#381 ‒ Alzheimer's disease in women: how hormonal transitions impact the female brain, the role of HRT, genetics, and lifestyle on risk, and emerging diagnostics and therapies | Lisa Mosconi, Ph.D.

Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com forward slash subscribe. I guess this week is Lisa Moscone. Lisa is a neuroscientist, neuroimager, and the director of the Women's Brain Initiative at Weill Cornell Medicine, where she leads research on how sex differences, especially menopause and hormonal transitions, shape brain aging and Alzheimer's risk. She's also a professor of neuroscience and a pioneer in brain imaging approaches that map Alzheimer's disease decades before symptoms appear. In this episode, we talk about why Alzheimer's disproportionately affects women and why women's increased lifespan over men does not fully explain that 2x difference. Talk about the idea that Alzheimer's disease is actually a midlife disease for women beginning long before symptoms and how menopause is fundamentally a brain event and what happens to brain energy, structure, and immune signaling during that transition. We talk about what advanced imaging reveals about preclinical Alzheimer's disease. We talk about Lisa's work in imaging estrogen brain receptors. We talk about APOE4, specifically other genetic risks and why they impact women seemingly more than men. Some of the nuanced evidence around menopausal hormonal therapy, risks, benefits, timing, formulations, and why the WHI caused decades of confusion. talk about Lisa's new initiative called the CARE Initiative, a global effort to cut women's Alzheimer's risk in half by 2050, along with some practical evidence-based strategies for supporting brain health throughout midlife transitions, including lifestyle, sleep, metabolism, mood, and the involving role of medications, including GLP-1 agonists and CIRMs. So without further delay, please enjoy my conversation with Lisa Moscone. Lisa, thank you so much for coming out to spend time with me today. Thank you for having me. This is actually a wonderful podcast because it combines two topics that we have spent a lot of time on in this podcast. It's two topics that we spend a lot of time on in our clinical practice, but it is probably, at least to my recollection, the first time I've brought them into an intersection here. So one of them is all things that pertain to women's health, in particular, the transition through pre, peri, and post menopause. Again, this is a topic we care deeply about and have very strong points of view on. And then the other, of course, is brain health, which I don't think there's a single person listening to this podcast who doesn't appreciate both the role of the dementing diseases and how they truncate lifespan, but perhaps much more importantly, how they truncate healthspan. And the reason I wanted to talk with you today was because you sit at the intersection of these two, which is you're asking the questions as they pertain specifically to women and brain health. So I just want to maybe start with a bit of your background. So tell me how you came to find this as your focus. It's quite personal for me. So I was born and raised in Florence in Italy. Which, by the way, I just want to say literally one of the greatest places on this planet. It's really pretty. I never appreciated how pretty Florence is until I moved. I'm quite proud. Whenever I go back, it's like, oh, this is really nice. As you may know, as people may know, in Italy, families really live together. So I was born and raised in Florence. My parents live in Florence. My grandparents were in Florence. And my parents are nuclear physicists, both of them. I come from an interesting family where half of the family has a PhD, usually in physics. The other half is in the army. So we're very disciplined scientists, some of us. And I grew up in this environment where everything was about physics and biology and studying and learning. And I decided to apply that knowledge to medicine. So I have a PhD in neuroscience and nuclear medicine, which is a branch of radiology. I do a lot of brain scans. Around the time that I started studying neuroscience and specifically memory and language, I was very interested in memory functionalities and cognition. My grandmother, who lived on the same landing as me and my parents, she started showing signs of cognitive decline. My grandmother was the rock of the family. She was this really strong, extremely intelligent woman who went through World War II and she raised the family. My grandfather was a prisoner of war being in the army for a long time and nothing broke her spirit until she started losing her memory, until she started losing the ability to communicate, until she started losing the ability of taking care of us. She could not remember how to cook. And that really broke my grandmother and broke us and led to a diagnosis of Alzheimer's disease over time. And what was even scarier is that my grandmother was one of four siblings, three sisters and one brother. All three sisters developed Alzheimer's disease and passed away from it, whereas the brother did not and was spared, even though they all lived to the same age. Which was what age? My grandmother passed when she was in her late 80s. And how long did she suffer with the disease? When did it start? At least a decade. It was very subtle. Very often Alzheimer's disease starts in a gradual way. At first, there's some mild cognitive impairment, which she was able to almost masquerade. She had strategies to find the answer, keep going about today without really telling us that she was having a hard time. But then it became quite evident, and in the end it was very severe because she was healthy otherwise. So her body was healthy, but her mind was not. So all three sisters basically succumbed to this in their late 80s, having the onset in their late 70s, which, again, I bring that up only to say this is a very typical trajectory. It's very typical. Unfortunately, it is quite typical. This might be a question beyond your research because I know you're not a clinician. But given that you had such a personal experience, one of the things people often ask me is, at what point do patients become aware of what's happening such that it creates enormous distress for them versus when is the cognitive impairment so severe that they are no longer suffering? And it's only those of us around them who are suffering, but we could potentially take some solace in the fact that they are no longer suffering. Do you have a sense of that from your experience? Yes. There's research in this showing that we're now able, now that we're getting better at diagnosing Alzheimer's disease, not just using clinical tools, but using biological markers, like brain imaging and biological fluids in blood. Now, we can tell when a person is at risk for Alzheimer's or is showing red flags for Alzheimer's fairly early on, and then it's possible to correlate that with what the patient is telling you. Because the tests, the cognitive tests that we've been basing the Alzheimer's diagnosis on for decades are quite... Quite late. They're a little bit late. They're not quite sensitive to the earliest possible manifestations of the disease, which are usually subjective. So what we're learning now is that there's a phase that is a preclinical phase where the disease is underway. You can see the proteins and the lesions either in the brain or in biological fluids. But objectively, there is no impairment. There is no deficit at that point on cognitive testing. Many patients would tell you that they don't feel the same. There's this idea that they are aware that something is changing, that their performance is not the same, that they're not performing as well as they used to. even just a few years prior. And it's very hard to say, is it just aging or is it something more severe? And now we're getting better at doing that, but it looks like the preclinical phase of Alzheimer's disease can last decades, where the disease is underway. It starts with negative changes in the brain that very slowly but surely eventually exceed the brain's ability to compensate. But it takes a long time. The brain is an extremely resilient organ. And unfortunately, many patients are in this gray area, if you will, where they know that something is amiss. But when they come for a neurological evaluation, everything is fine. When they go to see a neuropsychologist, they test with the normative value by age and education. So it's really hard to provide counsel and to offer a treatment plan if we are not able to diagnose the fact that they are, in fact, on the path towards Alzheimer's disease. That could last decades. It could last a really, really long time until the deficits are such that there is an objective diagnosis. And usually patients do experience discomfort and depression and anxiety for years until dementia is severe enough that they start forgetting who they are. Or they start forgetting that they have a family perhaps. Or they start forgetting why they are where they are. So unfortunately, it's a heartbreaking disorder. Lisa, how much of what you just described through the lens of Alzheimer's disease specifically is comparable in other forms of dementia, such as Lewy body dementia or frontotemporal dementia or vascular dementia? I mean, maybe just for the audience, we can put these all in context. Alzheimer's disease is the most common form of dementia, but it is far from the only cause of dementia. So do you want to maybe put it in the context of these others, both in terms of maybe some of the prevalence of these, but also any of the subtle differences in what you just said as far as onset and presentation? Yes. So dementia is an umbrella term that includes different disorders that are typically categorized in terms of pathology, which is the kind of lesion that every disorder expresses most abundantly, and also in terms of clinical symptoms and sometimes age of onset. Now, most people are familiar with Alzheimer's disease, and they usually think that Alzheimer's and dementia may be the same thing. It's a common misconception. Alzheimer's is the most common form of dementia, accounting for about 70% of all dementia cases. There are other types of dementia. Now we hear more and more about frontotemporal dementia, for instance, because Bruce Willis, unfortunately, has been diagnosed with that. In that case, the presentation is a little bit different. When we do brain scans, actually, we can tell whether a patient has frontotemporal dementia or Alzheimer's disease based on the pattern of changes in the brain. Frontotemporal dementia tends to occur a little bit earlier in life and predominantly is associated with aphasia, which is disturbed language production. Whereas Alzheimer's, it's more about memory function. It's more about forgetting things. However, at the end of the day, Once the dementia, the different types of dementia are quite severe, there is a lot of overlap in terms of symptoms that may occur. The pathology, the pathophysiology is different, but the symptoms at the end tend to overlap, so it's quite difficult to do a good differential diagnosis. Lewy body dementia is another form of dementia that is due to mutation in the alpha-synuclein protein. So it's a little bit different from Alzheimer's, where the main problem is an amyloid beta, a febrile amyloid better production in lesions that aggregate into plaques, and also neurofibrillary tangles inside neurons. So each one of these dementia has a slightly different biological substrate. Vascular dementia is also very common and tends to overlap with the other types of dementia. In fact, very often we talk about mixed dementia. It's quite rare for a patient to only have Alzheimer's, for instance, and not some vascular damage. It's rare for a patient to have only Alzheimer's disease and not also some features of Lewy body dementia. And for many, many years, the diagnosis was purely clinical. It was a little bit late. You needed to have very clear-cut symptoms in order to be diagnosed as Alzheimer's or Lewy body or frontotemporal dementia. Now that we have access to biological markers, we're getting better and better, and the diagnosis has been done earlier and earlier. So that is hopefully leading to better therapeutic routes for each type of dementia and development of pharmaceuticals that are able to. Right now, we're trying to reverse the damage that, at least in Alzheimer's, makes results. I think optimistically, we might say we're trying to halt progress. Yes, we're trying to move away from trying to reverse the dementia or very severe lesions. We're trying to move back in time. We're trying to catch people when they're still relatively healthy and the potential for delaying the onset of the symptoms or even preventing. Hopefully, the accumulation of the lesions in the brain is greatest, is feasible. So we're trying to work with people who are fairly young. And that is very new in the field of Alzheimer's. Even when I moved to New York, I was already looking at Alzheimer's prevention, what could be done. That was 20 years ago. And I was working at NYU, New York University, the School of Medicine, with my mentor back then, Dr. Moni DeLeon, who's really a pioneer in the field of Alzheimer's prevention. And his team was one of the very few teams in the world to work with individuals who were younger than 65 because everybody else was looking at those who were 65 and older. He was like, no, we need to start earlier than that. The point you make about the overlap is really interesting. It means that if you look at the prevalence of each type, it will not total 100 percent. So you said 70% of dementia will have an Alzheimer's component. What are the approximate numbers of frontotemporal, Lewy body, and vascular in terms of just aggregate presence? It's interesting. I think it's difficult to really come up with specific numbers, especially for vascular dementia, because it's always kind of intermixed. Lewy body is usually around maybe 10%, 20% frontotemporal, but it's the same. But it depends. I don't know that we can really say. Yeah. We're going to talk a lot about Alzheimer's disease today, and