The Link Between PCOS And Alzheimer’s Disease

Dale Bredesen, MD

Thanks so much, Felice. It’s great to be with you. I spent my career working for 30 years in the laboratory looking at one fundamental question: what is the basic molecular driver or drivers of neurodegeneration? Why do you get Alzheimer’s, Parkinson’s, Lewy body disease, or, on and on, so many different things—frontotemporal dementia, ALS? We spent a lot of time and published over 230 papers on this, looking at what drives it. I have to say, the big surprise is that we finally began to translate all this research back in 2012. I saw the very first patient I had not seen in over 20 years. I have been working on mice, fruit flies, and cells for all that time. But we saw the first patient in 2012, and I was so pleasantly surprised that she did extremely well, improved her cognition, and called me after about three months at my home on a weekend to tell me how great she was doing. I was very enthusiastic to hear about that. 

Then we began getting case after case. We have now had over 7,000 people who’ve been on our protocol. We published a clinical trial last year, which is a proof-of-concept trial. It is freely available online, as our other studies are. This came out in the Journal of Alzheimer’s Disease. You can take a look at that at any time. In that study, 84% of the people got better. Did not just slow their decline. They got better. We have people now who have been better for over ten years. As I mentioned, the woman who got better in 2012 is still better. She is now 11 years into this when normally she would have been either in a nursing home or passed away. We are very enthusiastic that the research translated very well into what you can do to prevent and reverse cognitive decline. I would argue that now if everybody does the right thing, we can make Alzheimer’s optional.

Felice Gersh, MD

What a wonderful thought to think that this massive killer is one of the main drivers of people’s deaths. It is just that what it does to the family members is unbelievable. I see so many of my patients who spend several years caring for one of their beloved parents who is in decline with Alzheimer’s, and it takes down the caregiver as well as the one they are caring for. It is such a huge, unfortunate epidemic. They are talking about it growing by leaps and bounds. Here you are saying it is preventable. That is why I love to focus on, is prevention. But I love that you are not just preventing; you are reversing, which most people think is impossible. You have done what is generally viewed as impossible. Now I want to add to your incredible list of accomplishments by helping to explain this to our audience of women with PCOS. 

First of all, help them to understand, and I will agree with you that they have many of the risk factors that underlie the evolution of developing Alzheimer’s and what those are in general. Then we will bring it back to PCOS. Then, of course, we are going to talk about what can be done to help prevent this horrible condition. For anyone out there who does not know this, women have, and you know the data, I am sure better than I, something like two and a half times the incidence of Alzheimer’s compared to men. That is age-matched. Women are especially vulnerable to this condition. I will give you my two cents on why I think that is. But I would love to hear what you have to say about the underlying risk factors that tend to exacerbate the occurrence of Alzheimer’s and then we will see how that matches with some of the symptoms and conditions metabolically and reproductively that are, unfortunately, having to be dealt with by women with PCOS.

Dale Bredesen, MD

Yes. To put it in perspective, over a million people now have died in the U.S. from COVID-19, and about 45 million of the currently living Americans will die of Alzheimer’s disease if we do not do something about it, which is why prevention and early treatment are the ways of the future. As you indicated, about 65% of the patients are women, and 60% of the caregivers are women. As Maria Shriver has pointed out over the years, this is unfortunately a woman-centric disease. 

Fortunately, there is a lot you can do. But let us go back for one moment to what the laboratory results showed us because they pointed us in the direction here and what they showed when we studied cellular signaling—what is going on in your brain. They showed that there are two major things that contribute to this loss of synapses: the loss of connections in your brain, which is what Alzheimer’s is all about. One of them is energetics—the things that support your brain. If you think about it, that is not too surprising. This is a degenerative disease. You prevent it and reverse it by improving the energetics. Those are mainly cerebral blood flows. You are looking at the blood that is coming into your head for oxygenation. You want to make sure you are not dropping that, especially if someone with sleep apnea is at risk, for example. The third thing is mitochondrial function. You want to make sure that your mitochondria, the batteries of your cells are doing well. The fourth is metabolic flexibility, the ability to go back and forth between ketosis and glucose utilization. 

In fact, Felice, if you simply do a PET scan on a patient with Alzheimer’s or pre-Alzheimer’s, the signature of Alzheimer’s is reduced glucose utilization in the temporal and parietal regions. It fits perfectly with what we discovered in the lab. It is showing you that you are simply not using this appropriately. This is largely because of insulin resistance. Energetics, one big one, and the other big one is inflammation. It is specifically your innate immune system activation, which is chronic, especially the memory part. It used to be thought that the innate immune system, which is the older evolution-free part of your immune system, the one that is associated with inflammation and has less specificity, had no memory, but it turns out that is wrong. In fact, the memory for the innate system lives in three sites. It lives in your bone marrow; it lives in your endothelial cells, which is why, unfortunately, people who have this high blood pressure get these increased thrombotic and embolic events. Then, third, it lives in your tissue macrophages. In your brain, those are called microglia. They are cells that will grab various pathogens, toxins, and even amyloid. Those are the two big things. It is too energetic, too much inflammation. It is literally a supply-and-demand situation. 

