Brain Fog, Memory Loss, and Alzheimer’s Risk During Menopause with Dr. Lisa Mosconi

So, sadly, almost two-thirds of all Alzheimer's patients are women. And for a really, really long time, the notion was that women live longer than men, and Alzheimer's is a disease of old age. Therefore, at the end of today, more women than men end up with Alzheimer's. That was actually the pushback that I, the first one on my list of pushbacks that I got when I was a PhD student, because I wanted to look at sex differences in Alzheimer's and people were telling me it's a waste of your time, because it's just aging. It's just longevity. It's just that women live longer than men. The views and opinions expressed on unpaused are those of the talent and guests alone and are provided for informational and entertainment purposes only. No part of this podcast or any related materials are intended to be a substitute for professional medical advice, diagnosis, or treatment. In our last episode of Unpaused, Dr. Lisa Mosconi helped us name something women have felt for decades, but were rarely believed. Menopause doesn't just change your body. It changes your brain. And Dr. Mosconi didn't bring opinions. She brought scans. She brought data. She brought a scientific explanation for that moment. So many women described with one sentence, I just don't feel it myself. In this episode, we go deeper into the why. Dr. Mosconi, the author of The Menopause Brain and a neuroscientist and leading researcher in the Menopause Alzheimer's connection shares what we now understand about the biology of Alzheimer's, including the long, silent phase that can begin in midlife and the real reasons women develop this disease more than men. And then we look forward. Dr. Mosconi explains the work underway to finally treat women's brain health as preventative medicine with better tools, better research, and ultimately risk calculators and real world clinical pathways that help women protect their brains long before symptoms begin. Okay, let's jump back in. I'm Dr. Mary Claire Haver, a board certified obstetrician and gynecologist and certified menopause practitioner. I'm also an adjunct professor of obstetric syngynecology at the University of Texas Medical Branch. Welcome to Unpaused, the podcast where we cut through the silence and talk about what it really takes for women to thrive in the second half of life. So your PhD is in what? I have a dual PhD in neuroscience and nuclear medicine, which is a branch of radiology. So I do a lot of brain imaging. Your family history is this what drove you to get this particular PhD. I graduated from university and then I had the year of training, Montessori, and the neurology and nuclear medicine, because I wanted to study nuclear medicine I wanted to look at the brain. I wanted to use brain scanners. I grew up with brain scanners, with scanners. My mom used to work at the accelerator at the CERN in Geneva. So I was very familiar with those concepts and I just really wanted to apply them to biology, which is what nuclear medicine does. And so I went to university and from day one, I was in my first exam with neuroscience, neuroscience one, and then I was stopped and it's only at the end of this five year four. I graduated in four, but it's at that point that my grandmother started showing signs of cognitive decline. And then when I was deciding on my PhD, I knew that I was going to do a PhD in neuroscience in nuclear medicine. But the topic became Alzheimer's because of that. OK. So what was the prevailing thought at the time as to the path of physiology or the causes of Alzheimer's? Yes, you know, it was really, really still in its infancy. We were just moving away from a diagnosis based framework where people felt that Alzheimer's was inevitable, that it was aging. The consequence of either your brain will. Aging or genetics or both. And people were just starting to appreciate that actually that was not the case and that the process of Alzheimer's disease is more like a continuum over time that you don't just suddenly wake up one day and boom, you have dementia. But rather that Alzheimer's is a slow and silent progressive disorder that takes many, many years to unfold. And that speaks to how powerful our brains are because if this progressive deterioration takes years, it also means that the brain is able to withhold and to really withstand the pathology at least for a certain amount of time until the damage is too severe for the brain to be able to function normally. And that's when we start seeing the first signs of cognitive impairment. The only way to know if the marks, the biological signature of Alzheimer's, which are present or not, which are amyloid beta plaques or Alzheimer's plaques and neurofibrillary tangles. So the plaques are between neurons and impair communication between neurons. Whereas the tangles are inside neurons and damage the neurons from the inside. So we have the plaques that damage the neuron from the outside and the tangles from the inside and all that creates inflammation that then leads to neuronal apoptosis or death over time. Yes. OK. So now we can actually measure that as you walk in the door because we have the tools to do that. Back then we could not. So the only way to measure these lesions or these markers was at postmortem. But that is Alzheimer's disease. The disease is the biology plaques and tangles. Alzheimer's dementia is the symptoms, is the memory loss, is the attention deficit, is the impairment in language, is the inability to conduct your regular activities. So the disease starts first and we