we know that Alzheimer's disease occurs disproportionately in women. It's about two to one. Do any of the other forms of dementia disproportionately occur in women? No. And that's actually something that was very interesting to us when we started looking at the association between female sex and Alzheimer's disease. because when I started looking into this, this was a while ago, I would ask the question, is it just my family or is there a bigger lesson that we need to learn? And the answer was that we've known since the 1990s that after aging, after getting older itself, being a woman is the strongest risk factor for developing Alzheimer's. But when I asked, can we do something about it? the answer was mostly, well, the point is longevity. It's just aging. The idea is that women live longer than men, and Alzheimer's is a disease of old age. So at the end of the day, unfortunately, more women than men have Alzheimer's disease. But there are two things that contradict, in part, this statement. And clearly, aging is important. Yeah. The first one, by the way, is just a simple actuarial analysis. I did this myself 10 years ago, back of the envelope, because that was the first guess. The first time I thought about that question was maybe in 2015. And the obvious answer was, well, women on average live two and a half to three years longer, that must account for it. But if you actually go through even something as rudimentary as the CDC mortality tables and slice them by five-year increments, you can't explain the increased prevalence by a factor of two to one on that delta in age. but I'm sure you have a much more elegant explanation for why this was not the case. One thing that came to mind, obviously, was that the difference in the longevity gap was not 10 years. It wasn't that wide. It was just a few years. And for instance, in England, the gap is about two years. But Alzheimer's disease and dementia, the whole category, is the number one cause of death for women and not for men. But then the other point is that if it was just aging, then women would have a higher prevalence of other age-related disorders and neurodegenerative disorders relative to men, only they do not. Right. Cancer and cardiovascular disease are also age-related. But even within the dementias, right, for vascular dementias, 50-50, Parkinson's disease with dementia is more prevalent in men. Yes. Frontotemporal dementia seems to be more prevalent in men. Lewy body dementia is about 50-50. So that just doesn't seem to be a good way or good reason to dismiss an important question. Is it safe to say the scientific community today has stopped with that sort of excuse, and we've now fully accepted the fact that there is something biologically different about women that is leading to this enormous mismatch? I wish we could say they would have passed it. Really? Yes. Yes. Yes, it's still a subject of very active debate in my field. Sorry, just to make sure I understand, we're debating why it's happening or we're debating that age is the reason that it's happening? We're debating that still. Yes, we're still thinking that survival and longevity is something that may be driving the higher prevalence. And the argument for this is actually not a bad argument. They say prevalence is something that you look at cross-sectionally. Yes. But what about the incidence? When does it come on? Yes. And the question is, if prevalence is higher but incidence is not, then it could be aging. It could be aging. That's right. So the question is, do women develop Alzheimer's at higher rates than men? And I'll just explain to the listener what that means. You and I obviously understand that incidence is the number of cases that occur over a given period of time. So you might say the incidence of this cancer is this many cases. per 100,000 people per year. Prevalence, as you stated, is the cross-sectional cumulative number of people at any point in time that have the given condition. And so to your point, if the incidence is identical at every section in time, but the prevalence keeps getting larger as time goes on, then you might have to ask the question, are fewer women dying of the disease and therefore accumulating cases. Yeah. And I think it's been very difficult to get a good estimate of incidence with the studies that we have because the diagnosis of Alzheimer's disease has changed over time and we're catching more people now even earlier than we did in the past. So there are more and more studies showing that the incidence is also higher among women, and especially in countries with low to middle socioeconomical status. Another way to think about this mathematically would be because, as you said, incidence is very complicated because the diagnosis is so complicated, it might be easier to look at mortality and tally up the mortality differences. Because if you really think that you would reverse test this hypothesis, is if you think incidence is too high, you should see men dying at a much higher rate at a comparable stage of disease to women. In other words, the women should be outliving the men with Alzheimer's disease if they're all getting it at the same rate, which I don't think is the case, of course, but that would be a way to test that hypothesis in the negative. Yes, that could be. In fact, in some countries, Alzheimer's disease is actually the number one cause of death for women over 65. That's staggering. Yes. Yes. What countries? European countries and also in some parts of the United States. So the data is just coming out because many scientists are in a way puzzled that longevity has been the only explanation for the disparity. And we're now looking at risk in ways that I think are doing more justice to the question that we could do before, especially by looking at biological markers, because we can see that. and this is a lot of my research, when we do brain imaging or we look at other biofluids in midlife and we compare, let's say that we have a population of men and women for like 45 to 65, and all these participants, all these people have a family history of Alzheimer's or perhaps the APOE4 genotype. So they are technically at higher risk for Alzheimer's than the average person, than people who do not have these risk factors. If you look at the brain scans of men and women, at least in my work, but it's been replicated, many other scientists and other teams, the women tend to show more red flags for Alzheimer's disease in midlife as compared to men of the same age. And this is quite consistent. And we've also seen the progression of lesions in the brain tend to be faster in women. So that when you compare men and women who have the same symptoms and the same level of dementia severity, the women's brains actually harbor more pathology. So what seems to happen is that we start developing the lesions of Alzheimer's, the pathology in the brain earlier on than men, starting in midlife. and we live longer with it, but we're able to compensate more in that the tests that we use to diagnose Alzheimer's are heavily reliant on things like verbal memory, which women have a little bit of an advantage in. And so it's more difficult to diagnose Alzheimer's in women early. Because they have a higher cognitive reserve in the metric you're using to test. Yes. So in a way, women are masking the fact that there is Alzheimer's in their brains, but not necessarily overperforming. But starting at a higher reserve. Yes. Starting at a higher level. So the idea is that we live with Alzheimer's longer. And that may lead to a higher number of Alzheimer's patients among women down the line. So that really changed the whole question about women's brain health and Alzheimer's risk, because what we and others have shown is that Alzheimer's is not a disease of old age. It's a disease of midlife with symptoms that start in old age. Alzheimer's starts in midlife with negative changes in the brain and that later on lead to the symptoms and the clinical diagnosis of dementia. But then that changes the question, right? Because if Alzheimer's is not a disease of old age, but it's a disease of midlife, and women have a higher risk of Alzheimer's disease, a higher long-life, long-term risk of Alzheimer's disease compared to men, starting in midlife, then the question that we should be asking, I believe, is, well, what happens to women and not to men in midlife that could then potentially explain the higher risk of Alzheimer's down the line? Yeah, I just wrote that down. I think that's such a profound statement, Lisa, and it actually reminds me of a statement I've made many times on the podcast, quoting one of our guests about something totally different, which is osteoporosis. The guest said that, look, osteoporosis is a childhood disease. It just doesn't manifest in childhood. But you reach your genetic ceiling of your bone density by the time, in the case of a woman, by the time she's 18 or 19 years old. So if a woman isn't able to create enough deformation in her bones and all of the things that lead to strong bones by the time she's 18, 19, her risk has already started, even though that disease won't manifest until she's 60. And I think your example is, frankly, even more terrifying, but it's well stated. So let's talk a little bit about some of the theories for this. I think you and I are in pretty strong agreement that age alone cannot explain this, even if it partially contributes to it. There must be some tail effect of age. Let's accept that. The first idea that I think would pop into anybody's head if they're thinking about this for more than two minutes is a fundamental difference between men and women is that men have a very gradual loss of androgens throughout their life. but they're never shocked with androgen deprivation. Whereas women have a sudden and shocking loss of androgens at about the time you're talking about in the middle of their life, they will lose their sex hormones. Of course, the question is, does that play a role? So where does that idea fit into this and what other ideas fit into it that could explain this? Again, this is a subject of very active debate in my field to the point that People almost feel like they have to take sides. It's very interesting. It's an interesting time to be doing this work. So I think a good way to answer is by, for instance, doing brain imaging, which is what we have been doing. And back in 2017, we published the first study, which is bizarre to think about it. It was 2017, but it was the first study showing the brains of women before and after menopause. Everything we had up until that point was done after menopause, looking at menopause more like an outcome. Whereas we were looking at what happens during the transition to menopause, which is the most neurologically active phase, if you will. And so we had, in the first study, we had three groups of women, premenopausal with a regular menstrual cycle, perimenopausal with regular menstrual cycles, and postmenopausal up to age 65. So no more menstrual cycles for over a year. No hormone replacement therapy in that group? No, no hormone replacement therapy. And then we had age-matched men because premenopausal women tend to be younger than the postmenopausal ones. And what we found was that before menopause, at the premenopausal stage of regular menstrual cycles, there were barely no differences between women's brains and men's brains. And sorry, Lisa, what type of scan are you using for this? So we are doing different brain scans. We use MRI to look at brain volume, to look at presence of lesions in the brain. Let's be very technical because I think this really matters. So we're going to talk about lots of different types of scans today, but the way I typically try to explain this to my patients and to the listeners of this podcast, and feel free to correct this oversimplification as someone who's trained in a radiographic field. I always want patients to understand the difference between imaging modalities and functional modalities. So when you look at a test like an MRI, you are doing it for anatomical resolution. And again, you can choose how you do that. You can T1 versus T2, this flare versus that. You can highlight white matter versus gray matter. You can highlight the vascular system. But you're looking for anatomic resolution. Conversely, if you do something like an FDG PET scan, you're not looking at anatomic information. You're looking at functional information. You want to understand how metabolically active, in the case of FDG PET, the cells are. CT scans tend to be much more anatomic, et cetera. Would you agree with that way to think about them? And how do you think of the suite of different radiographic studies that can be used? Yes, I think what's most important is what you're measuring. You can use different tools to measure different things. And the really good definition is whether you're looking for structure, information for functional information, for biochemical or pathological information. With MRI scans, what you can do is look at the anatomy of the brain for sure, is to look at volumetrics. You want to make sure that some parts of your brain are really nice and dense with neurons. Whereas if we find signs of atrophy, that could be a risk factor for future dementia. There's one part of the brain that we always look at is the medial temporal lobe, which is a combination of structures that are quite primitive, if you will, and that are highly involved in memory function and also emotional regulation. And there's one structure in particular, the hippocampus, which is considered a biomarker for Alzheimer's risk because the hippocampus, you really want it to be as big as possible. We want the volume to be really nice and large. But when we find reductions in volume and thinning of the structure of the hippocampus and the parahippocampal gyrus, which is right below, that is a risk factor for Alzheimer's. It doesn't mean you have Alzheimer's. It means that that is a red flag for potential Alzheimer's risk down the line. And then like you mentioned, this is called a T1 MRI. I would usually use it for volumetrics, also to make sure that there are no brain tumors, that there are no obvious vascular damage