the same.

What it’s essentially doing is deciding whether there is reason to pull back or whether there is reason to go forward. In this case, it is part of neuroplasticity. You can see it makes a lot of sense why this is a disease of neuroplasticity. It’s a good question. We don’t know if it can remodel once the synapse is already there. We know for sure it can destroy the synapse. The amyloid is produced by APP very rapidly. There’s some beautiful research on this by people like Professor Ed Koo and others showing that if you put the A-beta on the synapse, it literally will destroy the post-synaptic element. It will pull back. This is about going forward and pulling back. With this, you also can pull back on the neuron and ultimately collapse and kill it.

There are all sorts of levels of interaction from changing the chemical communication to changing the anatomical communication, to pulling back on the axon and ultimately killing the cell itself. People have compared synapse formation maintenance to marriages. There’s courtship and there is commitment. There is marriage and there is de-commitment. There can be divorce, unfortunately. The pre-synaptic and post-synaptic elements communicate with each other. In pain research, there are issues about the abnormal communication that can happen with these connections. In this case, you’ve got this ongoing communication and you can say, “This is not working for me,” and literally pull back. Unfortunately, when you have these various insults, it tells us that Alzheimer’s disease is a protective response to these insults, but part of that protection is pulling back. This is very similar to what’s happened with COVID-19. We’re all protecting ourselves from COVID-19 but it’s at a price.

We’re going into our homes. We’re not able to do the business we once did. Look at what happened to our schools. Look at what happened to our sporting events. This is very similar to a brain that’s in retreat that’s trying to protect itself. Therefore, we want to know what are those insults from which it is trying to protect itself. Let’s get rid of those. It also tells us the pharmaceutical companies that have said, “Get rid of the amyloid and everything will be fine.” That has not worked and we can see why. It’s because you have to get rid of what’s causing the amyloid. In the long run, it’s going to be very helpful to get rid of the amyloid, but we’ve seen a number of cases where people lower their amyloid without lowering their toxic burden or their pathogen burden. They clearly got worse. You need to address the upstream causes.

A lot of what you’re talking about is the basis of plasticity or neuroplasticity. It is important to Alzheimer’s cognitive decline, chronic pain, pretty much anything that involves the nervous system, which is almost everything and every condition in your body. In your earlier research, you identified three subtypes of Alzheimer’s. I believe that’s now grown to six. Can you walk us through those a little bit? I love that framework of getting different types of Alzheimer’s and different exposures.

As we begin to look at why people have this, that’s the key. We start to see that they fall into subgroups when we first published this back in 2015. We tell the patients, “Imagine you have a roof with 36 holes in it and you’ve got to patch those different holes. You’ve got to find out what they are first.” As we started to look at what’s driving this? This started with APP. We now know that APP can go one way and go the other way. It can go the good way or the bad way. What are the things that drive it to the bad way? It turns out that they tend to be in groups and it turns out there are six different groups. If you have ongoing inflammation, this can be from P. gingivalis, T. denticola, F. nucleatum, HSV-1, HHV-6a, Borrelia, Bartonella. There are lots of different chronic pathogens that they have in common that tend not to be acute pathogens. It’s not pneumococcal pneumonia. These are chronic pathogens like Lyme disease, tick-borne organisms and things like that.

HPP 196 | Alzheimer's Disease
Alzheimer’s is linked to one of the oral bacteria that is associated with plaque in your mouth. If you have bad teeth, you are at increased risk.


You’ve got a chronic inflammatory state as what’s seen in cardiovascular disease. Part of the response, and this is interesting to me, the amyloid that is produced by APP, and APP is the father of the amyloid that’s produced. The amyloid is part of the innate immune system. This is part of your inflammatory response just as COVID-19 is killing us with cytokine storm. These pathogens are killing us by telling us to make A-beta to fight the pathogens, which is downsizing and damaging our synapses. That’s type one or hot Alzheimer’s inflammatory. You typically see the high sensitivity C-reactive protein, hsCRP.