and others have shown that it can start as early as in the 40s and 50s. But having the lesions does not mean that you're going to develop the dementia. There are many individuals who do have plaques and tangles and never show symptoms of Alzheimer's. Do we know why? We're looking into why. And that is what is driving the field of Alzheimer's prevention. Because now we understand that even though you may have these lesions in your brain, some people for whatever reason do not develop inflammation and do not lose neurons because of that. Yes, other people do. And so we're looking at all the different factors that can lead down one pathway or the other. And we and others, I mean, the field, obviously, has identified multiple risk factors for Alzheimer's that together or in isolation can modulate your odds of number one, developing the plaques and tangles. But most importantly, I think number two, to determine whether or not the plaques and tangles will be harmful to your brain. OK. In a way that it will impact. Big-time osteoporosis. Like, yeah, yeah, you know, like, heart disease. So not everyone's going to have a heart attack who has atherosclerotic plaques. Right. Does it make sense? You in your book, The Menopause Brain. OK. Yes. Right. Menopause is one of the best kept secrets in society. It was. And do you came along? I was like, do we still say that? Is that still a thing? I don't think so. What made you write that at that time? You know, this was really interesting. I was starting menopause together with Dr. Robbie Green, Robert Adia. She was my mentor for many years. And now she's one of the best friends and colleagues that I could ever hope to work with. I have learned so much from her. Yeah. I started working with Robbie, who is a pioneer in the field of menopause in the Alzheimer's connection. Because that wasn't a thing. Oh, my God, no. You guys got laughed at. Oh, yeah. Yeah. Yeah, that's a nice way to put it. Yes. Yes. So I've always looked at sex differences in Alzheimer's. Since my PhD, that was the first thing I've ever done. Doesn't matter if you're a man or a woman in terms of genetics, response to genetics. And we started looking at mitochondrial DNA. So something that perhaps people are not aware of is that we all have two different types of DNA, three, technically. But the first is our typical DNA with the chromosomes, so the 23 chromosomes and the X and Y. But we also have a mitochondrial DNA that is completely separate from our chromosomal DNA. And what's specific about mitochondrial DNA is that, number one, it impacts energy production. Mitochondria are the powerhouse of the cell. Yes, the powerhouse of the cell. But also is 100 percent maternally inherited in humans. And so that I thought that could be an interesting way by which Alzheimer's risk is inherited from the mother to the children, because we do know that if you have a maternal history of Alzheimer's, your risk is a little bit higher than if your father is affected. And if you have both parents affected, your risk is higher than having just one parent affected. Risk does not mean that anyone is getting sick. Right. It just means that relative to another person, your risk is a little bit higher. OK. But that was my PhD. It's my doctorate thesis, which has now been replicated and people are talking about it and doing more work on. So that was genetics. And Robbie loved that work. And she approached me at a conference and we just started talking. And she said, you know, I love your work about maternal inheritance and the risk of Alzheimer's for women, which really nobody talks about. Even though we are now two thirds more likely, like, why is this important? Because a lot of women, a lot of our listeners may not understand that you're much more likely to get Alzheimer's if you're a woman. Yes. So sadly, almost two thirds of all Alzheimer's patients are women. And for a really, really long time, the notion was that women live longer than men. And Alzheimer's is a disease of all age. Therefore, at the end of today, more women than men end up with Alzheimer's. That was actually the pushback that I the first one on my list of pushbacks that I got when I was a PhD student, because I wanted to look at sex differences in Alzheimer's and people were telling me it's a waste of your time because it's just aging. It's just longevity. It's just that women live longer than men. I we get this while still in cardiovascular disease. And yeah, you know, doesn't matter. Yeah, must feel a little disease. Like, why are you looking at sex differences? Like you're just everyone's a human and we all, you know, I'm like. OK, I know. And so that was my PhD is the reason I moved to New York because I moved so a transfer to NYU medical. And I started working with Dr. Monee De Leon, who is a pioneer in the early detection of Alzheimer's disease and Alzheimer's prevention. So he was doing brain imaging and biomarkers on individuals in their thirties and forties. When everybody else in the field was still working with patients with Alzheimer's in their seventies, eighties and nineties. There was a complete switch of framework that I thought was brilliant. And what we have shown since and other people have shown is that Alzheimer's is not a disease of all day. It is a disease of midlife with symptoms that start in all day. So the idea is this disconnection between Alzheimer's disease and Alzheimer's symptoms of Alzheimer's dementia, where the disease starts in midlife for many people, not all people, but it tends to start in midlife. That's when we see the plaques and tangles