strokes. So that's a good first line. It's a good first baseline. But we also do usually T2 and FLARE scans that give you additional information on other parameters that are important like if you have gliosis in your brain which is a bit nonspecific but it is a sign of white matter integrity damage. It's a little punctuation in the brain that tend to emerge with aging, but could also be a sign of inflammation, of vascular insults. So it's good to monitor that. We can look at the vascular system in the brain. What I also like to do, and we have it in all our biomarker panels, is that we use MRI with some modifications. So we can do DTI, just diffusion tensor imaging, where you can see the structural connectivity of your brain, all the different fibers that connect the different neurons, and you can extract a lot of information from those images. And then we also use a modified version of an MRI to look at blood flow with ASL, arterial spin labeling, which is completely non-invasive and is also really quick. But it is helpful to look at whether the brain receives enough blood flow at any given time. And then we use spectroscopy. We do 31P, phosphorus 31 magnetic resonance petroscopy to look at ATP production in the brain. So far, it's the only technique, except there's one potential with PET that's still being established. But this technique can give you a good read on the ratio of phosphocreatine to ATP production, which we find to also be a potential biomarker for brain stress, almost. when the brain is in a state of energetic damage or crisis, that could signify that the neurons are under metabolic stress. So we do that too. And this is all MRI. So we can do everything in less than an hour. And you will get all that information on multiple sequences of one scan? Yes, we can do everything. Well, it's different scans. Yeah, I mean, you run the patient through different sequences, but under one table time. Yes, one table time. We do need to switch the coil for the spectroscopy scan. So we bring you out of the scanner for just a minute. We switch the coils and go right back in. How many coils do you need for that scan? At least three to six, but I think more, potentially. You switch from the hydrogen to the phosphorus. But that's just something the technician does. This is something you would have a really hard time doing outside of the brain because of motion. Yes. Oh, yes. One advantage of the brain is you lock that head in place. and it's a short distance under the magnet. Yes. So those are really good images. And then we also do positron emission tomography or PET scans. We use FTG, like you mentioned, that looks at metabolic activity in the brain. And we also use another tracer. It's called C11PIB, Pittsburgh Compound B, which shows Alzheimer's plaques in the brain. Is that what we would colloquially refer to as an amyloid PET? Yes, it's the amyloid PET. The tracer is the carbonated, has a C11, which means that you can do the FDG and the PIB right away, back to back. You don't have to wait. You don't have to clear one. And bring the patient back the next day. So you can do everything quickly. And another advantage is that PIB has a very clearer signal than the fluorinated tracers, which is helpful. The signal-to-noise ratio tends to be a little bit higher. so you get a clearer read, which is helpful for people who are younger because we're not using it diagnostically. We're using it for research. And the read is a little cleaner, so we get a better signal-to-noise ratio, I think. But other people think it too. It's all a matter of whether or not you need to make it. You need to have a cyclotron right there. You need to have a chemist that can make it for you and then just run upstairs and you inject because it decays really quickly. So you need to have this big nuclear medicine capability on site. If you don't, or if you prefer to use a fluorinated tracy that you can buy commercial, then it's perfectly fine. But this is all the scans that we are doing. And now, I'm really excited about this. We're also doing brain estrogen imaging. So this is the first time that people have been trying to measure estrogen and hormones in the brain for a really, really long time. It's very hard to do it for a number of reasons. Back in 2019, I went to my radiochemistry department and I said, we think that menopause is very important for Alzheimer's risk for women. And we assume that is the decline in estrogen levels that drive the increased cellular aging and biomarker risk of Alzheimer's in women. But that needs to be proven because all the information we have is from rats. So we need to see what happens in women. And we also need a tool to measure what hormone therapy is doing in the brain. And they said to me, well, that sounds really, really great, but we don't have it. And sorry, you wanted to measure estrogen or estrogen receptor density? I would like to measure both. What I can measure today is estrogen receptor density. Okay. So what we do is that we have estradiol, and we label estradiol, the hormone, with a fluorine 18 molecule. It's just attached to the estradiol. Then there's an injection. The estradiol goes in the body but accumulates in the brain. And the way it works is that this little molecule mimics estradiol itself and looks for the target. I think your listeners know this, but the way the hormones work is that the hormone is like a key that needs to open a lock and the lock is the receptor. and every type of hormone has a specific receptor. So estrogen has estrogen receptors, progesterone has progesterone receptors. The way that this tracer works is called fluorine-18-fluoroestradiol, that it goes up in the brain and it looks for the estrogen receptors. It binds to the receptors and it works like it kind of jams the lock. So the receptor just is almost frozen in time for the period of time that the estrogen is there. And then the F18 molecule starts shooting out gamma rays, and we can take a picture of that from the outside, and then we use filter back projection and other techniques to get an image of the brain. And we can use that with kinetic modeling to get a measure of estrogen receptor density in every part of the brain. So we can finally do that. And just in 2024, we published the first proof of concept study showing that we can get a signal, especially in the pituitary gland where the signal is specific, like it's not confounded by metabolize or by blood beam variables. And this is not counterintuitive. I mean, we would expect to see a high density of estrogen receptors in the pituitary gland independent of the disease we're talking about just because we want to see the feedback. I mean, I guess we'd expect to see it in the hypothalamus even more. Yes. Because we would want to get feedback for FSH and LH. Is that your thinking? Yes, totally my thinking. The blood-brain barrier is a big issue. But the pituitary is slightly... Outside. Isn't the hypothalamus outside, right? The hypothalamus is inside the blood-brain barrier. The pituitary is outside. The pituitary is half and half. Yep. So the back is protected by the blood-brain barrier. The anterior part is not. So the tracer goes in really easily, which is helpful to us. Yep. So for now, this is what we're doing. We're able to measure estrogen receptor density in the pituitary. Just go back to that for a second. How is estrogen getting across the blood-brain barrier outside of that access to half of the pituitary? There are transporters. And what's the time course? So if you injected me in the arm through my IV, how long until it traverses? And does it only traverse in the free component? Does the estrogen have to be unbound or does it bind to albumin or something else? It does bind. Yes. That's why we need kinetic modeling. So the timing is relatively fast. If we inject now, we can see uptake within minutes. And then what we do is that we keep seeing the tracer accumulating up in the brain. So we do a time activity curve or tracer uptake in the brain relative to the tracer kinetics in blood. And we need both to get a good sense of how much is actually sticking to the receptors and for how long and how much is just pushed back into the circulation. So the whole scanning time is 90 minutes, but the peak of uptake is within 30 to 35. So I would say between 30 and 15 minutes is when you get the most signal. And then you start to saturate. Yes. Also, there's a component of blood flow that you need to disentangle. There's a whole mathematical model that we're using. It's called the Logan Plot. And I mean, I don't know if your listeners want to know this. I don't know if they do, but I do. Okay, good. So what we do is then we have spent so much time trying to find a good reference region for the modeling. Because if you have a reference region that you know to be free or almost free of estrogen receptors. Right. It's your negative control. You can subtract it out. Yes, that's exactly the problem that it took a long time. We had to talk to preclinical scientists, to cell biologists, to pathologists, to people who really specialize in the estrogen receptors. And I've been working with Dr. Roberta Diaz-Brinton, who's a legend in my field. She's been doing this for, I don't know, 40 years. She knows everything about estrogen receptors. And working with her and looking at all the post-bordening studies, we found that there's a very specific part of the cerebellar cortex. It's this part of the brain that people say is mostly involved in movement control, but has a number of different functionalities. And there are estrogen receptors deep in the white matter of the cerebellum. But if you look at, let's say this is the cerebellum from the side, if you look at the inferior most part of the gray matter of the cerebellum, like the thinnest layer possible towards the posterior inferior part, that seems to be consistently void of estrogen receptors. Whatever receptors are found there tend to be beta receptors. So there are three types of estrogen receptors, alpha, beta, and GPR. And this tracer that we use is more specifically looking for estrogen receptor alpha. Oh, interesting. So you're not using 17 beta. You're using the 17-alpha estradiol? Yes. Oh, that's interesting. Why? I would have guessed you use the beta. I can talk about this for a very long time. Number one, it's not been developed. Yes. Even though it's the biologically active estradiol, right? Right. Yeah. But not in tumors. Interesting. In tumors is the alpha. And these tracers were developed for oncology. Ah. Yes. Got it. Okay. Yes. Because they, of course, care about breast tissue. Absolutely. Yeah. Of course. Yep. Yes. Okay. So it's hard to make ligands for PET. It takes years and years. You're working with what was developed off the shelf. Yes, we basically repurposed a tracer that is commonly used now in oncology to see if we could just apply it to the brain, which I think is a win-win situation because we don't have to reinvent the wheel. So by using this reference region, the other thing that needs to happen is that the signal needs to be the same. let's say if you're looking at women who are premenopausal, perimenopausal, postmenopausal, the signal in that reference region needs to be invariant, which we demonstrated. Therefore, we were able to do kinetic modeling using the cerebellum, that specific part of the cerebellar cortex as the reference. And by doing that, we show the estrogen receptor density in the pituitary gland starts increasing during the perimenopausal window, but is actually higher after menopause, which goes completely against whatever knowledge we had from preclinical studies. Although, let's think about it for a second. Think about it. Okay. I don't know that I would think that that's counterintuitive because as estrogen levels decline, you would almost expect the pituitary in a greater and greater appetite for estrogen to upregulate expression of receptors to say, I want more, I want more, I want more. And we know that it's screaming for estradiol because it's secreting more and more FSH and LH. So is that effectively what you think is happening? I think that's what's happening, but that does not happen in rodents. All the models that we have for menopause are based on preclinical work and animal models. And what happens in rats is that most studies utilize an ovaryectomy. So it's a surgical removal of the ovaries of the female rat. So you induce menopause surgically. You induce menopause, yes. And what the studies have found is that there is an initial overexpression of the estrogen receptors, but then there's a sudden crash. So the window of opportunity is very narrow. And when you translate into human ears, there's like an inverted U shape, but it's more like a little, like a Gaussian curve. It's so narrow that within no more than five years after the final menstrual period, the idea is that the estrogen receptors have declined to half the density that they used to have prior. And that's the prediction you would have had in women. Yes, but we didn't find that at all. We found that up to age 65, estrogen receptor density was still nice and high. So this is totally off topic, Lisa, but I just want to park this on the side so that we can come back to it. And hopefully between the two of us, we'll remember what I'm about to suggest. Would this not potentially suggest that a woman in her 60s who went through menopause 10 to 15 years sooner, who was not treated with menopausal hormone therapy, would still be a candidate given that she clearly has upregulated her estrogen receptors in her CNS and therefore at least physiologically suggests an appetite for estrogen? Yes. Okay. We'll come back to that in detail because, as you know, we just keep banging on all the greatest hits of the mantras of modern medicine, which says even if someone has finally come around to say maybe menopausal hormone therapy is not the worst thing you can do to a woman, I'm being facetious, you better give it to her the day she enters menopause. God forbid we take all of these women who are out there who were in their 60s who were deprived of hormones 10 years ago and give them hormones. Their window is closed. The door is shut. That was the concern. And