We recommend that everybody, please check your hsCRP. It’s important for your cardiovascular disease, but it’s also important for your risk for Alzheimer’s. Type 2 Alzheimer’s is atrophic. You can imagine this easily. You’re going to have to pull back either because someone’s attacking you and you’re fighting them, or because you don’t have enough money or you don’t have enough support. You want to give yourself Alzheimer’s disease, get rid of all your trophic factors, all your nutrients, and all of your hormones. A big risk for people who have sudden drops when they’re relatively young is estradiol. That’s one of the common. Studies out of the Mayo Clinic is showing that people who had an early oophorectomy at the age of 40 or younger and who didn’t have hormone replacement therapy doubled their risk for Alzheimer’s, even though the Alzheimer’s came on years later.

Your APP is responding to this support level. If you drop your vitamin D, your B12, increase your homocysteine, drop your estradiol, testosterone, pregnenolone, progesterone, thyroid hormone. All of these things are critical supports nerve growth factor, brain-derived neurotrophic factor. These are all critical supports for your synaptic production and maintenance. That froze you again into a synaptoclastic state. You simply cannot afford those 500 trillion-plus synapses, nearly quadrillion synapses. That’s Type-2 or cold Alzheimer’s. There’s one that has some of both, which is type-1.5, which is glycotoxic. This is sugar-induced Alzheimer’s. There’s a striking relationship between sugar and Alzheimer’s disease. About 80 million Americans have insulin resistance. It’s incredibly common. This is because our diets have more simple carbs than we made evolutionarily to handle.

What do we do? We ramp up our insulin. We end up getting insulin resistance, which has shown in the vast majority of people with Alzheimer’s. You can trace the molecular pathways. The IRS1, which is one of the signaling molecules downstream from insulin becomes phosphorylated to shut it down. It’s as if you were living with a son who’s playing loud drums all the time. You’ve got some earmuffs for you and your spouse. Your spouse puts on a Brahm’s Lullaby. You can’t hear it. That’s exactly what happens to our brains. Our neurons depend on insulin as one of the growth factors. When you can’t respond to insulin, you start downsizing. You start losing these synapses. That’s type-1.5 or glycotoxic or sweet Alzheimer’s.

Type-3 is toxic. The toxins come in three different kinds, metals and other inorganics. You live around air pollution. You have too much mercury or things like that. Organics things like toluene, formaldehyde, and benzene. The third one is biotoxins. We find many people who don’t realize that toxins produced by molds do increase your risk for Alzheimer’s. It’s not all molds. There are five big groups. There are Stachybotrys, penicillium aspergillus, Wallemia, and Chaetomium. Those are the big five. You could easily check your house. There’s something that the Environmental Protection Agency put out called an ERMI score for EPA relative mold index. You can check it in your house easily. You want your score to be less than two in your house. If you’re sitting up there at 8, 10, 12, you’ve got some concerns because you’ve got molds in your house that are far too high, then you need to check to see if you got exposed to these toxins. We see this all the time where people come with Alzheimer’s for no reason. When you check it, you find out that’s the thing. That’s type-3 toxic Alzheimer’s.

Type-4 is vascular. That’s also very common. If you don’t have enough vascular support, that increases your risk for Alzheimer’s. One of the most common things we’re seeing is people who have sleep apnea or have decreased oxygenation at night. It’s incredibly important to find out whether you have good oxygen saturation. It should be in the 96% to 98% range. We’re all concerned about oxygen saturation with COVID-19. You can even check it during the day on your iPhone. Type-5 is traumatic. If you’ve had head trauma, you are at increased risk for cognitive decline associated with Alzheimer’s. Also, an increased risk for CTE, as were shown in the film Concussion. These are all the subtypes and different people have different drivers. We need to identify those and address those drivers of cognitive decline.

I love that framework of those different subtypes. We’re talking about cognitive function and brain health. In any of those different subclasses, is depression or anxiety a trigger for Alzheimer’s or is it a part of one of those subtypes?

Depression is especially common. When people would have trouble with their thinking, they go to the doctor and the doctor says, “It’s depression. It’s not Alzheimer’s.” It turns out they’re much more closely related. They used to also say, “It’s vascular dementia, not Alzheimer’s.” These are closely related. Depression and anxiety are both relatively common precursors for dementia. If someone said you have dementia, be careful. Make sure that you’re doing okay with your cognition. Your cognition should begin to come back and be back to normal as you are recovering from the depression. That is associated with risk. Depression is associated often with systemic inflammation, which is one of the precursors for Alzheimer’s. It’s one of the risk factors.