Therefore, there is a tremendous amount you can do, starting with looking to see what is a risk factor for you. Do you have insulin sensitivity? Do you have metabolic syndrome? Do you have obesity and inflammation? Do you have nutrient deficiencies? Do you have hormonal changes? Unfortunately, all of these things are risk factors, and I am always after people as well. Please check your oxygenation at night. It is easy to do. Wearables are so helpful to us that you can check things like your heart rate variability. Looking at your stress levels and things like that, we can address all of these things that are risk factors for Alzheimer’s disease and, as I say, literally make it optional now.

Felice Gersh, MD

Well, when you say that list of all those things, it just rings so many bells in my mind concerning women with PCOS. If we look at them, this is not talked about about the risk of Alzheimer’s dementia for women with PCOS; it is hardly a peep out there in any of the literature. If you think about it, then we will look at all of these things. One thing that is very pervasive in women with PCOS is this low-grade chronic inflammation. Another is insulin resistance by age 40. Women with PCOS have about a sevenfold increased incidence of diabetes compared to the regular population. No hypertension, no endothelial dysfunction; we talked about the artery lining and women. One of the things that we can touch on is the production of nitric oxide, this amazing gas that helps to maintain the health of the lining and also prevents platelets from clumping and causing abnormal clotting. 

In order to have healthy arteries, you need nitric oxide. Women with PCOS make less of it. They tend to have more endothelial dysfunction, which of course manifests very heavily in pregnancy-related complications, which we now know is the ultimate stress test for women, and then sleep apnea. You have mentioned that women with PCOS have twice the incidence of obstructive sleep apnea and sleep-disordered breathing. 80% have obesity, have abnormal dysbiosis, and have leaky guts. What is interesting is that they have a lower threshold to trigger the inflammatory release of cytokines compared to others, people’s immune cells, and hormonal imbalances. In women with PCOS, a lot of people focus only on the elevated androgens, particularly testosterone, but they also have a defect within their ovaries with that process of converting testosterone into estradiol. They produce estradiol insufficiently. 

One of the things that I would love to have you touch on as well is one of the things that endeared me to you instantly when I learned about your protocol for reversing Alzheimer’s: for women, you always included estradiol. If we try to dissect some of these one by one and talk about what is going on in the brain regarding estradiol, the glucose transport system, and then inflammation, what is happening in the brain? I love that you started explaining what is going on in the brain, so maybe a little bit more on that, and then we will talk about, well, going forward, what are we going to do?

Dale Bredesen, MD

Yes, and there is a tremendous amount that everyone can do. I think that is the good news. This was not known 20 years ago or 15 years ago. We reported the first reversals of cognitive decline in 2014, published in More than 100 documented cases in 2016; and 100 documented cases in 2018. then, as I mentioned, a trial last year, and we have just started a trial at six sites this year, which is a randomized controlled trial. It is so clear that there is a lot you can do. But let us go back to the basics because you can explain exactly why this happens. 

If you look at the brain of someone with Alzheimer’s, the first thing you see is that it is shrunken, unfortunately, it truly is a degenerative process if you synapse. The second thing is that you see these clumps of what are called amyloid. Amyloid is made largely from a single peptide, which is called the amyloid beta peptide. Unfortunately, people have gone after—that is, that must be the bad actor. Let us just remove that stuff; let us suck that out of the brain. that has not worked very well at all. Therefore, we want to know why that is there. What happens? It is quite a beautiful story. Amyloid is a little piece of a larger protein, which is called amyloid precursor protein, or APP.  This APP sits across the membrane. as part of its outside, most of its outside, and a little bit of inside. It communicates the outside of the cell with the inside of the cell. It is in many cell types, but mostly in neurons in the brain and mostly at synapses. It is a perfect contender for things that are related to synaptic loss. 

Now, what that does turn out to be fascinating. This thing is a molecular switch. What happens is that it goes back and forth when things are good, you have not too much inflammation, you have plenty of support, etc. Then this thing is cut at a single site, and it produces one peptide for the outside of the cell and one for the inside, and it says things are good. We are going to make and maintain connections. By the way, estradiol has a dramatic positive effect on that. Estradiol binds to receptors in the cell, enters the nucleus, and alters hundreds of genes. guess what? One of the ones that increases is the one that cuts that APP at that single site, which is called the Alpha Secretase. You can literally trace the molecular pathway of estradiol to make your brain function better. Now what happens to that same thing that is putting you in this growth and sustaining mode? Also, when things are bad—too much inflammation, not enough blood flow, sleep apnea—as you mentioned, all of these problems come up. Then it says, I have to go into a protective downsizing mode. 

By the way, this is the same thing that happened to our country during the pandemic. What happened was that early in 2020, we were told there was a new insult. SARS-CoV-2.  You are going to have to socially distance yourself, you are going to have to isolate yourself, and you are going to have to not go to work—all these things. Of course, the country went into a recession. This is the same thing that happens to your brain when things are not good. It throws you into a protective mode and says, Aha, you cannot make those two things grow now. Got to recede. So what happens is that you now get caught at three different places and make four different peptides, from two inside the cell and two outside the cell. Guess what? NF-kappa B, which is one of the inflammatory mediators, again affects hundreds of genes, and two of them are the ones that cut at the beginning and end of the amyloid peptide. You now have these four different peptides, which are called sAPP-Beta, A-Beta, the thing that everyone vilifies in Alzheimer’s, JCasp, and C-31, and these things are saying just the opposite change. 