forming again when we do brain scans, but then it keeps progressing over time, usually for decades, until the plaques and tangles reach a certain threshold after which brain performance is no longer maintained. And then we see the changes in memory, attention, language and whatnot. So that completely changed the question and the conversation finally for us because if Alzheimer's disease is not a disease of all day, but it's a disease of midlife in women have a longer, have a higher, long term, lifetime risk of Alzheimer's relative to men starting in midlife, which we now know to be the case, starting at age 45, a woman has twice the risk of Alzheimer's as respect relative to a man of the same age. Then the real question is, well, what happens to women in midlife? Right. What happens to women in midlife that does not happen to men in midlife? And that could potentially explain the higher long term risk. And that thing is menopause. So it wasn't until the nineties that we discovered that estrogen impacts the brain. Yes. And that is ridiculous. So the first study is showing that estrogen is not just a reproductive factor, but is also a brain hormone was published in 1992. And it was only replicated in 1994, 1996. When do we get to the moon? Yeah. Right. Yeah. Right. Men landed on the moon like 30 years, 20 years before. We were all made aware of the fact that reproductive hormones, sex hormones in quotes, are actually brain hormones too. So in other words, we know more about space than we do about the female brain. The women's health initiative, when did they start writing it? They started the grant in 1991. They started. Yeah. Yeah. They started writing the grant. Before we even knew how estrogen worked in the brain. And then we just say they did it wrong. They're thinking they did something incredible, incredible. When no one was talking about prevention. They just went for it. So I think that is very commendable than the way that the results were disseminated. Right. We can't demonize the study because it was groundbreaking. It was incredible. It was incredible. And we still use the data today for prevention. Sadly. So you've said, and you've walked me through the story, and I think it's important for the listeners because I think it's fascinating about estrogen and estrogen receptors in the brain. So you're like newly met to PhD, you're on fire, you're ready to study this. And you're like, what we didn't scan, we didn't see. Yes. You know, like if we don't look for it, it's not there. Yes. Right. And so you go and decide, I want to study estrogen in the brain, but there was a problem. Oh, there were plenty. So there were two sets of problems. The first set is that nobody had done it before, which I don't know because I assumed that since menopause is something that impacts all women. I would find a lot is universal. All women got willing. If you live long enough, you'll go through menopause. And we all know as women that menopause is not nothing. Right. There are neurological symptoms, but evidently the idea that some of the symptoms that can occur during menopause are neurological in nature was not a well known or common understanding. I still get pushed back in 2026. No, no, no, no. This is just aging. No, no, no, no. Yes. You know, come on. It's hot flashes. I'm like the neurotransmitters, you know, like the vasomotor symptoms are in the brain. Yes. They come from the brain. They are neurological in origin. And that was the first problem. The second problem. So, and then we set out to do the studies, right? And that is, those are the brain scans you mentioned before where that was back in 2015 when I was like, well, I've been studying midlife women for the risk of Alzheimer's, but I also have information on menopause. Right. And so we went back and we, we talked to all the women in the study and that was so helpful because what we were finding was this, that if you, in my hands at least, but it's been replicated increasingly, if you look at brain scans of midlife women and midlife men, the women, and, and this is very, very important. We work with women who have either a family history of Alzheimer's or an APOE four. So they're high risk. So they're, they're high risk relative to people who don't have these markers. But if we compare these groups, the women consistently and significantly show more red flags for Alzheimer's in their brains relative to men of the same age. And this is very consistent with preclinical work in animal studies as well. But we couldn't find an explanation for that other than sex. But what is it about sex that is driving this, right? Which factors and what other parameters could be involved in? We were looking, I promise everything, we were looking at family history, of course, APOE four, genotab, we were looking insulin resistance, diabetes, heart disease risk factors. And we could not quite really explain the difference. And then we looked at menopause and we worked with the OBGYN department, of course. That was wonderful, actually, to work with colleagues who had never thought about Alzheimer's. We had never thought about menopause. It was, it was lovely. And we classified, they classified the women as premenopausal, regular menstrual cycle, period menopausal, irregular menstrual cycle, postmenopausal, no menstrual cycle for 12 months or longer. And then we matched them with men of the same age, because postmenopausal women are a little bit older. Premenopausal women and men, no differences. Period menopausal women and men of the same age. You can see the red flags popping. Mild, but you do see an