What we’ve found especially is it’s associated with the toxic subtype. People who have type-3, and we hear this story all the time, especially for people who are in their 40s and 50s because it’s the young people that tend to get the type-3 toxic. Whereas the older people are the ones that tend to get the type-2. Type-2 is more a disease of your 70s. Type-1 is a disease of your 60s. Type-3 is more a disease of your 40s and 50s. By the time that you get a diagnosis, the underlying changes have typically been evolving for about twenty years. Therefore, what we use to think as a disease of the 60s, 70s, and 80s is a disease of the 40s, 50s, and 60s. That’s playing out over time and then you get a diagnosis later.

This is why we recommend everybody to please get evaluated and get a cognoscopy as you’d get a colonoscopy when you turn 50. When you turn 45 or if you’re older than that, or if you’ve got a strong family history, please get evaluated. The depression tends to suggest type-3. The young people in their 40s and 50s that are getting cognitive changes suggest type-3. People start with a non-amnestic abnormality. They start having trouble with planning. The typical story is, “I can’t do my job anymore,” and yet it can be memory sparing early on. It’s not always but it can be, and then memory is affected later. If you’re having trouble with navigating, planning things, doing your job, learning your new iPhone, word-finding or recognizing and remembering faces, please get evaluated. Depression is commonly a harbinger of type-3 toxic Alzheimer’s.

You can find a lot of this information at and his book, The End of Alzheimer’s. I want to turn now to your ReCODE protocol. You’ve spent decades studying Alzheimer’s and cognitive decline, both the etiology as well as the treatment. You’ve put it into a nice program for people. Let’s start with nutrition. People who follow this show are familiar with the Mediterranean diet, the basic elimination diet, and the lower carbohydrate ketogenic diet. Which type of diet would you recommend for the majority of patients that you see who have Alzheimer’s?

Let me preface that by saying that what our research showed is this is a disease that has many different contributors. Even for one person, there are typically several like 10 to 25. People will have some degree of inflammation, reduced hormones, trophic factors or nutrients. They often have some toxic exposure. They often have some multiple subtypes. Often one is dominant but they’ll have multiple. Therefore, we realized we have to attack all of these things. There’s a core and it starts with basics. For each person, we need to look at, are there specific pathogens that we need to eradicate? Are there specific toxins that we need to remove? All these sorts of things. It helps for everyone to start with the right nutrition, exercise, sleep, stress, and brain training. Those are the big five at the beginning, then detox and pathogens after that.

For the diet, we use what’s called KetoFlex 12/3. The idea is the thing that works best for cognitive decline is a plant-rich and mildly ketogenic diet. This is published in multiple studies. We’d like to get people to check their ketones and they should be between 1.0 and 4.0 millimolar beta-hydroxybutyrate. We’re hoping that it will be as good to do breathalyzer in the future that we’re evaluating that now. The best way to do it is to do the fingerprint and check your ketones. You don’t have to do it that often, but to check that you get into some mild ketosis, and you already indicated things like this is going on in lots of places for many different reasons. For the brain, the thing that works the best is for it to be plant-rich. It’s flexitarian. You can have some meat or fish or not, as you wish. For people who want to be vegans or vegetarians, no problem.

HPP 196 | Alzheimer's Disease
There’s a striking relationship between sugar and Alzheimer’s disease.


For people who want to have fish and meat, it’s great. Make sure it’s wild-caught fish. Make sure it’s pastured chicken. If you’re going to have some chicken, be aware that there’s some arsenic in many chickens. Be careful about that. If you want to have some beef and things like that, no problem. Have the grass-fed beef. That will give you a better omega-3 or omega-6 ratio. A wild-caught salmon is great stuff. Be careful, there’s a lot of farmed fish that aren’t particularly good for you.

All of these things have bad news. We want to have a SMASH fish, Salmon, Mackerel, Anchovies, Sardines, and Herring. That’s the SMASH fish. Those are the little guys that give you the good omega-3s without giving you all that mercury. KetoFlex 12/3, what this means is you want to have fasting. It turns out to be incredibly good for your brain. It surprised the heck out of me as a researcher. As a researcher for many years, I didn’t think what we were going to end up with would have anything to do with whether you ate fish or not, anything to do with various vitamins. I thought that stuff was all hokey years ago. It’s turned out I can’t deny the science. It shows where things go with your APP signaling.