Put your resources not into new bridges, new synapses, etc. Put your resources into protection. By the way, the amyloid, again, that has been vilified, is a wonderful anti-microbial. It kills viruses, it kills bacteria, it kills spirochetes, and it kills fungi. This was first shown at Harvard by Professor Robert Moyer and Rudy Tanzi. I think it fits perfectly with what we found in the lab. This is now switching. You are going into a different mode. Therefore, you are going to continue that downsize until someone figures out why it is happening and addresses those things. Now, an important piece, with respect to the inflammation part. Well, what kills us when we have COVID-19 is a cytokine storm, as this is just a dramatic outpouring of cytokines. 

Again, there it is because the innate system and the adaptive system are not aligned. Normally, what happens is that the innate system turns on the adaptive system, which seeks out the pathogen, destroys it, everything’s cleared, and it resets the innate system. Now everyone’s happy, and you are not inflamed again. But with COVID-19, you just do not get there for some people. You die of a cytokine storm. Well, guess what? In Alzheimer’s, the same thing happens. You’ve got an ongoing problem. You are not able to clear it, but it is not as dramatic. You are dying of cytokine drizzle. Instead of a cytokine storm, you do not die in a week; you die in 20 or 25 years. 

In fact, that was one of the surprises I was taught: that this is a disease of old age—60s, 80s, and nineties. Guess what? It turns out that the underlying changes in your brain begin 20 years before a diagnosis. This is a disease of our 30s, 40s, and 50s that is being diagnosed far later, which is why, again, if we jump in early, there is so much that can be done. That is why estradiol is so critical here because it is pushing you over. It is one of the features that pushes you toward the growth and maintenance side and away from the protective downsides. Now, of course, if you still have ongoing inflammation and ongoing pathogens and toxins, you cannot move them back there. But once you address those things, all of these things together literally change this molecular switch so that you are again in growth and maintenance mode.

Felice Gersh, MD

This is so amazing. I hope all of you heard that all of that focus was a little bit misunderstood on the amyloid data. We just have to let it go, move,  and understand what it does and does not do, and then focus on these new understandings, which are so huge, including the benefits of my favorite hormone, estradiol, and what it can do in the brain. Of course, on the opposite side, what happens, you said, if you do not have that, and then what happens to the brain? It goes into this other modality stage, which is theoretically protective but not when it just never ends. If we look at some of the other issues, say, insulin resistance, what is the biggest role there? I know some people say, That is okay, just eat facts. Is that an okay substitute for not having proper glucose transport into the brain?

Dale Bredesen, MD

Yes, such a good point. I go back to when I learned medicine, which was way back in the 1970s and 1980s. The idea was to make a diagnosis, write a prescription, or send me to surgery. The new medicine has changed that dramatically. As such, we now need to understand physiology. What are all the things that play into this problem? Here is the issue with insulin: What happens is that normally your brain requires one of only two things to have its energy, because, of course, it has to have the blood flow or the oxygenation, but it also has to have substrates, either glucose or ketones. Unfortunately for so many of us as we get over 40, both of those fail. When I see patients who have cognitive decline, to me, that is an energetic emergency. They are sputtering on energy. 

Here is why, what happens is because of processed food, because of high-fructose corn syrup, because of high-carb diets, and unfortunately, because of low-fiber diets. All these things contribute. You have now developed this insulin resistance. In fact, what is amazing is that you can see it biochemically. The insulin receptor interacts with a signaling molecule called IRS-1. IRS-1 has different phosphorylation sites when it is active; when it is signaling, it is phosphorylated on Tyrosines, but when it is now resistant, when it is now shutting down and saying, Okay, do not bother me; you have been pushing me too much, it is phosphorylated on serine and threonine. Some beautiful work out of UCSF shows that for people with Alzheimer’s, you always see this push in the brain toward the serine-threonine and so literally toward insulin resistance. Unfortunately, because of these high dyes, your insulin is going up; it is signaling crazy. Finally, if you are listening to music that is too loud all the time, you just put earmuffs on. You say I am not going to listen to that anymore. Of course, your spouse comes in and puts on a bronze lullaby. You do not even hear it. 

What happens that shuts down the ability to utilize glucose optimally? What happens, will you still have ketones? No, you do not. Because what happens is that high insulin prevents you from making ketones. When we see patients, we have to restore both of those, which is, as my wife points out, Dr. Aida Lasheen, who has been so fantastic about showing us how this is all working together. As she points out, you have to have metabolic flexibility. We are trying to do both. We try to restore the ability to utilize glucose, but we also restore the ability to produce ketones. 

Often, we start because of this emergency; we just give some exogenous ketones, or at least have something to get that brain going again. Then over time, we want to make you insulin sensitive and then ultimately make you be able to make your own ketones, have endogenous ketosis instead of XYZ, and have ketosis. That is the way the brain works best. We see it again and again. People just come back to life. Their spouses say They are so much more engaged. They are able to do things. They are able to remember things that they could not before. Absolutely, insulin resistance is one of the most common and severe problems when it comes to the risk of cognitive decline.