in fact, when we were writing the protocol for this study, I said to my team, we're going to do 35-65. And they're like, we should do maybe 55? I said, no, no, no. We're going to do 65. We're going to try and map the whole window of opportunity. And they're like, I don't think that's a good idea. It's a little bit far ahead. And when my and say, well, we're just going to do it. When the results were coming in, you know, and sometimes you have a feeling. No, yeah, sometimes you have to trust your intuition. And it's a more interesting question. It's a more interesting question. I think it's worth it. Maybe, obviously, we will concentrate around age 52, 53. But let's try to map the extremes because we keep talking about this window of opportunity like we know what it is. But it's speculative at this point because we have not been mapping it using biological indicators. So anyway, we did it. And I think it paid off because obviously all the women in the study are naive to hormone therapy. So no one was taking hormones of any type. Does that mean that the premenopausal women obviously were off oral contraceptive? And how long had they been off oral contraceptive? In the vet first study, it was interesting. Most of them had never used breast cancer. It was very interesting. So really, really a naive population. But at least three years, that was the exclusionary criteria. And for the postmenopausal women, they were all never users of hormone therapy. Now that we have hundreds of women in the study, we can be more flexible and account for different things statistically or try to stratify between past users of hormone therapy, never users, current users. We also have users now, which is very interesting. And what are you seeing in users? It's not published yet, so I'm not sure that I'm allowed to talk about it. But just anecdotally or descriptively for now, we do see that the windows shift. The curve is shifted. So we now have women who are older than 65, and we're starting to see where the estrogen receptors are starting to come down in terms of density. But in the hormone therapy users for now, it seems like the curve does not stop at that age. It looks like maybe there is preservation of density. And then the question is, is this a good thing or not? Because we don't know if the estrogen receptors are functional. We don't know if the transcriptional pathways are still working the way they're supposed to do. Like, are we stimulating receptors that are not functioning? We should maybe explain to people what we mean. So let's riff off each other on this. But steroids work by driving these transcriptional factors. So when estrogen or testosterone binds to the receptor, what it's really doing, what matters is what it's doing inside the cell. It has to go into the cell. It has to go to the nucleus. It has to bind to the DNA. And it has to say, hey, start making RNA that's going to make protein that's going to do those things. And it's that process of transcription and translation that matters. And so what you're saying is, hey, don't get too excited, Peter. All we're able to check with this assay is, does the hormone bind to the receptor? The assay can't measure whether the mechanism of that is translated all the way through to protein. Yes, because the idea is then there's a system. There's a supply and demand system, which is like the brain is calling for hormones and the ovaries are delivering the hormones. As long as the feedback loop is stable, we know that usually the estrogen receptors are doing what they're supposed to do, which is more blood flow to the brain, more energy production in the brain, a stronger immune system, more neuroplasticity, more synaptic growth. But we also know that with age and with disease, the estrogen receptors, as many other receptors, may start to malfunction. They may also go through conformational changes. That means that the output may not be as good. Say more about that. I mean, if I'm going to be honest with you, that's a terrifying thought. What can we point to in the periphery to help us understand that, where it's easier to study this question? I was thinking oxidative stress. Okay. Right. So estrogen, one functionality that estrogen does is to attach itself to estrogen receptors in the mitochondria. And the mitochondria are the energy factory of every cell in the body, including neurons. What the mitochondria do is that they transform energy into ATP, or they take the byproduct of glucose metabolism. And there's a structure called the elytraum transfer chain that produces oxidative stress and free radicals at the same time that they're making ATP. Usually the balance favors ATP. But if the estrogen receptors change conformation, that may lead to a less favorable balance where more oxidative stress is being produced relative to the amount of ATP that is being made. So yes, there's still energy that's being produced, but there's more oxidative stress. And this is an issue in the brain. But couldn't there be other explanations for why we see the inefficiency of the electron transport chain there? Like, I'm thinking of something even more basic. Couldn't we do a similar experiment of 35, 45, 65-year-old women and look at the periphery and look at mRNA expression of something very straightforward in response to estradiol administration? So you take hormone-naive women, inject all three of them with estradiol, and measure for equal amounts of estradiol how much mRNA gets produced for something that we would predict. That's a clinical trial. Yes, but according to this hypothesis, we would expect to see declining mRNA, which would suggest at least possibly that something, and of course, to make it a really cool study, you'd still want to do the labeling study to assume you're getting at least equal amounts of binding. You would normalize. You would basically say, look, I'm going to take the strength of the binding signal, and I'm going to normalize it to the mRNA that comes out. Yeah, you could if you had the money. You have the money. Well, not for this. No, but that's an interesting question. There are so many interesting questions. But this is a jugular question. Yeah. This question implies, can we throw more estrogen at the problem? In fact, I don't know about the periphery, but for the brain, studies have shown that timing is really important. So if you have tissues, you don't know, tissues that are healthy, and you introduce estrogen, estrogen is supportive of the neurons. But if the neurons are diseased, if there is ischemic damage, there's amyloid pathology surrounding the tissues or tangles inside the neurons, then estrogen makes it worse. What's the evidence for that? It's the studies that Dr. Brinton has done many years ago looking at how estrogen impacted mitochondrial function. This is specifically mitochondria, but there seems to be evidence for that in clinical studies as well, like the Women's Health Initiative, which you have very elegantly unpacked. There's clearly an age-related benefit-to-risk ratio when it comes to hormone therapy and brain health. And many people have argued that the women in the Women's Health Initiative, the memory study component that looked specifically at dementia incidents, those women were potentially too old to start taking therapy, hormone therapy at that age. granted different formulations, higher doses of hormones. It's not what we do clinically today. Nonetheless, it confirmed this kind of timing hypothesis, especially for those whose MRI scans showed evidence of an existing, not a pathology necessarily, but for instance, vascular lesions or white matter hyperintensities. In sub-analysis, the idea is that women who already harbor damage in their brains may not be responsive to hormone therapy the same way that women with healthier brains would be. This is completely to be demonstrated. So two comments. The first is, do you think we have a sense of the difference between the two variations on that theme? One variation is once disease has set in, estrogen is unlikely to reverse it. But that's different from estrogen will exacerbate it. Yes. Let's unpack that. The second is, as you pointed out, in the Women's Health Initiative, we were dealing with oral conjugated equine estrogen, which is known to actually slightly increase coagulation, which of course would be an enormous concern for exacerbating the vasculopathy that would accompany this disease. And therefore, whereas we don't see that at all with topical estradiol, we don't see any evidence of an increase in vasculopathy. We don't see any increase in ASCBD risk. So therefore, we might assume that, hey, topical estradiol is much safer than, much is a strong word, but is safer than oral estradiol and that we might not see that risk. So given those two comments. And also the progestin. That's exactly right. The progestin as a whole, I mean, my belief still remains that if there is some meaningful, clinically meaningful uptick in the incidence, though not mortality of breast cancer, the progestin is the most likely culprit. But also for vascular damage. So the MPA, the kind of progestin that was used in the Women's Health Initiative has later on been shown to potentially increase the risk of vascular damage. And that's the reason we don't use it. Yeah. So couple that with conjugated equine estrogen taken orally. Those are getting a bad rap. They still serve a purpose. I would like to see more research done on the very specific types of hormone therapy because there are so many different options that one can work with. And what I would really like to see is what these therapies do in the brain because everything you said makes perfect sense, but it's not been seen. I want to see it. We can do it. We have the tools now. In your study, obviously, you have to be clean and as neat as possible, so you have to normalize everybody to the same point. I assume you were injecting a bioidentical. Well, actually, did you inject? We just inject the ligand. Yeah, you've never. Okay, I got it. And then we work with the menopause clinic at Walcarnet Medicine, which is where I work, or the OBGYN department. and we have women who are now going on hormone therapy for menopause, the vast majority use transdermal, estradiol, with or without micronized progesterone. That's kind of standard of care today. It's not necessarily always, but the women that we tend to recruit for this study, obviously, like you said, need to be similar in terms of what kind of therapy they're taking. I also want to see the CEE's compound. I would like to see oral estrogen and the other formulations and see if we get a differential signal or not. Yeah, I think that would be very interesting. But I think the most important question would probably be answered through the lens of the formulation of the day, which is going to be transdermal estradiol and, as you said, oral micronized progesterone. I've done a bad job of navigating on this on this journey because I've taken us so far off the path into these details But look, I think you have to sort of follow your bliss. This is incredibly fascinating Let's bring it back up for people to kind of the surface level from the ocean floor we've established through this discussion that Something is happening in the brain of a woman. Oh, by the way, I meant to ask one final question on that topic You had male controls age matched for which study For the estrogen ligand study? No, we're doing only women. Got it. Okay, so I was going to ask, so we don't know if in a man's brain the estrogen ligands remain constant or I would predict will go up slightly as he ages because his estradiol is going down with testosterone. Yeah. So the idea is that the brain compensates for changes in estradiol levels and other hormone levels by increasing the density of the estrogen receptors. So when usually the brain really loves stability, the human brain is built for stability. So when hormones are fluctuating throughout the menstrual cycle, the concentration overall is still predictable. So the brain needs to make very little effort to maintain a certain number of receptors. This is another thing that is very interesting. The receptors are not just there. They'll just happen to be in the membranes or in the... The brain needs to make them. So it's an active process. And when estradiol levels increase, then the brain needs to make fewer receptors. So we see this decrease in estrogen receptor density. But when estrogen level, estradiol levels come down, then there is this compensatory adjustment where the brain will overexpress or make more of these receptors in order to just grab every little bit of estradiol that is in the circulation. The question is, when does this mechanism crash? Eventually, estradiol levels will be permanently low and the brain is going to have to give up because making receptors is a very metabolically expensive process. So eventually, there will be a state or a stage where estradiol is low and the estrogen receptors are low or gone. But when does that happen? It's after 65, it seems like. In our studies, it seems to be after 65. And what I'm trying to do now is to get more people to also use ligand. And we're also working to make new ligands that could look at the better receptors that can give us better signal in other parts of the brain. We want to look at the hippocampus, the amygdala, the frontal cortex, the serocinical cortex. We hire specificity and better signal-to-noise ratio. How quantitative is your assay? It's fully quantitative. You know what would be so cool? First of all, how much radiation does it expose? Very little. Very little. Okay. How many millisieverts? It's six millicuries. Is that the equivalent to six millisieverts? No. That's less. That's 0.6 millisieverts? It's less than one. Yeah. Okay. This would be a very cool study, just out of pure curiosity. Very expensive, so you might not do this. I would love to take a group of 35 year old women and scan every one of them the day they get their period and then every five days for 30 days. And just because that's your natural experiment of exactly what you just described. That is going to be the absolute highest, absolute lowest level of estrogen and progesterone