Fasting turns out to be very helpful. It does activate autophagy. It gives you more ketosis. One of the things that ketones do interestingly is to increase your level of brain-derived neurotrophic factor. They remove an inhibition to produce the protein from that gene. All of these things show that you want to get 12 to 16 hours. If you’re APOE 4 negative, we recommend everyone find out their APOE status. It’s easy to do. You can do it on 23andMe and lots of other ways. You want to have 12 to 14 hours. If you’re APOE 4 negative, 14 to 16 hours, and some people even go longer. People will do time-restricted eating and go to a 6 or 8-hour window to get yourself some best.

You have to look at what is your BMI. If you’re incredibly thin, be careful. Make sure you go through cycles and you’ll get some more carbs once a week. In general, you want to have a low carb diet. Especially simple carbs, it’s very contributory to cognitive decline. One of the things we’re seeing is that people with continuous glucose monitoring is a very helpful thing. There are all sorts of so-called biohacks that people can now use to help themselves. Checking everything from blood pressure to glucose, to ketones, to oxygenation, to heart rate variability. All these things are easy to do now. The quantified self is becoming more and more important for those of us interested in avoiding chronic illness. That’s the diet part.

KetoFlex 12/3 is similar in many ways to the Mediterranean diet. Specifically, biochemically you do better if you induce this state of ketosis. For the first couple of months, we recommend to people if they can’t get into it endogenously, no problem. Simply take some ketones. You can do this by taking ketone salts or ketone esters. You can do it by taking things like MCT oil or coconut oil. Be careful if you’re taking the oils. You could increase your LDL particle number. You want to check and you can then use the unsaturated fats imbalance to make sure that you don’t go too high and hurt your lipid profile. I go into this in the book. There’s a lot that you can do. Exercise is critical. You want both some strength training because that improves your insulin sensitivity and you want to have some aerobics.

Both of those improves oxygenation. Blood flow to your brain turns out to be more important than we ever were told in the past. Sleep is one of the most misunderstood and underappreciated preventions for Alzheimer’s disease. If you have a reduction in your oxygenation while you are sleeping, which so many of us do, then in fact that correlates directly with a reduction in the volume of different regions of your brain, including ones that are critical for Alzheimer’s disease and for memory formation. It’s important to make sure that you’re getting enough sleep and that it’s high-quality sleep. We see this all the time. People not getting enough sleep or dropping their oxygenation at night, contributing to their cognitive decline. Stress is another contributor. As your cortisol goes up, your stress level goes up, your brain size goes down. That’s been published repeatedly.

Brain training is helpful. Brain training by itself has gotten a bad rep because people who are doing that and nothing else may not do as well, but in the background of all the rest of the protocol, it’s very helpful. Optimizing hormone levels is critical. Supplements have gotten a bad name because when you take this stuff, people will tell you, “If you take this one pill, you’re going to reverse your cognitive decline,” which is ridiculous. There are 36 holes in the roof. The supplements are good for a couple of holes. They are helping with some of these things. They are helping you get into ketosis. They’re helping you optimize your vitamin D. They can help you increase your brain-derived neurotrophic factor.

There are all of these good outcomes you can have, but you need to do the other pieces or you’re hurting yourself. We got to give the concept of you’ve got a house that’s burning down. Don’t do one thing. Trying to rebuild the house as it’s burning down makes no sense. Put out the fire and then rebuild the house. That’s the critical piece. You’ve got to have the right hormones, the right nutrients, the right trophic factors, and then making sure that you’ve got the appropriate vascularization. For some people, using something called EWOT, Exercise With Oxygen Therapy can be very helpful to get the right amount of blood flow.

There is a personalized program. We have a computer-based algorithm that shows you here are the things that are contributing to your decline or your risk for cognitive decline. We call this PreCODE, Prevention of Cognitive Decline versus ReCODE, Reversal of Cognitive Decline. The bottom line is that Alzheimer’s should be a rare disease and can be a rare disease if everybody has the appropriate prevention and treatment, especially early on treatment. Please don’t wait. Many people say, “I’m going to wait until I’m worse. I’m not that bad yet.” That’s the opposite of what you want to do. You want to get in early.