Felice Gersh, MD

That is so critical because so many people think that just eating a high-fat diet will fix everything. There is no easy panacea for that. You’ve got to get back to basics. You said, You have got to fix that insulin resistance. You keep talking about energetics, which is so interesting, mitochondria. Maybe you could tell that not everybody knows what mitochondria are. Just as a side note, estradiol is key to mitochondrial function. I always have to throw that in. But can you explain what mitochondria are, and how they are so important for brain energetics,? What does that mean—having energy in the brain—and what is the brain even doing exactly that it needs energy for?

Dale Bredesen, MD

Yes. Again, you bring in the blood flow and the oxygenation; that is a little bit like filling your car up with gas, but something’s now got to use that gas. Things now have to make energy, and that is where the mitochondria are so critical. People say they are batteries in your cell, but they do much more than that because they participate in calcium signaling. They participate. They have their own little genome. They just do so many amazing things. Unfortunately, they can be damaged as we age. There are a lot of mitochondrial toxins out there, unfortunately. You want to keep your batteries in good shape, you want to feed them appropriately, and you want to keep them humming because having them optimally work is so critical. energetics. Absolutely.  Of course, it turns out that energy is important not just for Alzheimer’s but for other neurodegenerative diseases. Now, as Dr. Christopher Palmer from Harvard has shown recently in his book Brain Energy, they also turn out to be important for psychiatric illness as well as other illnesses as well. 

Unfortunately, this is something that is commonly a problem that can lead us to these complex chronic illnesses, such as Alzheimer’s. Another good example is Parkinson’s. Parkinson’s is related to the reduction in one complex, which is called a complex-1 of the mitochondria. If you take a complex inhibitor over time, you will develop Parkinson’s disease. We know that these things play a crucial role in many diseases. They are important for energetics, but also for buffering and for all sorts of cellular signaling. They interact with the rest of the cell. As has been pointed out, these were originally bacteria millions of years ago that invaded and ended up becoming part of it is almost like there is a wonderful employer-employee relationship or more, I would say, a more collaborative relationship where they are working with your cell, they are providing the energy your cell is providing them with the substrates, etc. This is why it is so critical to have your mitochondria functioning, hitting on all cylinders, and having the appropriate ability to go back and forth between burning ketones and burning glucose.

Felice Gersh, MD

I have heard some terms for mitophagy or mitogenesis. What if you have had a lot of damage to your mitochondria? Is there hope to get them back online and working better?

Dale Bredesen, MD

Absolutely. You mentioned mitogenesis and mitophagy. What happens is that we recycle cellular components, and so mitochondria, as they get worn down, get essentially dismantled, and the parts are used once again. So mitophagy is essentially eating the mitochondria, dismantling them, cutting them up, and then you can use the parts once again, and there is mitogenesis. By the way, things like CPQ can enhance your mitogenesis, as can things like cold plunges and things like that. You can make more mitochondria, and you can recycle and break them down. Now, one of the interesting things is that if you prevent getting rid of the old batteries, guess what happens? You develop Parkinson’s. It is critical that we break these down as they become less effective and that we now replace them. Yes, there is hope. Again, doing the things and getting on the optimal protocol for several months helps to build these things up and improve the overall function.

Felice Gersh, MD

Now, a lot of people have heard of Coenzyme Q10. That gets thrown a lot around. You mentioned some different items that may be related. Maybe you could just make a couple of comments on CoQ10, coenzyme Q10, and what can help promote it? Is it important? Does it make sense to take a supplement with it now?

Dale Bredesen, MD

Yes or no? It is not a cure, but it definitely can help your mitochondria. What happens is that your mitochondria have this absolutely beautiful pathway where they convert the food you eat, which is essentially a stored way to have things that are in a reduced state. What happens is that you are literally taking these from a reduced state to an oxidized state and again accumulating the energy that comes. This is an oxidation-reduction reaction, a classical chemical reaction. It is essentially saying, and again, a little bit like a battery, it is essentially taking something from the food that you are eating and saying, those electrons in your food are wanted more by oxygen. We breathe in oxygen. It is down here at the other end, and it is going to go through one step, another step, another step. 

CoQ10, by the way, is in there, and one of the messengers in those steps is slowly breaking down that food and ultimately handing those same electrons to the oxygen to produce water. It is a beautiful system whereby the oxygen is going to be getting these electrons, your food is going to be giving the electrons, and you have now captured the energy as it goes. It is a little bit like having a waterfall and capturing that energy as the water comes over the waterfall. So this is why, yes CoQ10: One of the things, and of course there are various cofactors that I have mentioned, is giving people things that are still l-carnitine, for example. There are fat-related, oxidation-related, and multiple ways to support these things. Absolutely, one of the most important things to do is support your mitochondrial function. Again, back to your energetics, make sure your blood flow is good. If you have vascular disease, it is important to address that. Make sure that your oxygenation is appropriate. Make sure that you are able to go back and forth between burning glucose and ketones. All of these things are important.