increase. Postmenopausal stage, men of the same age, really significant difference. Wow. Yes. That was back in 2017. And we published it and no one has seen those brain scans before. And that was menopausal stage. So we had a group of women who were premenopausal, period menopausal, postmenopausal. And we could show how the Alzheimer's plaques are nowhere to be seen. In premenopause. In premenopause. You can start seeing them in my studies, always in the frontal cortex, in peri menopause, and then they're a little bit everywhere after menopause. Still very mild, right? They're not within the Alzheimer's impaired range, but they're there. You can see them. That's why I say red flags. But what was most striking was the difference in brain glucose metabolism, which is something that Robbie has shown time and time again in rodents, in animal models of menopause and Alzheimer's combined. And what we have shown in these are brain scans that are all over the internet at this point. You can see the difference in those first images where the premenopausal brain is nice and bright, the perimenopausal brain gets a little bit darker. And the postmenopausal brain is much darker in the same brain regions that are typically hypometabolic or impacted in clinical Alzheimer's patients. And quantitatively, that is a 30% difference. Now, that was cross-sectional. Pushback immediately. Right. But that, you know, this is just. We're talking about glucose uptake. Yes, it's glucose uptake in those two ways metabolize. It's glycolysis. Okay. Yes. But we've also done spectroscopy studies to look at ATP production, where ATP is the cellular energy. And we do show the same kind of imbalance. So glycolysis is the very top of the glucose metabolism chain. ATP is at the very end. So we know that the entire metabolic pathway is disrupted. So for our listeners, we're talking about the Krebs cycle, if everyone remembers from biohospitality in high school. Yeah. And you basically start with glucose and we break it down through several steps until we get energy or ATP at the end. So what she's saying is I'm trying to take it down for the laypeople. The HAs are not there. We are disrupting that pathway. Yeah. This episode is brought to you by Expedia and Visit Scotland. Start your story in Scotland. Experience the pool of wide untamed landscapes and fresh cuisine that feels rooted in place. Discover castles steeped in legend and feel the genuine warmth from locals you meet in a place that will stay with you long after you leave. Start planning your own Scottish holiday today at Expedia.co.uk slash Visit Scotland. Have you ever felt like you were living just a B or B plus life? It's so dangerous to live that more dangerous than a B minus or a C plus life because when you're living a B or B plus life, you don't change it. You think it's good enough. Is it? I'm Susie Welch. I host a podcast called Becoming You. People think, OK, an A plus life is not available to me, but there is a way. We are all in the process of becoming ourselves. Listen to Becoming You wherever you get your podcasts. Instagram teen accounts with automatic protections on who can contact teenagers and the content they can see. Instagram teen accounts have contact limits on by default, so teenagers get messages from people they know, not strangers and default content settings. Plus teenagers under 16 can't change these default settings without parental approval, so parents can help teenagers connect safely. Learn more at instagram.com slash teen accounts. Now, we need to talk about something that went viral. When Robbie testified at the FDA. Oh, God, yes, I did. She talked about in her studies that we see and now help me walk me through this so that the basic listener can understand the brain will start utilizing some of its own white matter for fuel in menopause because glucose metabolism is impaired. Yes. So meaning it will turn around and grab whatever it can for energy. The brain will protect itself and white matter is kind of the insulation. So that's fatty material that that lines our neurons and that got twisted into the brain eats itself somehow, which went viral, of course. Social media. Can you kind of explain what that is? Yes. One of the many functions of estrogen is that when it binds to estrogen receptors, that activates the glycolytic pathway, which means the brain starts burning glucose to make energy. The brain is always burning glucose to make energy. The brain runs on glucose for women until menopause. And that is wonderful because neurons need a lot of energy to just function correctly. What happens when estrogen declines or fluctuates? What happens when estrogen declines or fluctuates is that the estrogen receptors are not activated the same way. And that has a negative feedback effect on the way that the brain uses or not uses glucose to make energy. And when estrogen is very low after menopause, but even prior, what happens is that the brain starts glitching because it can't get all the energy that it needs from glucose. And because the brain is an exceptionally intelligent organ, of course, doesn't just sit there and decides that we're all going to develop dementia. It switches tracks. So it says, OK, if I can't burn glucose for energy because the mechanisms are not working, I'm going to go hybrid. I'm going to start burning other sources of energy. Inferts is switches to amino acids. OK. It's an easy switch chemically. But the problem is that the brain also needs amino acids to make neurotransmitters. So that could backfire. So then the brain says, well, no, no, no, no, no, I