in the brain in a 30 day window. And the fact that it's quantitative means you can now really develop a sense of how quickly can this compensation occur and what's the highest high and the lowest low. Yes And then compare that to estrogen levels in blood Yes I think it so important to clarify that estrogen levels in the circulation have nothing to do or very little to do with estrogen levels in the brain Really? Yes. Oh, okay. So say more about that. That's the problem that we're having, I think, clinically, is that we can measure estrogen in blood, but that will tell you nothing about whether or not you're having half flashes or forgetfulness or any of the neurological symptoms of menopause because... Because we don't know the receptor density. We don't know the receptor density. And also the brain levels of estradiol are very highly regulated. And it's basically all the hormones in the brain are sheltered from changes in the circulation. So these transporters are active. They're active, yes. The brain calls for hormones. Let's talk more about that. I thought this was like the passive diffusion. No, not necessarily. Apparently, there are periods of time where it could be and times where it's not, which is why you can't just push stuff inside the brain. It's so hard to get a tracer that goes in because the brain doesn't want a lot of molecules. A lot of things just can't come through. This is unbelievable. Yes. It's so difficult to come up with this. So you're telling me that if we did my thought experiment of every five days or every day, it's just a thought experiment. Every single day you draw a woman's blood throughout her cycle and you're going to see estradiol go from next to nothing to 200 and back down. You see that in blood. Yes, that's what I'm saying. Yes. In the brain, we don't know. And so you're saying in the brain it could be uncorrelated. It certainly would not be partially, partially correlated. There has to be a response, but it can't be as dramatic. So what do you think is driving it? Let me ask a question a different way. This is now becoming a very complicated thought experiment. If you did this on a woman every single day for a year, and she had, say, 12 normal cycles throughout a year. But one of those months, she had the flu. And one of those months, she was sleep deprived because, you know, whatever was happening. One of those months, she was under a lot of emotional stress. One of those months, she was eating well. One of those months, she was eating garbage food. One of those months, you see where I'm going with this? Yes, you will need a control for every single one of those moms. Of course, because they're twins. So I'm going to give you a, we have identical twins. I see. And so you have one of her sisters is perfectly doing the same thing every time. But also she kind of serves as her own control in a way, right? Because. I mean, there must be a month that she's okay. There's a month when she's perfectly okay in January. In January. I don't know why. But you see where I'm going. What I want to sort of understand is how much do the externalities of her life, which obviously impact her peripheral physiology and must impact her central physiology. How much do you think, if you had to predict, how much would you guess those are the drivers of the brain's demand for estrogen? Hopefully, they're not the drivers. Hopefully, hormonal production and hormonal demand is skewed mainly by hormonal needs for the brain because if that weren't the case, we would have a lot of trouble thinking straight. And I think that's one of the reasons that the brain really very tightly regulates entry of nutrients or chemicals from the circulation, because if the levels of receptor activity were to fluctuate too quickly or too frequently, that could lead easily to cognitive impairment or to mental confusion or to an inability to just function. But at the same time, it is important. Your lifestyle has an impact. I don't know that the impact would be visible on a month by month. This is hopefully not. But over time, the poor lifestyle, sleep deprivation, high stress levels, that in theory would negatively impact the brain itself, of making perhaps the receptors are not as functional as they used to be, or estrogen uptake is not as tightly regulated or carefully planned as it used to be, and then there could be glitches that are more long-term. Does it make sense? It makes sense. It basically says we are only at ankle-deep water at this point in terms of our understanding of this process. Yes. Yeah, it's really just the beginning. And this is a reason that I launched CARE, which is my new program of research. Can I mention? Of course. So I just launched a $50 million program of research sponsored by Wellcome Leap, which is an independent subsidiary of the Wellcome Trust. It's called CARE, Cutting Alzheimer's Risk Through Endocrinology. As I mentioned, it's $50 million unrestricted, which is amazing for this specific question. And CARE is effectively the largest research program on women's brain health, menopause, and Alzheimer's disease ever attempted. And what we're doing with CARE is, it's like the movie Oppenheimer. I think people are familiar with that movie where Dr. Oppenheimer was in charge of designing the research program and then basically inviting other scientists from all over the world to work with him on a sprint. It's called a sprint. So it's a three-year, just three years. It's a high-risk, high-reward research initiative, which for them ended up with the atomic bomb. With us, we'll hopefully end with a means to half the risk of Alzheimer's disease for women by the year 2050. That is our target. We estimate that if everything goes according to plan and we hit all our marks, then we should be able to reduce the risk of Alzheimer's for an estimated 330 million women globally and given current global conversion rates to Alzheimer's, we could potentially prevent 55 million new Alzheimer's patients among women in the next, hopefully, 25 years. And one of the things that we're doing with care is, so we have three different components. Trust One speaks a lot to what we've been discussing so far. We want to understand how neuroendocrine aging, and specifically hormones really speak to Alzheimer's risk for women because all the predictive models that we have so far are sex aggregated. So we look at things, at risk factors that work for men and women, but they're kind of genderless. The fact that sex has been removed statistically, but there are things. How is that even possible? That's the vast majority of models. So when we say that we do talk about this now, that Alzheimer's risk is multifactorial but potentially preventable in about 45% of cases, that 45% comes from studies that have looked at all sorts of risk factors in cohorts that combine men and women. And more often than not, the predictive models adjust for sex as a covariate. So you want to statistically remove the effects of sex and see whether diet is associated with Alzheimer's disease. We can't get the raw data and reinsert? Yes, this is what we're doing with here. Okay, good. Yes, yes, yes. So whatever we know about Alzheimer's disease so far is genderless. It works for men and women, which is still, it's a wonderful start. To give you one example, you're saying when we sit around and say that having an ApoE3 and an ApoE4 gene increase your risk of Alzheimer's disease by about 2x, that should be more nuanced. We should say in a man, it increases it by x. In a woman, it increases it by y. Sixfold. It's sixfold increasing. So that's something I did not know. We usually talk about this, at least I usually talk about it, without differentiating between sex. Clearly, that's a mistake. So if we're talking about comparing people who are heterogeneous, so one copy three, one copy four versus two copies three, what's the relative risk increase for women specifically? So women who are heterozygous through the APOE4 allele have a fourfold increase in dementia risk as compared to non-carriers. But women who have two copies of the E4 allele, then the risk is between 12 and 15 times higher relative to non-carriers. Yeah, so this is about twice the risk of men. Yeah. Yes. Okay. Let's now talk a little bit about the role that hormone replacement therapy or menopausal hormone therapy can play in women with or without an E4 allele. Let's also talk about it in the context of initiation of therapy at an appropriate time, just to start. So what do we know about this? This is a tortured part of our field of research because, unfortunately, there's only one clinical trial that's ever looked at hormone therapy and Alzheimer's incidence in women, and that's the Women's Health Initiative Memory Study. Which, of course, had a lot of hair on that dog. In that specific study, the risk of dementia was increased for women who were taking the combined estrogen-progestogen therapy, which in that case, like you said, it's oral conjugated equine estrogen and MPA. And the risk was also 50% higher for women who were taking only oral estrogens following a hysterectomy. However, that risk increase was not significant. Now, that's the only clinical trial we have, looking at the incidence of Alzheimer's disease relative to hormone therapy use. And all the women were postmenopausal and by a long shot. Unfortunately, we don't have clinical trials where hormone therapy is given in midlife for relief of menopausal symptoms, which is the appropriate indication, where we also measure the incidence of dementia because those trials are just not feasible. It would be like a 20-year, 30-year trial, and it's just not possible to do it that way. In that case, observational research offers more information about whether there is a differential beneficial effect relative to initiation timing. And we do know that observational research is subject to bias. So this is just more descriptive than definitive. However, it is interesting that meta-analysis, which are statistical integration of all available data, do show the timing of initiation matters and also the type of formulation. So women who do not have a uterus, who have received a hysterectomy, which is the surgical removal of the uterus with or without the ovaries, are typically treated with estrogen-only therapy. They don't have to. You can also have a progesterone, but generally practice says, let's just go with estrogen. Whereas women with a uterus need a progesterone, whether a synthetic progestin or micronized, or what people say bioidentical progesterone. Now, if you look at these two factors, when you start, which is within 10 years of the final menstrual period, or over 10 years of the final menstrual period, and whether you have a uterus or not, This is what the study, the observation of research so far shows, the 32% reduced risk of Alzheimer's or dementia for women with a hysterectomy who have undergone a hysterectomy and they're taking estrogen-only therapy. Significant, very consistent risk reduction across all the studies available, almost all the studies. We have now one from Northern Europe that does not show that protective effect. This is when hormone therapy is initiated within 10 years of the final menstrual period. For women with a uterus starting hormone therapy within 10 years, there's a 23% risk reduction, which is, however, a trend level. Some studies show an increased risk. Most studies show a reduction in risk. So we need to better understand what's happening there. When we look at starting hormone therapy more than 10 years after the final menstrual period, there is no obvious benefit for estrogen-only therapy for women with a hysterectomy. And there is an increased risk for women with a uterus who were taking estrogen and progesterone of any type. We do not yet have enough studies. I'm pre-empting your question. I can see it forming. We can't yet separate progestins from micronized progesterone. We cannot yet look at each specific type of hormone therapy because the data is just not there. We need to do more research. Also, I will add, this is a fairly old-fashioned way to look at this question. I would argue that today with the tools that we have and the data that we're able to collect, what would make more sense, and I'm sure you were going to say, wouldn't it be better to, yes, it would be better to start hormone therapy today and look at biological markers of Alzheimer's as the therapy is progressing. In fact, what would be ideal is to start hormone therapy today, look at the estrogen receptors, use brain estrogen imaging to monitor whether the therapy is doing what it's supposed to be doing and also look at biological markers of Alzheimer's to make sure or at least to test whether they're either not showing up or they're being delayed in their progression or evolution relative to a placebo group, which is what we're trying to do now with CARE. Fantastic job anticipating both questions I had and saving me from answering them. Does this mean that one of the initiatives in CARE is actually a prospective randomized trial that will administer MHT at the appropriate time during perimenopause. I have a whole soapbox on why we have to start this in perimenopause. You don't wait till menopause. And then we prospectively follow the various markers? Half is yes. So we only have three years. Running a clinical trial in three years is just not feasible from start to finish. So what we're going to do in the three years, our goal is to provide evidence at convincing scale that hormone therapy has, or doesn't have, but we're hoping it might have a beneficial effect on biological markers of Alzheimer's by working with women who spontaneously decide to start hormone therapy. So you don't have to enroll in randomize. You follow women who do go on hormone therapy and women who do not. And that's what you can do in three years. How will you match them for health consciousness? There's an inherent, I think, bias that slips into women who opt into hormone replacement therapy because the barrier to entry is high. Most women who want hormone replacement therapy are going to face an uphill battle with their doctor who, no disrespect, but their doctor is ignorant, busy, just