Felice Gersh, MD

You talk a lot about vascular health and blood flow. They talk about vascular dementia. Is there not that much difference between vascular dementia and Alzheimer’s, or is that a totally different condition?

Dale Bredesen, MD

It is a great point, and it is a spectrum. When I was training, we all learned to calculate something called a Kuczynski score. That was supposed to tell you whether it is vascular dementia or whether it is Alzheimer’s. Well, guess what? It turned out to be much more related than was thought. It is very clear that in Alzheimer’s, one of the earliest changes is a change in the blood vessels. There is no question that they are intimately related. But you are, there are people where it is 90% vascular dementia and there is very little, if any, Alzheimer’s, and there are others where it is pure Alzheimer’s with a very little vascular component. 

As you can see, since we are talking about energetics and inflammation, you do not have to have a vascular component you can get. There are many ways. That fact is one of the things that we discovered and published a number of years ago. You can get there with chronic inflammation. You can get there with hormonal laws, you can get there with toxin exposure, and you can get there in different ways. But vascular, a component of vascular, is already common. You can get there with some head trauma as well. These are all important. This is why, when we evaluate and treat people with cognitive decline or the risk of decline that we want to prevent, we look at all these different variables so that we know what to address to get the best outcomes.

Felice Gersh, MD

It is so amazing when you talk about looking at what is going on in each individual because I have patients that come in and they tell me their mom was diagnosed with Alzheimer’s. I will say, based on what they said, they just said, The individual is clearly insane. She cannot remember anything, and she is getting lost in her own home. It is a late stage. They say you have Alzheimer’s, and they did not do a single test. It is just so amazing. It gives me so much hope that people out there who are listening are going to demand proper care. Do not assume anything. You’ve got to check it out. Just find out. one other thing I want to ask. In terms of vascular, way back in medical school, I learned about this thing they called the blood-brain barrier. It is, well, not such a good barrier. Is there a function of the impaired blood-brain barrier in the development of some dementia or what the heck is the blood-brain barrier anyway?

Dale Bredesen, MD

Yes, it is a great point. What happened many, many years ago? In autopsy studies and animal studies, people were studying the brain and injecting dyes,  and what they saw was that certain dyes would exit vessels in other organs but not in the blood-brain barrier. They knew something was different about the vessels in the brain than elsewhere. What they found is that there are tight junctions there that are preventing this. However, for years, it was okay; things do not cross the blood-brain barrier. It turns out, though, that there are many, many cells, organisms, and things that have the ability to get across that barrier anyway. 

There was an interesting study done several months ago where they wanted to ask, Okay, if someone gets a candida infection or yeast infection and the candida gets into the bloodstream, how many months can you keep that out of your brain? How good is that blood-brain barrier? They did this in rodents, and they injected the candida, which they looked to see. The surprise was that the candida crossed the blood-brain barrier within minutes. Then the response of the blood inside the brain was exactly what you would predict. It was an early Alzheimer’s response. You are producing this amyloid that is trying to kill the invading organism. We have had to modify the idea of what the blood-brain barrier is sure to do. It can exclude lots of molecules, but you have many of these organisms that will get through very, very quickly.

Felice Gersh, MD

Well, that is such a revelation, because I know I was taught not that, but I am sure many of us older doctors were taught that it kept things out. So just recognizing, number one, the amyloid data is trying to deal with it in a beneficial way. But it is too much. It is too much and that infections, so having respect for infections and what they can do and how they can get into the brain and then creating this chronic state of inflammation and degeneration on top of all of this I cannot move into therapeutics where I want you to talk all about all you learned about how to reverse Alzheimer’s, which also applies to how to present it without touching on giving hormones to older women. 

Most of our listeners are probably in the reproductive age group, but if many of them are older, we now know this was said by academics. I am sure it will not shock you that PCOS disappears at menopause. It is; how can it disappear? It is a metabolic dysfunction. Well, now they said, Guess what? It does not disappear. It just ends up blending in with all the metabolic dysfunctions of menopausal women. It does not disappear, of course. But in terms of the hormones, I said that it endeared me to you forever that you utilized estradiol as part of your protocol. I cannot let anyone leave this interview without hearing what you have to say about giving estradiol for brain health in older women. This whole thing is going to give you dementia. I know you people have heard this now from the Women’s Health Initiative: estrogen gives you dementia. It drives me crazy. Can you just say a few words about estrogen, estradiol, conjugated equine estrogens, the brain, and menopausal women? Because whether you are in menopause now, ladies or not, you are going to be.

Dale Bredesen, MD

Yes, it is such a good point. Again, we are only interested in the best outcomes. How do we get people to prevent and reverse cognitive decline? We have seen such wonderful results. In fact, there is a whole book that I wrote with seven of the survivors called The First Survivors of Alzheimer’s, and they wrote their own stories. It turns out that if you look at what gets the best outcomes, that must include optimizing hormones. As I mentioned, you can see the biochemistry beautifully. Estradiol literally signals to your APP that things are good. I cut you at one site, and I am going to generate these two peptides that will now help grow and maintain synapses. Dr. Anne Hathaway is someone I work with frequently, for example. But anyone who works with patients with cognitive decline and has had wonderful results, along with Dr. Kattouf and Dr. Deborah Gordon, worked with me, and we all published together the results of our clinical trial last year. 