I love the lifestyle approach because you went through all the major five factors of lifestyle, which are key for everyone no matter what your condition is, but especially with regards to cognitive decline. Let’s go back a little bit. You mentioned that Apolipoprotein E, APOE shuttles fat around. To bring that into the treatment aspects of it. You’re talking about a mildly ketogenic diet, not full ketosis but mild ketosis. It’s a Mediterranean style diet but lower in carbohydrates where you have that 12/3 approach. You’re fasting for twelve hours overnight ideally, and there are three hours you have between dinner and bed. If I were to go into PubMed now and look at high-fat diets being a risk factor for Alzheimer’s, I might find some research supporting that. How does that contrast with a ketogenic diet, which people hear right away? Ketogenic is a high-fat diet so that can’t possibly help with this condition.

I’m glad you brought that up because that is a common misunderstanding. There are many misunderstandings in the Alzheimer’s field because people will isolate one variable and then try to apply it out of context. I wrote a whole chapter in the book on how to give yourself Alzheimer’s to let people know and recognize that I’m doing a lot of these things already. If you want to give yourself Alzheimer’s, what you want to do is go out and have a cheeseburger, Coke and French fries every day. You’ll damage your liver, you’ll get metabolic syndrome and ultimately you’ll get cognitive decline. You’ll also have vascular disease, so forth and so on.

When you damage your blood vessels and you get metabolic syndrome, you increase your insulin resistance because you’ve got those simple carbs and then you get the saturated fats. That’s the worst combination. Dr. Mark Hyman has pointed out this horrible triangle, which we call the Berfooda Triangle. It’s like the Bermuda Triangle. You don’t want to combine three things. Those are saturated fats, which you’re going to get in hamburgers, butter and stuff like that, which without the simple carbs, they can be very helpful. It’s those two together and then low fiber. That triad is incredibly damaging to your vessels, to your heart and to your brain.

That’s why when you go out and look it up on PubMed, you say, “High-fat diets, high saturated fat is going to kill my brain.” Yes, if you’ve got a lot of carbs on board. However, people get very good lipid profiles, specifically the simple carbs, when they get rid of that sugar. We were the only evolutionarily designed to handle about 15 grams of simple carbs per day. It’s a little bit like jumping off a roof. If you start doing that every day, you’re going to get arthritis. You might kill yourself. You might get a broken leg. We weren’t meant to do certain things. Our bodies simply can’t handle that degree of simple carbs. Unfortunately, we’re exposed to it all the time because of processed foods and because of the food industry. Once you get rid of those, having a high fat and an intermediate protein diet is very good. You will not get the bad lipid profile and you will not get the bad cognitive profile. That’s the misunderstanding. It’s looking at the whole thing together as opposed to one component.

HPP 196 | Alzheimer's Disease
Our neurons depend on insulin as one of the growth factors. When you can’t respond to insulin, you start downsizing and losing these synapses.


Some of the guidelines are extremely lenient like the American Heart Association guidelines for how much added sugar you can have. I tell the practitioners all the time, “If you have people who have metabolic syndrome, prediabetic or diabetic, even that is way too generous for these patients.” I’m sure it holds true with this. One more question along those lines. Oftentimes people ask about statins having a place in the effective management of Alzheimer’s.

The best situation is where you do the right things with your diet, exercise and sleep. You don’t have to get on a statin. You shouldn’t need a statin. If you do the right things, if you’re not eating the wrong stuff, then in fact you won’t need one. What we usually say when people come in is, “Don’t change what you’re on. We’re going to fix all the other things. After you’ve begun to see some improvement, we can now slowly wean you off these things.” When people get on the protocol that we developed, they can get off their statins. We see this all the time. They don’t need those anymore. They get off their anti-diabetes drugs. They don’t need them anymore.

They lose their Type-2 diabetes. They get off their antihypertensive drugs. They don’t need it. Hypertension is because something is going wrong. You can fix that. All of these things that they needed before, they can begin to get off. They’re allowing you to do all the wrong things. You want to be able to do the right things. That means changing some behaviors and that’s hard for all of us. There are all sorts of interest in how to take micro-steps, how to make small changes, one change at a time. As Arianna Huffington was saying in her Thrive Global, instead of going from 7 sodas to 0, go from 7 to 6.5. Go slowly and ultimately do the right things.