believes it's bad. And so the women who ultimately end up on hormone replacement therapy had to jump through a few hoops. They're also probably a little bit more health conscious on average because they're willing to go through the brain damage of having to beat the system and fight and make sure that they can get what they rightly deserve. Whereas the woman who says, I'm not going on hormone replacement therapy, it's less of an active decision. It's probably more of a passive decision. Now, of course, I can come up with some examples. Maybe you have women with a very strong family history or a personal history of breast cancer that might be equally health conscious, but they decide to opt out for reasons that have to do that. So that might be one way to match them. But otherwise, you have to be very careful with this type of analysis. Yes. Because the healthy user bias runs deep. Yes, absolutely. It's one of the concerns with observational research. The other concern is that women with the most symptoms are also more likely to start hormone therapy. And there seems to be an association between more hot flashes, like the severity and frequency of hot flashes, especially at night, and amyloid beta levels in plasma and white matter hyperintensities in the brain. So there's a few things that we need to ascertain. And I think the way to do it is, number one, with education. And I think that a lot of my colleagues and you and your colleagues are doing a fantastic job of making sure that women understand that hormone therapy is on the table. And then they can come to us, the research sites, where they also have access to the gynecology department, to the menopause clinics, where our clinicians are open to the notion that if you do have the symptoms of menopause and if you're willing, interested in starting hormone therapy, that is perfectly doable. So I think by working with us, certainly there shouldn't be much of a barrier to access hormone therapy if indicated. We do follow professional guidance. Is there any woman who is in that perimenopausal transition who you think needs to be cautious of hormone replacement therapy as far as her brain health is concerned? I think the concern about starting hormone therapy before menopause is that hormone levels are fluctuating. Using birth control, for instance, by blocking ovulation, we make sure that once you do go on birth control, you receive a standard dose of hormones that have been tested and that can be clearly monitored, right? You know exactly what dose you're given at any given time. Whereas with hormone therapy for menopause, depending on what you're doing, you can't really do a blood draw every day or every moment. So the concern is once your level of estradiol are low enough, then we should be fine. But if they're spiking and you put more hormones in the system, you may amplify the spike. Our view is that once women are symptomatic, so we're not doing this based on blood, but women can be symptomatic for a year, six months, or three years. There's just so much variability in the system. But there's evidence that as soon as they're symptomatic, both from an estrogen and progesterone standpoint, although the estrogen tends to be the symptoms that dominate, the benefits accrue immediately with respect to vasomotor symptoms, bone health, cognitive performance in the short term, sexual health and sexual function. and that waiting until a woman has completely stopped, her FSH is 40 and her estradiol is unmeasurable, at which point everybody would say, yep, she's in menopause. You could spend five years getting to that point from the moment you started having symptoms. And again, there's evidence that you've actually taken steps backwards with respect to health. Now, what's the trade-off? The trade-off is you're going to have loops, meaning, you know, you're going to have ovulations that force their way through the system and you're going to have all sorts of estradiol spikes. I can tell you that clinically, most women are far less bothered by this than the reverse. At the end, it's really about feeling better. To your point, this requires nuance. This is not a set it and forget it policy. This is something where, and I had Rachel Rubin on the podcast. This is where doctors like Rachel matter because they understand how to titrate the system. They understand, oh, you know what? Even though normally you might put somebody on 200 milligrams of micronized progesterone when they're fully in menopause, you might only need 50 milligrams today and you might only need 100 milligrams next year. So it's not an on-off switch. It's more like a precision medicine type of approach. It would be so good to have more research happening in parallel because I noticed that there are many clinicians who are now open to working with their patients to address the needs of the patients and kind of base what they're doing on their own experience and their relationship with the patient. I think for them, and I know a lot of them, I'm friends with many of them, what I think would be lovely to have is data that really works in parallel. So you have maybe not clinical trials yet, but at least some information that can help guide the diagnostic process. And the challenge is there's not a natural owner to doing that study. It's not as simple as here's the latest version of a GLP-1 agonist and we're going to go out and we're going to test whether it's more or less efficacious for weight loss or type 2 diabetes where there's an obvious sponsor for that research. Here, we're talking about drugs that are cheap and not protectable. One thing that is probably interesting is the selective estrogen receptor modulators. Yeah, so let's talk about CIRMs a little bit. CIRMs are very interesting compounds because, like we were talking about before, there are different types of estrogen receptors, at least three types that we know of, the estrogen receptor alpha, beta, and GPR. And they are distributed differently in different parts of the body. For instance, within the brain, we have some structures like the pituitary gland and the hypothalamus that contain similar amounts of estrogen receptor alpha and beta, but are predominantly alpha because they're more reproductive tissues. So the alpha receptor is more abundant or more expressed in reproductive tissues, whereas the beta receptor, for instance, is more expressed in the cognitive parts of the brain. So what some scientists and clinicians have been trying to do is to develop compounds that selectively attach themselves to the beta version of the estrogen receptors. And for instance, I'll go back to Robbie, Dr. Robbie Brinton. She developed what I believe to be the first neuroserm. So it's a neurological selective estrogen receptor modulator that comes from plants, actually. She looked at all different phytoestrogens and compounded them together into a formulation that's been shown to bind with very high affinity to estrogen receptor beta specifically. And that means that, at least in animals, she tested that very thoroughly in animals and she did a phase one clinical trial. We're now doing a phase two B in women. But what she found is that this specific substance leaves your reproductive organs alone, but goes up into the brain and binds to the estrogen receptor beta with high affinity, therefore stimulating cognition in terms of memory, for instance, or executive function. function and also supports mitochondrial activity because she's done a lot of work on mitochondria and seems to improve neurogenesis as well. That's pre-clinically. So we're not looking at whether that formulation can improve brain energy levels in women and hopefully memory performance. And also we are hoping reduce the risk of developing Alzheimer's plaques. And we are working with women who are very early postmenopausal. Is this pre-IND or is this in phase one yet? This is phase two, but it's considered a supplement. So the FDA considers this a supplement. Because it comes from plants? Yeah. What's the name of it? Phytocerm. Phytocerm. Yes. To be clear, it's a GRAS approved FDA supplement? Yes, it is approved by the FDA. So the purpose of these studies is to be able to make claims. It's not regulatory. It's not regulatory. They have done all the regulatory phase. We are now doing a clinical trial very specifically to test whether it supports cognitive function and brain energy levels in women at risk for Alzheimer's. And Rob is also looking at half flashes and visomotor symptoms in a separate clinical trial. The reason I brought it up is that I think is a fairly unexplored avenue for support of brain function and also for relief of menopausal symptoms in women. Because it makes sense to go for the source of the symptoms that they have, flashes, the eye sweats, the insomnia, mood symptoms, cognitive symptoms, they start in the brain. So it would be wonderful to have a molecule that's never been associated with an increased risk of cancers to any reproductive organs and just goes into the brain. It does what it's supposed to be doing in the brain. But then we miss the activity in sexual organs. We miss the bones. I mean, there's still so many benefits. Well, not the bones. I think there are estrogen receptor beta in the bones. But you're not going to get it with a CIRM. Not with this specific CIRM, no. But there may be other CIRMs that are developed in the future. But we have the perfect one. It's called estradiol. Why are we afraid of this? I mean, I think this is the problem, right? We have to stop giving the fear-mongering people an excuse, which is there is no evidence that estrogen causes breast cancer. This is a fallacy. This is a complete fallacy. The Women's Health Initiative data by itself makes it very clear. Not a single additional woman died of breast cancer as a result of taking even the conjugated equine estrogen. If there was any increase in incidence, but not mortality of breast cancer, it was due to the MPA, which again, how many women take MPA today? Today, no. Yeah, exactly. We have no women taking MPA today. Women are all taking bioidentical micronized progesterone. I want to be very careful that I never let someone have that out of saying, but estrogen causes cancer. It doesn't. There's no evidence that it's causing cancer. Yeah, I think the word cause has been misleading women for a really long time. It has. Because the idea is that you have no risk of cancer, you have no cancers already, and somehow you take this molecule, this estrogen molecule, and boom, you get cancer. That's not what's happening. No, but that's what women are being led to believe. Yeah. And again, the analogy that we should have women understand is the analogy between testosterone and prostate cancer. Yeah, that's a good one. It was a very good analogy because it has been unequivocally demonstrated that testosterone, either endogenously or given exogenously, does not drive prostate cancer. Does that mean that when we have a man for whom we're treating him for prostate cancer, if he's not a surgical candidate, that we don't do androgen deprivation therapy? No, of course not. We do androgen deprivation therapy. But once a man has surgical therapy for his prostate cancer, guess what? We resume testosterone replacement therapy. He had prostate cancer. We're giving him testosterone. But guess what? Doesn't increase his risk. So here's why I believe that we're so brain damaged on this topic. The urologist has a marked advantage over the clinician who treats breast cancer. And it comes down to a very simple protein called PSA. It's the PSA that gives the urologist and the urologic oncologist a marked advantage, which is we can always follow PSA. So when you have a man who has a Gleason 3 plus 3, which is a cancer, and you're trying to decide, okay, he has prostate cancer, but is it the kind that's going to kill him? Or is it the kind that's just going to stay in his gland and stay localized? You watch and wait those men. We don't operate on a Gleason 3 plus 3, even though it's cancer. But do we chemically castrate that man? Not a chance. If his testosterone is 900, we rejoice. If his testosterone is 300 and he's feeling symptoms of hypogonadism, do we give him testosterone? Absolutely we do. And we follow the PSA and we follow the MRI. And if we need to do a biopsy, we do a biopsy. And if his cancer changes, we treat him. I think it's the fact that we don't have the equivalent of the PSA for breast tissue. And in fairness, and in fairness to those who have to make these decisions, we miss the blood biomarker that allows us to cheaply and easily track the disease. But that doesn't change the underlying pathophysiology. I have nothing against CIRMs. I didn't mean to get on my soapbox. But I don't want women to come away from this discussion thinking estrogen is bad. Oh, my God. But they should be coming away with the opposite, which is estrogen is very important for their brains. Estrogen is certainly on the table. And I think that we have put ourselves in a difficult situation where now we need to re-educate not just the patients, but also the entire medical and scientific community based on newer data. I don't know how this really happened, but we have been stuck with the Women's Health Initiative for decades. It doesn't happen in other fields of research, don't you think? No, it did. This has happened, I think, in other fields of research. Yeah, sure. Think about the literature or think about the phobia around dietary cholesterol. Oh, okay. Think about how much you can't eat the yolk of an egg, you can't eat shrimp. Yes, I think. Dietary cholesterol raises cholesterol in the blood that causes heart disease. I mean. But did it all come down to one trial? Because this is just one trial. That's a fair point. You're right. In the case of dietary cholesterol, it came down to a couple of epidemiologic studies, a couple of clinical trials, none of which asked the question exactly, but the public was either misled or confused about the difference between the chemical structure of dietary cholesterol, which is esterified versus non-esterified endogenously produced cholesterol. And the story is much more complicated. To your point, though, the Women's Health Initiative cost more than a billion dollars 25 years ago Yeah And therefore it not going to be replicated So it was a study that had at least three or four fatal flaws in the design some of which I think are justifiable The most fatal flaw in my mind is they just used a garbage formulation of estrogen and progestin But that's what they had. Exactly. And it's not the only thing they had, but they made the decision to use. Yeah. They made the decision to use what doctors were prescribing most frequently. I think that's a forgivable mistake. The real fault lies with the PIs and the media who, I believe, very nefariously promoted a false agenda. Again, when was the last time the NIH did a press conference on a study like, really, press conference? Post-game analysis? Really? That's what we're going to do? That's strange. Very strange. And I think there are certain members of the media who I will refrain from naming who simply got it in their mind that this was the way it was. And they have been completely immune to any form of logical intervention to show them otherwise. Even when seven and even 19 years later, subsequent analyses find the same thing. 