Women always do better when they have bioidentical hormone replacement therapy, not just HRT. Now, of course, this is an area of great controversy, and I do not pretend to be an expert in it. I am interested in cell signaling and how we make people better with their cognition. But experts, you and Dr. Hathaway will decide: when do you want to do this? I recognize that in a best-case scenario, you want to start around the time of menopause. However, she found that even people who are much older are still getting benefits from HRT. When used appropriately and optimally. Again, I cannot argue with the data. People tend to do better. Now I know we keep getting these things, starting with the WHI read even more recently. This is a problem. But these are typically the wrong molecules. You are trying to use something that is not bioidentical, and then you come to the conclusion that you should not be doing this. Well, you should not be doing it with that molecule. I think we can all agree on that. But depending again, depending on patient by patient, most people, do better. 

When you include this as part of the overall protocol, we have to remember that this is a precision medicine approach. This is not one size fits all. We are looking to see if you have certain pathogens; take care of them. If you have certain toxins, we are going to address them. If you have a leaky gut, as you mentioned earlier, or if you have a poor oral microbiome, in fact, the pathologist shows us that organisms from the oral microbiome, such as P. Gingivalis, are found in the brains of patients with Alzheimer’s. That is what amyloid is all about. It is literally sequestering them and killing them. Now, one critical point I want to mention before we finish here is that there are four stages—four fundamentally different stages—when you are developing Alzheimer’s. If everyone simply remembers to get in early, then we will have very little dementia. That does not need to be a lot. 

Stage one, you are asymptomatic. So often, people, even in their late twenties or in their thirties, can already show beginning changes. If you do PET scans or spinal fluid, the great news is, who wants a spinal? I do not want to have a spinal tap every year. The great news is that there are now blood tests. One arm that is already on the market and available is called PTAL 181. This is exactly what I was talking about before. This is telling you. Aha. Your APP signaling is on the bad side. Now, if it is starting to go up, Okay, great. The earlier you get in, the better off you are. Stage one is asymptomatic. 

Stage two is called SCI, or subjective cognitive impairment. There is something wrong with what your spouse may know, but you are still able to score within the normal range on standard cognitive testing on average, as the epidemiologists have shown us over the last 10 years. In fact, you have a tremendous window of opportunity, so we recommend everyone who is 40 years of age or older, please get evaluated and get a cognoscopy, which is again, we all know to get a colonoscopy when we turn 50, and if you are 40 or over, get a cognoscopy. If you are 65 and you have not gotten one, do not worry; get one. Now get checked out. That looks like blood tests. It looks at a simple online cognitive assessment. Then, if you are having symptoms, you want to include an MRI with volume metrics. But if you are not having symptoms at all, you do not need the MRI. That is the second phase. Those two phases are 100% treatable. 

The third phase is now called mild cognitive impairment. It is unfortunate that they chose the term mild. It is telling someone, Please do not worry; you only have mildly metastatic cancer. It is a relatively late stage of Alzheimer’s disease. But the good news is that in our trial, 84% of those people improved. Unfortunately, many of them did not improve all the way back to perfect, which is why I say, Please get in on those first two phases. But if you do develop the third phase, do not give up. There is a lot that can be done, and we can improve you most of the time. Each year, those people with MCI score abnormally on cognitive tests. Each year, 5 to 10% of those people convert to the fourth stage, which by definition means you have begun to lose your activities of daily living. That is dementia. That is the concern we all have. We do not want to wait for dementia. 

We have all just heard about Fiona Philips from the UK, who has just announced that she has been diagnosed as having Alzheimer’s. Unfortunately, many celebrities will wait and wait. When you want to do the opposite, get in early and address it early for the best outcomes. You then do not have to progress to these other phases, though. In this final phase of dementia, you lose the activities of daily living, and now we do see some of these people improve, but it is harder and harder—no surprise as you get farther and farther along. If we could just get everybody to come in early, things would be so much better. But of course, the doctors have done everything backward. We have told our patients that it is probably normal aging; do not worry about it. If it is Alzheimer’s, there is nothing we can do anyway. Do not worry. People wait and wait and wait. We need to convince them to come in as early as possible, not as late as possible. In fact, the outcomes will be so much better.

Felice Gersh, MD

Well, that was so important for everyone to hear that there are different stages and that you can completely reverse the first two. Let us assume because our audience is women with PCOS primarily or health care providers that are taking care of them, that we now know that women with PCOS have many of the risk factors for developing Alzheimer’s, just as they have risk factors for having cardiovascular disease. know your risk. then you can take proactive steps. Let us assume everyone listening is either caring for or has these risk factors, and they are maybe in stage one or maybe stage two. We will leave the other ones for dealing directly with the health care professional. But in terms of all you have researched, where should they start? How are they going to reverse what may already be happening? But they do not even know it because it is asymptomatic or not very perceptible; they just know they are not quite the same as they were before. What are the positive steps? Tell us all.