need the amino acids for a number of different functionalities. So I'm going to start burning fat. And that is called beta oxidation. And in the entire body, when you go into a state of very low glucose, the body starts burning fat, which is one of the key principles. So diet, there you go. The same thing can happen in the brain. So the brain starts burning fat to produce ATP. What happens then? Well, the brain is a very fatty organ. There's a lot of fat, good fat, than like you said, insulates. Yeah. So actually, when you look at MRI scans, you'll need a little bit of gray around the brain that is the gray matter, but everything else is white, right? That's white matter, which means fat and other things. So what is the easiest accessible source of fat to burn the white matter? And so the brain, at least in animal models, starts utilizing a little bit of this white matter as a source of energy in rodents, very specific Alzheimer's models. That long term turns into the word that triggered the brain itself, which is called catabolism. Anabolism, when you're building tissue, catabolism, you're breaking it down. It does sound unpleasant. It was kind of scary. It was kind of like the brain eats itself, but I knew it is not an autoimmune disorder. It is not an autoimmune reaction. It is not phagocytosis. It's an adaptive response. Yeah. It's remodeling. It's more like energy preservation in that case, I would say that in rodents, backfires, if it doesn't stop after a certain amount of time, and if it just doesn't stop, it will lead to white matter degradation and then we're on a loss. But this is in rodents. We need to consider that female rats tend to die quite soon after the end of the reproductive life. So reproductive senescence for animals is a little bit like the end of the line. Right. So their lifespan matches the reproductive span. Right. Most mammals don't have a protractive menopause like humans. Exactly. There are a few, but we're really the... Yeah. So women live at least another 20% of their lives. And they're not a great menopause model other than taking out ovaries. We don't have a perimenopause model. You know, you don't... So, you know, if there are some female rats that live quite long, some specific strands, and then Robbie uses them to look at the natural menopause transition, but still, still, it does not really replicate brain aging in humans. And that's why translation of research is so important. That's why Robbie reached out to me and we've been working together ever since because she can probe the mechanisms doing experiments, which we will never be able to do on women. But we can apply those findings to see if similar mechanisms or patterns are present in women. Okay. Very often they do, but sometimes they do not. That we have shown by following women over time. And this is actually not published yet, but it's hopefully soon. We have shown evidence for adaptation as part of menopause. So definitely there are changes in... Now I can say changes because we also have published and we're doing longitudinal studies where we're following women over time. And we do see that the metabolic changes are progressive in some brain regions, not all brain regions. We do find that the gray matter is reduced in some regions and not others. But we also find evidence of compensation. Okay. Some parts of the brain ramp up their metabolic activity as other brain regions decline. So overall, cognitive performance is preserved. And I think this is very, very important to say because I know that our work has perhaps not been fully understood. And the notion is that if you have these things that you have a disease or a pathology, whereas we're always saying, no, no, no, what we're trying to do is really understand how the brain, women's brains respond to a very significant transition, not just from a reproductive perspective, but also from a neurological perspective and how that could reflect an inflection point for Alzheimer's risk for some women. Menopause does not cause Alzheimer's. What we're understanding more and more is that it kind of unmasks a vulnerability or multiple vulnerabilities. Right? It's when some women develop anxiety or depression is when some women have more severe symptoms of multiple sclerosis. That's when the risk for stroke increases. There's like a cellular aging accelerator. I guess if you have an underlying vulnerability, that becomes more evident. Right? And it's important to study that because then we can offset that the risk. Right. Which is what we're trying to do. We have hope. We can intervene earlier, see who's at risk and provide hope. Well, let's talk about the statistics that a lot of women aren't familiar with. And I'm not fear mongering here. I think it's important that our listeners, especially younger listeners who are like, is this, you know, oh my God, I don't want to get older. This sounds terrible. But I think if you know, then you can prepare yourself and you're not so blindsided when you start having symptoms. So women are twice as likely as men to be diagnosed with an anxiety disorder or depression. And so when I looked at the data on SSRI prescription use, so that's a marker for how many women have depression or anxiety because these are the medications we use to treat. We have about a 10% use before perimenopause. And then we double that. Now, part of that is because a lot of practitioners are not comfortable prescribing hormone therapy and will default to giving a patient an SSRI to treat a hot flash and to treat phase of motor symptoms. But we do see a doubling. So we go from 10 to 