19 years later, we see the same. And by the way, to my knowledge, that's the most recent publication. Maybe there's something even newer. But 19 years post, we're seeing not one additional woman died of breast cancer in the CEE plus MPE group relative to placebo. And that's even with the MPE, the MPA rather. Where's the press release on that? I know, I know. There's a tendency, I think, to amplify the negative results as opposed to the positive results. like even with the association with Alzheimer's, there are a few studies that came out of Northern Europe showing that hormone therapy, those are retrospective studies that looked at women who have Alzheimer's today and were taking hormone therapy starting before the Women's Health Initiative crash. And in those studies, there is an association between taking hormone therapy at any age and an increased risk of dementia. There are two studies. They're all over the news, all over the news. Hormone therapy causes Alzheimer's. Right, but the 10 studies that show the opposite, it's crickets. Yes, there are studies with like half a million women from the United States where, by the way, the vast majority of studies show the protective association that just never make the news. And that I find is a pity because it leads to a very unbalanced conversation where so many women today are like, oh, I need to go off hormone therapy because of this observational study that is a correlational study, right? Not even a trial. But I think it's so hard to disentangle scientific information when it's a headline. You're hit by the headline and it's very hard to really understand the context and the nuances and just the fact that even in these studies that make the headlines, those women were taking hormones before the Women's Health Initiative crashed. You can see that they start with a certain number of women in the study, and then the number just plummets, right? So at the end, you're left with this subpopulation of women who just happen to be still on hormones. I won't even pretend to disentangle that I could predict the biases that are inherent in that type of a study. Observational research is hard. That's like the worst example of observational epidemiology. I couldn't disentangle that. Like, I couldn't even tell you what corrections you need to make. I think your intuition a few moments ago was the right one, which is the only way we're going to get better data on this. It's by generating the right data. We don't need more observational epi on this question. What we need are better and better biomarkers that allow us to do more rigorous prospective, randomized control trials. We need RCTs and we're not going to get hard outcomes because it takes too long and it's going to cost too much. But we could look at C2N, we could look at P-tau, we could look at any of the other brain metabolomics, we could look at so many things. And so I guess my question for you is clinically, I mean, most people listening to us aren't going to have access to an estrogen tracer. They have to be in a clinical trial. Or in a status rate. Yeah, yeah. So clinically, what do you think of C2N? What do you think of the commercially available versions of PTAO and these other studies? Do you think that these are ready for prime time? Do you think that... For prevention or diagnosis? Yeah, do you think that physicians and women could use these as tools to track interventions that they're making? Oh, to track interventions? Oh, yes. Yes, totally. This is what we're doing with care. Okay. So we're using these specific... You're using commercially available assays. Sometimes. We do have the machines by the smogs. And so we are our centers, our sites, basically, they run their own assays. But it's the same machines that are used by commercial entities. And we are using those as surrogate outcomes of Alzheimer's risk. We're using not just the brain scans, but also the blood based biomarkers because they're much cheaper. They're minimally invasive. They're easier to read. We do need to have more long-term data to really establish their predictive value for each individual. Right now, they're being used either diagnostically, which I think is very smart, or for research to try and better understand if we can use those markers to really predict who is at risk and who is not, and what is the positive predictive value or negative predictive value for any given individual. And I think studies like CARE and other prospective cohort studies and large-scale biorepositories, I think they're so important, like the UK Biobank, thousands and thousands and thousands of blood samples that can be used and analyzed for these purposes. So one way to maximize the potential of observational research in a three-year span is to leverage data from all over the world. because a lot of the information we have comes pretty much always from the same studies, mainly North America, some European studies. And the population in those studies tends to be quite homogeneous, predominantly white individuals with a certain level of education, overall healthy. So what we're trying to do is to get data from all over the world. So with CARE, we have access to female-specific data from six continents. We don't have it from Antarctica, but we do have data coming from six continents. And all together, with the other scientists involved in CARE, we are estimating receiving data from over 20 million women, especially longitudinal data. So that's going to be a treasure box of data for scientists who are interested in addressing these questions. And yes, that's what we're going to do. So that's the first component of care is to firmly establish neuroendocrine aging and really reproductive history for women. All these different factors that seem to emerge already at puberty and then are perhaps even more unmasked during pregnancy and the postpartum period. and then tend to repeat themselves around menopause. There seems to be a continuum that you can kind of leverage a woman's reproductive history as a potential stress test for future cognitive decline and Alzheimer's disease or the opposite, cognitive resilience. This is something that has never quite been done formally and in a standardized fashion. So we are trying to do it now. For instance, high blood pressure is a risk factor for Alzheimer's for both men and women. It may be even worse for women. Some studies suggest, there's a suggestion, but effectively pre-eclampsia during gestation, right, during when a woman is pregnant, is effectively a stress test on the body. It gives you a preview of whether or not you may have chronic hypertension when you're older. And usually if it starts during pregnancy, it may present itself again during menopause and then it may remain stable. Same for mood changes. If during puberty, your neuroendocrine system is activated in such a way that you're more likely to suffer from anxiety or from depressive episodes or from mood changes, then things may stabilize as you get older, but then they could actually come back during pregnancy and they could be unmasked again during menopause. is so common for women. And we know that midlife depression is a risk factor for Alzheimer's more for women than for men. So we're trying to put it all in context, not just what happens to you today, but what happened to you in the past. I believe, and I'm sure you might agree, that hormonal history should be considered a vital sign. That was nice. Yeah. So do we know if, let's take two examples. Let's take the blood pressure example. Hypertension is a risk factor for Alzheimer's disease in men and women. And vascular. Yeah, vascular health in general. Men too. Do we know if when we see hypertension being a greater driver of risk in women than in men, that we're not picking up the same underlying risk that is being driven by something else, such as the neuroendocrine system? We do not know that. So we don't know if independently these are all the case. Absolutely. there are very few studies that have looked at neuroendocrine variables at all. Very few. In fact, if you look at the Lancet Commission, for those interested in Alzheimer's disease, whenever it comes to Alzheimer's prevention, we look at the recommendations of the Lancet Commission, which every few years produce an update. And as of 2024, we have this risk model that accounts for approximately 45% of Alzheimer's cases. So modifiable risk. Modifiable risk. So there are 14 modifiable risk factors that have been established to be meaningful and replicable by the Lancet Commission that altogether account for about 45% of Alzheimer's risk. And those are sex aggregated risk factors. They're valid for both men and women. What is completely missing there is anything that is female-specific or male-specific. And what they say, they have a section about menopause and hormone therapy, and they conclude that hormone therapy may increase the risk of Alzheimer's, especially for women with an oophorectomy. We were all like, what happened? One just has to be somewhat dismissive of these things. I mean, I realize it's easy for you and I to be dismissive of them because we know. Oh, I'm not dismissive. I'm really like, what can we do to change this? Because it's so important with women who do get an oophorectomy to also be aware of the hormone therapy. No, no, no, no. But just to make sure I understand. Yes. They're claiming that it's not the oophorectomy, that it's the hormones that follow the oophorectomy? Well, we do know that undergoing an oophorectomy before menopause increase is associated with an increased risk for Alzheimer's. But what they say is that hormone therapy can also increase the risk of Alzheimer's disease, especially for women. So what's the data for that? It's a couple of studies. Yeah, my point is it's total nonsense. The studies that suggest that if a 40-year-old or a 35-year-old woman undergoes an oophorectomy, that she's better off without hormones than she is with hormones. I mean, I just don't believe those studies. I don't believe those observational data. Yeah, I agree. I mean, do you? I think observation of research needs to be cautious. But specifically those studies? Well, do I believe the studies? That's the study that was done. Let me reframe it. If your 35-year-old sister was in a car accident or had an ovarian cyst rupture or something like that and needed to undergo an oophorectomy, she's 35 years old. She is now sitting in front of you in menopause. She's mechanically, chemically in menopause. And she's got hot flashes and she's got all the symptoms that a 35-year-old woman would absolutely have in spades because of the abruptness of this. And she came to you and said, do you think I would be better off with or without hormones? What would you suggest? With hormones, I think this is standard of care at this point. But do you think you would be increasing her risk of Alzheimer's disease by telling her that? No, that's why I'm so puzzled. That's my point. Okay, so that's my point. We're in alignment. We're in alignment. I mean, whatever we know about hormone therapy that is especially beneficial for women who experience early menopause, and especially when early menopause is triggered by an oophorectomy, this is in professional guidelines. My only point here is that these commissions sometimes cherry pick data to fit their agenda. That's the point. Why is that an agenda? Is it even an agenda? I don't know. What is concerning to me is that neuroendocrine factors that are important for women, I think it's undeniable, are not part of these recommendations for Alzheimer's prevention. And when they do identify... Well, they are. They are, but they're in the wrong direction. This one is not positioned as a recommendation. It's more like we don't know enough. I want to pivot and ask you about something else. This is not something you think about. That's fine. But it's something we are thinking about a lot. Which is, do you believe that independent of weight loss and insulin sensitivity, GLP-1 agonists are going to have a protective effect in the brain? I think it's really interesting and it makes sense. See, that's the thing. Biological plausibility needs to be present for any study to be done. And sorry, I just want to complete my train of thought. When you do observational research, which is also relative to the GLP ones, you need to have a hypothesis that is based on something. You can't just do a fishing expedition. You need to have preclinical work showing, for instance, that once you have a norephorectomy, estrogen is beneficial. If you start right after the surgery, you keep taking it until the natural age of menopause. That we know from preclinical research. That is your biological plausibility. So then you do translational research. You power your observational study to assess a hypothesis that is based on preclinical work. That is still observational, but is solid. If instead your study is showing the opposite, there is some issue there. So that is my concern. when it comes to some kind of research that gets published, it