When you’ve got a cognitive decline, you have a choice. You’re either going to be going to a nursing home or you’re going to be getting on the right things and getting better. That’s a strong incentive to do the right things over time. There are all sorts of workarounds. That’s the good news. Many people will say, “I can do A, B and C, but I can’t do D.” Do some of the things. The most important thing is people get improvements and sustain their improvement. That is unprecedented. When you get on a drug, you may get a little bump and then you go right back down to declining. We have people with over eight years of sustained improvement.

This woman from 2012 did 12 out of 36 things. She wasn’t able to do them all. That’s okay. It was enough. You close enough of those holes, the other ones snap shut, which is the good news. Essentially, you’ve gotten over that threshold. You’ve gone from synaptoclastic signaling to synaptoblastic signaling. Dr. Dean Ornish saw the same thing with cardiovascular disease years ago and showed that once you get over that hump, you’re now starting to pick up the plaque in your artery instead of laying it down. This is the same story. Do what you can. Get workarounds where you need to and you’ll do much better.

Speaking of people making positive steps forward and making progress, how many people have you helped now and put through your ReCODE protocol?

There are over 5,000 people who are now on the protocol. You can go on It’s a wonderful website started by Julie G who’s an APOE 4 who’s done doing very well. She’s gone from 35th percentile to the 98th percentile on our cognitive testing. She’s absolutely brilliant and an amazing lady. She wrote part of this next book with me along with my wife, Dr. Aida Lasheen. She’s been fantastic and started this website. The vast majority of those people are on some version of the protocol. The main issue is for a lot of people, we don’t have enough follow up information yet. People will either not get a baseline. We know they improve, but we can’t compare it to something because they didn’t get the baseline.

The ones who do, we see repeated improvement. We published 100 examples in 2018 who had all their baselines and then all showed sustained improvement. We’re working on one where we have PET scan improvements, MRI improvements, cognitive scoring improvements, striking improvements on all these different quantitative tests. One of the interesting things in follow up has been looking at the electrophysiology. We’re looking at quantitative EEG, looking at evoke responses where you can see improvements that you can’t deny. This is not a placebo response. These are objective and sustained improvements. When you go off and we’ve had people go off, and then about 7 to 10 days later, they will begin to see some decline. They go back on and they’ll improve once again. There is a time linkage to people getting improvements.

The bottom line is we don’t know how many people have shown improvement because we haven’t had the documentation for all of them. That’s one of the things we’re doing. We’re in the middle of the first clinical trial. We tried to do a clinical trial when this all started back in 2012. It was turned down because the IRB said, “You’re doing a multi-variable trial. You can only change one thing.” We said, “That’s not the way this disease works. You have to change multiple factors.” This is a systems biology problem. We were finally okay to do this in 2019. We’re finally allowed to start the trial. It will be completed in December of 2020. It should be published in 2021.

We’ll have to have you back on once that clinical trial comes out. I’ll watch out for it. I know you have a new version of your book, The End of Alzheimer’s. Tell our readers how they can learn and follow you in the future.

You can go on to or also Apollo Health was set up specifically to write code to do these algorithms. Twenty-first-century medicine is about getting larger algorithms, getting larger data sets, and looking at what’s causing the problem. In our trial that I mentioned, all the previous trials predetermined the treatments, “We’re going to give this drug or this lifestyle change.” This is not the way to go. What you want to look is what caused it for each person. Do you want to address those things? This is personalized. You can look through

You can search for his book, The End of Alzheimer’s on Amazon or wherever books have been sold. I want to thank Dr. Bredesen for being on and helping us make Alzheimer’s of rare disease. Make sure you share this episode out with your friends and family on Facebook, Twitter, or LinkedIn, or in a Facebook group where people talk about how to reverse Alzheimer’s and cognitive decline. I’ll see you next time.

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About Dale Bredesen

HPP 196 | Alzheimer's DiseaseProfessor, Department of Molecular and Medical Pharmacology
David Geffen School of Medicine at UCLA, Los Angeles, CA
Founding President and CEO, Professor Emeritus, Buck Institute for Research on Aging, Novato, CA

Dale Bredesen is a Professor at UCLA and Founding President of the Buck Institute for Research on Aging. His work focuses on the mechanisms leading to neurodegeneration, and with his research group he has published over 220 scientific papers, leading to the first description of the reversal of cognitive decline in patients with Alzheimer’s disease. His book, The End of Alzheimer’s, is a New York Times bestseller and is now available in 32 languages.

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