20% after age 40. And then we go to 25% at age 65. And then women are twice as likely to develop Alzheimer's three times more likely to develop an autoimmune disorder, including those that attack the brain, including multiple sclerosis, four times more likely to suffer from migraines or headaches. Yes. And then more likely to actually be killed by a stroke after menopause. And that's a ratio that's two to one or even higher. No one taught me this, you know, when I was in training in medical school. Me neither. So this is all kind of new information. Yeah. I looked it up when I was writing the XX brain. And I was I pulled these stats from your book. Yes. I figured this is all research that we had to do kind of from scratch by pulling information from different fields to really. I think it's important to have a big picture, you know, like a high level understanding of what your risks may be and how to protect yourself against those risks. And I think it's really important to know that prevention is on the table. Yeah. And we have a lot of power to make the right choices and protect our bodies and brains. I think, I think because we can't see our brains, we really don't have some kind of direct line of access to our brains. They feel so foreign, almost like I can't touch them. They can't really, they don't quite, because it doesn't quite belong to you, your brain, until you have symptoms, right? Then you realize, oh my God, I do have a brain. How can I take care of my brain? But I think it's becoming a more and more common place to pay attention to mental health and brain health. And there are many things that we can do. What I'm seeing in my patients, in clinic and definitely when people, you know, sharing their stories on social media is the cognitive and the mental health changes that are really acutely happening where we build a life for ourselves, right? We build a family, we build a job, we build this wonderful, beautiful life that is messy and complicated and, you know, all the things, you know, that all the jobs and the hats we wear as women, and we've got it. We've got it managed. We have good days, we have bad days, but, you know, we are in control of our lives. Yeah. And then we're not. And the common theme in this, we're not, seems to be perimenopause. There's an inflection point. I love the way you describe it. So walk our listener through, in general, what is happening to our brains before menopause, you know, perimenopause and then postmenopause? From a brain perspective. It's a really good question. And I think we need to do more research to really be conclusive and talk about old women as far as I know, we are still one of the very few teams that are looking into it at this point in time. And we are learning more and more. That's shocking to me. You know, menopause is now on people's minds, but it was not until recently. Well, what happens is this, that hormones are starting to change and the pattern of hormones is starting to change. And what we have learned and we're learning more about is that the brain is in part and neuroendocrine system is a hormonal organ that responds to the action of sex hormones from the ovaries, which are predominantly estradiol and progesterone. And at the same time, the brain uses hormones to communicate back with the ovaries and these hormones are called gonadotropines. So they're usually FSH and LH that we focus on most. So as long as estrogen and progesterone are flowing up and FSH and LH are flowing back down, the brain has a very clear plan with the ovaries. When the ovaries start glitching and they're running out of follicles and their sex of varion hormones start to fluctuate, the brain gets confused. The reason being, so actually this is a very important thing. That I was hoping we would talk about that. When I talk about estrogen being neuroprotective, I'm really talking about estrogen, the endogenous hormone. Estradiol coming from the ovary. The endogenous hormone that the ovaries make because of this feedback loop. I'm not talking about estrogen therapy, but a lot of people make the assumption. The same. Yes, especially now that people use this term of bioidentical hormones, it's even more confusing because you're thinking, well, if the estrogen I make is neuroprotective and I can take the same estrogen from a patch or a pill, then that estrogen also needs to be neuroprotective. It's assumed to be neuroprotective. Not so easy. We would wish. Right. That would be fantastic. But the point is that estrogen alone doesn't quite matter. Can we talk about the biology of estrogen? Yes. Okay, good. The way that estrogen works, and let's just look at the brain, is that estrogen is able to cross the bloodstream barrier by causing diffusion and also potentially transport mediated channels that are being investigated now. And then it goes in the cell and looks for estrogen receptors. If estrogen will bind to an estrogen receptor, it's like a key that needs to open a lock, actually, it's like a key that needs to get jammed inside the lock. And together, they go inside the nucleus of the cell. They look for DNA and they bind to a specific part of DNA. That's called the ERE, estrogen receptor element that is in the promoter part of the DNA. So it directly triggers transcription, which means protein synthesis and cell function. So hormones alone, if you don't have the receptor and if the system is not responsive, the hormones alone don't do anything. They have to bind to something. Yes. They need to bind to the receptor and the binding needs to be functional. It needs to be able to get to the