Dale Bredesen, MD

Yes, great point. We developed a prevention program called Pre-Code Prevention of Cognitive Decline and a reversal program called Recode Reversal of Cognitive Decline. What this consists of is two pieces. You have the core because everybody wants to do the basics. that consists of seven things. It is diet, exercise, sleep, stress, brain training, detox, and some targeted supplements. Each one of these things has very specific things, which I outlined in the book, and we also have them on the website, etc. You can see what these critical pieces are that you need in a plant-rich, mildly ketogenic diet. That is what works best for getting you to be insulin-sensitive and metabolically flexible, resulting in mild ketosis. Each of these things has specifics for exercise. One of the things I love is that exercise with oxygen therapy helps with oxygenation, getting the energy to the furthest reaches of your brain. Those are the seven basics. 

Then, beyond that, you want to have the evaluation and look to see if you have specific pathogens. They could be coming from your mouth. You may need to go on the dental side, and, for example, you may have an undiagnosed abscess that can be seen in cone beams. You may have a leaky gut. Just as you mentioned earlier, we see a number of people who will have chronic infections they are unaware of, often from tick-borne illnesses, Babesia, Bartonella, Borrelia, Ehrlichia, and Anaplasma—all those sorts of things they do not even know they have. They just know that their cognition is not what it is. They have often had some brain fog. We root those things out, find them, and get rid of them. Because again, your amyloid is saying, Hey, you have not gotten rid of this problem, so I am just going to sequester it, and I am going to try to kill it and put it off to the side. 

Well, after a while, you have more and more of this stuff all over your brain. So unfortunately, when you have an inflammatory state, these things literally become a fort with soldiers that have got cannons, and it opens up and is letting out the guys that are not good, who are now spewing all this stuff around and unfortunately damaging your synapses. You want to look at those things and then toxins, and the toxins come in three varieties. It is inorganic air pollution that has turned out to be a very important risk factor for Alzheimer’s. Again, great. Just good living, helpful. Get out of the house. You get out into the clean, fresh air. Get down to the ocean, where you get some nice, clean, fresh air, work your two legs, or wherever you want to go. That got great fresh air. 

Then, of course, in the inorganic is also mercury and some of the heavy metals. Number two is the organics: glyphosate, toluene, benzene, formaldehyde, all of these things. Of course, they are part of your toxic burden. The third group is biotoxins. This is unfortunate. Many of us live in homes built of mold and food built of wood that got wet. Unfortunately, we have mold living, and we hear this all the time. I just heard about another patient earlier today who had huge, huge levels of these mycotoxins that are so damaging that they damage your nervous system. They damage your immune system. They damage your kidneys. They can be associated with an increased risk of cancer. This is a tough thing and important, again, to just get out, get away from this stuff, and you can easily have your home evaluated. 

It is those two things. It is the seven basics, and then it is the specifics. Let us find those things that, unfortunately, the vast majority of doctors are not doing the tests for and they do not know how to treat, which is why you hear people say every day that Alzheimer’s is untreatable. No, not at all. We have published very good results. We have published the best results in the world. far.  I have trained over 2,000 physicians from 10 different countries and all over the U.S. to follow this protocol. Of course, it is a little bit like learning surgery. Some of them do it better than others. Both of them do it well. Some of them do it not so well. It is good to know how successful your doctor has been. If the doctor is a trained doctor with other patients who have had cognitive decline, Yes, I agree with you. I would urge everyone to please get active prevention or early treatment. I know a lot of times you people go in and the doctor will say, What are you here for? You are not doing that badly. Well, yes, the doctor should be saying the opposite. Thank goodness you came in early and did not wait until this was severe and there was less that could be done.

Felice Gersh, MD

Well, you mentioned the word precision medicine. I think that says it all. You cannot assume what is going on. You’ve got to check it out. You need someone who cares enough to learn how to investigate the problem. I just would like to elaborate a little bit on the topic of that mildly ketogenic plant-based diet, just so that people will have an idea of what that means if you are eating for breakfast, lunch, or dinner.

Dale Bredesen, MD

Yes, great point. By the way, you can order this. We worked with a company called Nutrition for Longevity, and they can now deliver this. The easiest way to do this is to go on KetoFLEX12/3. com and you can order these, and they will bring them to you very easily. But the bottom line is, again, that it is all about getting the optimal biochemistry. What has worked the best so far is what we call Keto FLEX 12, slash 3. This means it is a flexitarian diet. If you want to have fish and meat, great; make sure it is wild codfish, low-mercury fish, grass-fed beef, pastured chicken, pastured eggs, etc. If, on the other hand, you want to be a vegetarian, no problem. Just make sure you are doing okay with your vitamin B12 and your vitamin D; make sure you are getting enough choline; and do things that are all important. Either way, good. But you want to get yourself into that metabolically flexible state again. 