gets published because that's the day-to-day you have. And regardless of whether or not your conclusions are in alignment with pre-clinical research, you publish it anyway. That's a question mark for me. And everybody falls back on the Women's Health Initiative. Once they find an increased risk, it's like, well, the Women's Health Initiative found so-and-so, even though it goes against biological plausibility. So for the GLP-1s, I think there's a lot of potential. There's actually someone I know who's developing ligands or tracers for GLP-1s in the brain. And I think that's going to be really interesting. Do you have a sense of what the mechanism of action would be beyond two things that are important, which are metabolic? It's totally logical that even if you have some insulin resistance absent diabetes, making that better is going to make it better. We appreciate that obesity is accompanied, even if it doesn't come with diabetes, it's still accompanied by inflammation. And as we reduce inflammation, yes, all those things. Yes. But the real question I'm asking is if I took someone just like you, and I'm assuming I know I can see your health and you're in perfect health, but you are at high risk for Alzheimer's disease. Will they take a GLP-1? Yes. If we put you on a micro dose of terzepatide, low enough dose that I'm not going to take weight off you because I don't want to take any weight off you. I don't want you to suffer the consequences of sarcopenia or anything like that. Is that going to provide protection for your brain? This is the question I want to know. This is the study I want to see done. And of course, you can only study this prospectively with very good brain biomarkers. We're not going to be able to do this study for 20 years and follow a bunch of women. But if we have, as I think we are, getting to the place where we have really good biomarkers, can we start to ask this question scientifically? We can start. The question is never interest. I think so many scientists are interested in testing it. The problem is always funding. It's really expensive to do this kind of research and do it well? And who is going to sponsor it? Hopefully the NIH. I mean, historically, the NIH has been the biggest source of research fundings in the United States. This is clearly a national level problem. It's a bipartisan problem. Hopefully this is happening. It's not my field necessarily, but even just the fact that people are developing ligands and tracers for GLP-1s, everywhere in the world, including the brain, I think is a strong indication that there is a lot of interest. As of today, I don't know how to answer. I really don't know how to handicap that. The data look somewhat promising, though. I have seen some unpublished data, which, as you pointed out a few minutes ago, I mean, you have to take that with caution. So there's lots of things that you have to be mindful of. But I have seen some unpublished data that suggest that very low 2.5 milligrams of trisepatide, as an example, is meaningfully reducing blood-based and CSF-based markers of neuroinflammation and protein aggregation. And again, we're talking very small numbers here. You know, we're talking like N of 20. Yeah, but you have to start somewhere. Yeah, you'll pilot. And that's really interesting. So I wondered if you had a more informed point of view, but it sounds like you're equally interested. But yeah. Well, Lisa, this has been a very interesting discussion. It's really the discussion I wanted to have was kind of this intersection of the brain and Alzheimer's disease. Unfortunately, I feel like we are still a little bit in the dark because while it appears that the neuroendocrine differences between men and women probably account for the majority of these differences, there may still be other things, right? We still don't understand if women are more susceptible to hypertension, dyslipidemia, insulin resistance, sleep disturbances, all of the other risk factors. We don't know if they're disproportionately affecting women. And so I guess we're left with the following question. Ultimately, if you're listening to this podcast, you might take interest in all the nuances we've talked about. But if you're a woman, you want to know what should I be doing different? What should I be doing different than I'm already doing. And so what is the answer to that question? If you're already paying great attention to your sleep, if you're already paying great attention to your nutrition, if you're insulin sensitive, if you're managing all of these things that we've talked about, is the big takeaway from this discussion that if you're on the fence about hormone replacement therapy, it's probably something that should be in your purview and you should probably think about it more seriously. What would you say to a woman who's either about to go through menopause, in menopause, or just out of menopause, who's coming at this purely through the lens of her brain? I don't know that many women who really check all the boxes. I think whenever patients come to the clinic, to the Alzheimer's Prevention Clinic at Welker Nut Medicine, which Richard Isaacson launched, I think it was 2013, most of our patients come to us because they're really scared that they may be experiencing early-onset dementia. And we go through a series of tests, and more often than not, these are midlife women. What they're describing could be attributed to midlife changes, including menopause. In some cases, clearly, there's an increased risk of Alzheimer's that needs to be mitigated. At this point, what we do for Alzheimer's prevention is predominantly behavioral. So the ABCs, if you will, of Alzheimer's prevention are lifestyle-based and then include managing medical conditions like high blood pressure, insulin resistance, diabetes, obesity, all the cardiovascular risk factors. That can be done with a combination of tools that leverage diet, exercise, stress reduction, sleep hygiene, and whatnot, and also medical, pharmaceutical routes when appropriate. For women specifically midlife, I do think that having a serious menopause conversation is important, not just for the short term, not just for the symptoms of menopause that one may be experiencing today, but because the research is moving so fast. And I do feel as a midlife woman, I do pay attention to all the things you mentioned. I am extremely conscious about my lifestyle and so disciplined. It's almost ridiculous. Like this morning, I couldn't find anything that I wanted to eat for breakfast. So I just skipped it because I'm not going to have a bagel for sitting in the morning. I want to have all those answers, but we need to also wait for the research to get done so that we can then give women the right information. It's the first principle of medicine, right? First of all, do no harm. And I think as long as lifestyle is concerned, it is important to be very consistent. And I think a lot of people, especially in this country, try a lot of different things. And then maybe those things don't work out. They feel like they're not working out and they switch from a keto diet to veganism and then go back to something else. And I think consistency is important. We do know that some very specific patterns are conducive to brain health. And I think it's important to embrace them and stick with them for long enough time. Like exercise, yes, but there's so many different ways to exercise. That at least we have information that is specific to women, including women in midlife, which is the association between intensity and gains, where gains is not building muscle mass, but more like for health, overall health, follows almost like an inverted U shape, where moderate intensity exercise, if performed frequently enough, is conducive to the greatest gains, which I think is the zone two. It is, but it turns out to be a little bit more complicated in that intensity matters and duration matters, and it depends on how much time an individual has. And so the less time an individual has, the more they have to prioritize intensity. That makes sense. The more time they have, the distribution curve actually skews to lower intensity. But if you're in sort of a sweet spot in the middle, then you're probably going to get the most bang for your buck at a modest level of intensity, which might actually be even north of zone two. I'm overdue for a discussion on this because I feel like sometimes I talk about this and I ironically create confusion by not being nuanced enough, which is a rare accusation for me. I can imagine. So I think I need to provide a little more nuance on that. But you know what I take from what you're saying, Lisa, which I agree with, by the way, that is the single most important thing to do is maximize the known lifestyle levers because it buys us more time. And I am more optimistic today than I was five years ago about treatments for dementia. Yes. Five years ago, I was in a state of despair. I thought this is a disease that will never be treatable. I really believe that once the proteins started folding in the brain, like there was just nothing that could be done. And now when I look at treatments like clotho and just full disclosure, I'm a co-founder of a company that is trying to develop a clotho injection. And I look at the potential around GLP-1 agonists and I look at the ways that we're getting better understanding of hormones. And I look at other molecules, exercise, memetic proteins. I'm starting to think we just need to hold on long enough. Like if you can delay the onset of something by 10 years through all of these modifications, that could be the difference between a normal cognitive life and a cognitive life that is cut short. And unfortunately, that's not the answer to the person who's 75 today who has dementia. And that is tragic. And I wish I could say, don't worry, tomorrow we're going to have something that's going to reverse this. I don't believe that personally. Maybe that makes me a pessimist, but I absolutely believe that in a decade, we're going to have things that are going to make a real difference. And therefore, if you're sitting here and you're 60 years old and you can keep checking all those boxes, as you said, that could be the difference between you being the candidate who gets the rescue before you're fully in the throes of the disease versus not. I completely agree. And whenever I mention lifestyle and people are always like, oh, yeah, sure. But really, it's so important and not that many people are as consistent throughout the years. And when we talk about brain health, I think it's important to understand that the brain is not the same as the rest of the body. And people are so used to seeing results quickly. Within a matter of weeks, you can lose a couple of inches or you can grow muscle. The brain is built for stability, whereas the rest of the body is built for change. if you want to make an impact on your brain cells, you need to hit them frequently enough and long enough that that change is going to be recorded as an epigenetic mutation or as an epigenetic change or as something structurally permanent. And that, thank goodness, takes a really long time. Thank goodness it's a long time on the bad end. Yes. But that's the price you pay on the good end. Yes. So the good news is it takes a while to cause damage. The bad news is it takes a while to create resilience. Yes, but you can create resilience, which I think needs to be emphasized that this is not like a woo-woo wishy-washy thing. It really can give your brain cognitive resilience and brain reserve, which is what you want. In the end, you want your neurons to be strong. And you do that by having your body, for instance, move. We know the movements produces BDNF in the brain, produce iridine in the brain that support the health and growth of your dendritic, your synaptic extensions, for instance. We know that if you reduce inflammation, if you reduce oxidative stress, which is something you need to do from the outside, your brain will do better, will age less. So these are all things that are very realistic, that every one of us can do on a daily basis. we can all make good choices that support the health of our brains in the long term or not. And then it will show. It may not show today, but it may show 10 years from now. So this is really the time, I think, to invest in brain health, because at the end of the day, we all want our cognitive lifespan to match our lifespan. This is what we're trying to do. And then we do research as fast as we can. I was so happy to have the opportunity to launch care because it's very high speed research that should deliver in three years. I was joking with my daughter that by the time she goes through puberty, I may be going through menopause and I want an answer by then. Yeah. So hopefully. I'm really grateful for the grant you have. And I think, frankly, I did the math on this once. I believe that the entire Manhattan project in today's dollars was about three, four billion dollars, which, by the way, that's a paltry sum of money for what it accomplished. Right. I mean, it changed the course of history for all its good and bad. But three to four billion dollars is a trivial investment for the United States government. I would love to see an investment of that size to tackle this question, because if you think about what you're going to be able to accomplish in three years with $50 million, can you imagine what a, I hate to use the term because it's so overdone, but what a moonshot would look like here. And look, it might have to just come from the private sector as it has in your case through the Wellcome Trust. But nevertheless, I'm sure there's somebody out there listening who's thinking about what this type of a moonshot could look like. That would be wonderful. And scientists from all over the world are ready to do this kind of work and really hope they would be able to do more. Well, thank you for taking time away from both your family and your work to come out and visit and share your insights with us. Thank you for your time. I appreciate it. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice. 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