DNA, speak to the DNA and tell the DNA what to do. The things that can happen is either we're telling the DNA to make more of certain things or we're telling the DNA to make less of certain things. So what can estrogen with the receptor do? Well, for instance, can make more BDNF, brain derived neurotrophic factors. And that is a good thing. That's wonderful. It's a protein that really supports a synaptic plasticity and growth. It keeps your neurons healthy. Which is why we say that estrogen is neuroprotective. By activating these pathways, it supports brain protection. Things that we want to make less of, for instance, pro-inflammatory cytokines. We say that estrogen is anti-inflammatory, reduces oxidative stress because it goes through the DNA and say, stop making TNF alpha, stop making interleukin 6. Right? So it turns off the pro-inflammatory response. So that's why estrogen is so important for brain health. And we are now able to measure that using brain scans, which again is the first time ever. And your research, one of the things that fascinated me was you were the first or your team to document that across the transition, we actually upregulate the estrogen receptor. Do I too? Look at it. Yes. Yes. Okay. So for those of you who are listening on our YouTube, we will have the images for you to see and we'll get the images and they'll be linked in the show notes as well. Great. So back to 2019, we had been studied menopause for a bit. And the assumption was that the differences that we were seeing between women at different menopause stages, but also at that point over time, were directly caused or associated with changes in estrogen function. But that needs to be proven. Right. So I went to my radiochemistry department and I said, I need a tracer to use with brain imaging to look at estrogen in the brain 2019. Right. And they said to me, well, we don't have it. And I said, hmm, that doesn't sound so good to me. So you had no way to study estrogen in the brain because there was no tracer available. There was no tracer. So tracer is something to use in radiology. Explain what a tracer is. So tracer in our case, we do positive termination, tomography or pet imaging, which is that kind of technique, you know, when you look at the brain and some parts are red, blue, green. So that's positive termination. Just like here. Yeah. And what we do is that in this case, we take estradiol and we just attach a floating 18 molecule to the estradiol. Floating 18 is a radioactive is a very, very low dose radioactivity. But what is so special about it is then that becomes a tracer or a ligand. And you just injected in the bloodstream and it behaves exactly like estrogen. So it's lipid soluble. So it gets right through inside the brain. And then it looks for the estrogen receptors and it binds to the estrogen receptors. But we have this teeny tiny little thing attached to it that emits gamma rays, which means it shoots out light. You light up on the stand up. Yes. It's like a GPS or it very similar to when we do thyroid studies. Lots of women have had this, a tracer that picks up thyroid hormone and they're looking for activity for different autoimmune thyroid diseases. Yes. So we use it for all sorts of things for breast cancer. We use it for heart. But there was nothing available for estrogen. No, no, no. So this tracer was available. This is called the Florida estradiol. And we have been using this tracer for breast cancer for a very long time, but that's from the neck down. It's really hard to get stuff in the brain unless the brain accepts whatever tracer. The brain protects itself. There's a blood brain barrier and it's very protective. Yes, which is great. Right. For us as humans, not so great if you're trying to see what's happening. But this tracer actually crosses and it binds especially to that structure in red. Okay. So walk everybody through the images. Yes. So these are three brain scans or three different women. One is premenopausal. One is perimenopausal in the middle. And the last one is postmenopausal, early postmenopausal 52. And what we're looking at is the way that the estrogen tracer binds to estrogen receptors in the brain. What's important to know is that estrogen receptors are everywhere in the brain, but they're more abundant in some regions than others. So we are looking for the hot spots in a way. What we were looking for based on animal studies was a reduction in estrogen receptors because that we were saying before, the brains of female rodents are not well suited to outlive menopause. And so what happens that soon after the end of the reproductive spin, the brain stops making estrogen receptors and you can see the down regulation. It really just disappeared. You expected this to happen in humans. So when women go through menopause, they'll just stop making estrogen receptors. But what did you find? The opposite. So when we found that I drove my students insane, I was like, you've done it wrong. They're like, no, I haven't. And I was like, go back. I just cannot believe it. And we just kept enrolling participants because it was like, maybe it's just a fluke. Yes, some kind of abnormalities, but it really holds. And now we have hundreds of women in the setting. We still see this. So premenopause, we're looking at women who are at the peak of ovulation. So we have a lot of estradiol, endogenous estradiol in the brain. So all the estrogen receptors are taken so you don't see any binding, basically. Everything is kind of bluish, greenish. But then at the perimenopausal stage, when estrogen is actually this late period, so