Now, one paradox is important for everyone to remember. Many people say, Well, I can fast now for 20 hours; be careful. Remember that Alzheimer’s is ultimately a network insufficiency. There is not enough support, not enough blood flow, and not enough oxygenation. If you starve yourself, you can hurt yourself and go backward. You have got to be careful. On the one hand, you want to become insulin-sensitive. On the other hand, you do not want to starve yourself to do it. You want to ease yourself into that over several weeks. The things that you eat are large salads. I use them myself, and again, I love eating these with my wife, who is incredible at making these amazing, wonderful salads. Of course, I do it as well, but not nearly as well as she does. She is a fantastic physician who gets this and has taught me a lot of it. It is going to be, you might romaine lettuce, you might want arugula for your nitric oxide, by the way, that you mentioned earlier. 

Then, it may be a couple of hard-boiled eggs, not overcooked, hopefully. and then it may be some beans. It may be a little fish. It may be all sorts of carrots. It may be some beets. You do not want to overwhelm yourself. Beets can be somewhat sweet. These are infinitely variable. That is the thing I like. You may want to have more of a classical dinner, for example, or supper, or even a late lunch. You might want to have a piece of salmon, and you might want to have some asparagus, which is wonderful now. Again, organic, local, and always the best. You do not want to have a lot of mashed potatoes. You do not want to have a lot of bread. What we try to avoid is simple carbs, and grains, because so many people are sensitive to grains, which can induce a leaky gut. Of course, for so many of us who want to avoid standard dairy, A1 dairy can be a big proinflammatory problem. Just as you indicated earlier, people who are taking oral estrogen, a bad idea, can be inflammatory. 

Those are the sorts of things that you can eat that are delicious, fulfilling, have all the great stuff in them, and are good for your gut. You also want to include some probiotics. You might want to have some fermented beets or sauerkraut or something like that. Probiotics, prebiotics, and postbiotics; are all helpful. Then, of course, it’s a good idea to check your gut and see if you have a leaky gut. Do you have SIBO? SIBO is turning out to be so common that it can be a problem. Again, we are realizing that human physiology is so complicated. But the good news is that we can see patterns where we can address these things and make it so that virtually nobody needs to get dementia associated with Alzheimer’s disease.

Felice Gersh, MD

Well, that is so reassuring. just how much we have in common. I created, but I did not create what I call, the breakfast salad, because you have to engage. I know. Yes.  Start your day with this incredible breakfast salad with all the kinds of things that you mentioned. You will be full for so many hours, and you are getting all those polyphenols, fibers, antioxidants, and everything. We have barely scratched the surface, and everyone wants to read in detail about the different supplements and your regimen. How can they find out more about your research, past research, ongoing research, future research, the different books, and publications so they can know what to do for themselves and their family members?

Dale Bredesen, MD

Great point. I have published three books. The first one, called The End of Alzheimer’s, came out in 2017. It is now available in 33 languages. Whatever language you use, is likely to be available in the second one. Then, what happened at the first one? People said, Well, we want more details. I drilled down with specifics and worked on this with Julie G. One of the patients who is doing extremely well is going from the 35th percentile to the 90th percentile. She has sustained her improvements for over 10 years. She is doing great. Also, my wife whom I mentioned earlier, and the three of us wrote the second one, which is called The End of Alzheimer’s Program. This is now the program to go on. The third one is the one I mentioned earlier, which is The First Survivors of Alzheimer’s. 

I have to say, for anyone who reads that, that seven different people write their own stories about watching their parents pass away from Alzheimer’s and being told that they are going to go in the same direction and then get better. If you can read that without a tear in your eye, I am impressed. You are a pretty tough person because they are amazing and beautiful stories. Of course, one woman talked about looking at her children and realizing she has the gene. The children had the gene. My, what is going to happen to them? She has recovered beautifully and is now realizing we have ended it with that generation. We should be able to end this disease in this generation. 

In those three books, you can also go to DrDaleBredesen.com. You can also look at Facebook, which is Dr. Dale Bredesen, on Instagram, or Twitter. Then, perhaps most importantly, we are now establishing the first place in the world where people can come for hope for neurodegenerative diseases. This is called the Precision Medicine Program for Neurodegenerative Disease. This will be at the Pacific Neuroscience Institute in Los Angeles. I am very enthusiastic about that. For the first time, we will be able to get these larger data sets that are needed. The other thing I should say is that there is a documentary that has been made on this work by NHK, which is the CNN of Japan, and it is now circulating. It just played at the Manhattan Film Festival, and it is circulating. I think it is going to play in Charlotte in September, in Charlotte, North Carolina. It is going around it. It is called Memories for Life: Reversing Alzheimer’s. If you get a chance, you can check that out as well.

Felice Gersh, MD

Well, this is a story of hope. I just always emphasize: know your risk; but the risk is not destiny. But if there is one thing that you have proven, it is that there is no destiny to have Alzheimer’s, no matter what your ancestors had or where you are even right now, in the vast majority of cases. Destiny is what you create, know your risk and then read these books. I can tell you, just be prepared and know I am in Orange County. I am going to come and visit. Okay, great place, and stay up on all of this. This is such amazing, groundbreaking work. Thank you for all you have done, and everyone out there should take action today. Do the things you can to keep your brain working well. I know I have read that the thing that is feared the most in a heart attack is not cancer; it is dementia. We can do all of this. What a story of hope. Thank you again so much for coming and joining me for this interview.

Dale Bredesen, MD

Thanks so much, Felice, for having me. It was great to talk to you.