the estrogen is kind of down, we start seeing the red blob in the middle of the brain. That is the pituitary gland. Is that part of the brain that is actually talking to the ovaries and sending down the FSH and LH, saying, I need more estrogen. And what we found was in more estrogen receptor density, there are more estrogen receptors rather than less, which was expected in peri. But there are even more after menopause up to age 65. And people thought was crazy when I said we're going to go all the way to 65 because I wanted to map the curve. Right. And they thought it's too late. It's too late. So for 15 years, the brain is trying. The brain is trying. This is how I read it. This is the brain's attempt to compensate for the fact that estrogen is very low. So when usually hormones and receptors work in balance, when you have a physiological level of hormone, you only need these many receptors. If you have a lot of hormone, then you need fewer receptors, which is a conservative right. It takes energy to make the receptors. So it's good to kind of lie, sit back and relax. But the whole if the hormones go down, that is an up regulation. That is likely an attempt to just grab every little bit of estrogen that's present in the circulation. It's also in a way a bit of a distress signal because what's happening in the pituitary, you can see is that the FSH and LH levels are increasing. Right. So it's the brain telling the ovaries. Please. Do you want it? I'm still here. That is amazing. And then after age 65-ish, we see the signal attenuate. We haven't yet. We're doing it now. Look, as of now, I think we're the only team doing this. Amazing. As far as I know, we are the only team with an active IND, too, with the permission from the FDA to use this tracer for the brain. I'm hoping the more and more people will start doing it. At the same time, I'm directly sponsoring development to new brain tracers for estrogen. Because this is good enough for the pituitary, which is very interesting. But we want to be able to measure more and to get more information out of the brain scans. And the other thing we're doing now is that we're looking at hormone therapy and what kind of effect it has on these receptors. But this was, this was stunning when we found it. And you know the response that we got and people just don't believe it. Do not believe it. Repeat the study. Yeah. Don't waste money. So I was told do not waste money. Now it's time for the MIDI pause. I'm Dr. Mary Claire Haver, host of the podcast, Unpaused, bringing you a word from MIDI Health. Let's talk about something that I think about a lot and something I know many of you lie awake worrying about. Dementia. Here's what I want you to know. The choices you make today directly affect your brain health tomorrow. And you have more power than you think. As a 57 year old woman, I am taking small steps daily to protect my brain, like staying active, eating well and managing my stress. These are things I find work for me, but they may not be right for everyone. Every woman deserves the conversation. And that's why MIDI Health is dedicated to changing the way menopause is treated with a personalized approach to each woman's specific needs. I personally lift weights two to three times a week. Resistance training is important because having more muscle is directly linked to better cognition and brain health. Strong body, strong mind. It's all connected. In my workouts, I try to do at least 150 minutes of cardio per week. Zone two training usually at a moderate pace where you can still hold a conversation. Your heart, lungs and brain all benefit. I also eat to fight inflammation, whole grains, healthy fats, lean protein, colorful fruits and vegetables and prioritize protein, at least 30 grams per meal. And arguably, most importantly, I protect my sleep and manage my stress daily. Sleep is when brain clears waste and consolidates memory and chronic stress speeds up brain aging. By getting quality sleep and setting boundaries, you putting your health first and getting ahead of any dementia symptoms. It may not be right for everyone, but every woman deserves the conversation. Women who start hormone therapy early in menopause have shown lower rates of dementia, stronger bones and lower heart disease risk. You deserve a conversation. If you want a clinician in your corner who understands what your body and brain need right now, that's exactly what MIDI is built for. Go to joinmidi.com, J-O-I-N-M-I-D-I dot com. And connect with one of their clinicians today. So what are you most excited about right now? I am super excited that I started working with Dr. Regina Dugan, who is the former director of DARPA. DARPA is the Advanced Research Program Agency for Defense, which is basically the research arm of the U.S. military. In other words, she's the first woman to ever run DARPA and she is brilliant and she is a powerhouse. She's magnificent. And she launched Welcome Leap, which is an independent subsidiary of the Welcome Trust, which is based in London, one of the world's largest philanthropic organization. So Welcome Leap takes after DARPA, which means that they sponsor high risk, high reward, three years research programs. And this is not NIH. This is not an independent. It's independent of NIH, fully independent. And so this is where you got the $50 million. Yes. So they asked me to serve as program director, which is a huge honor. And I was able to design my own program of research. They gave me a $50 million budget, which I was like, oh my God, is this Christmas? It's got to be Christmas. And what I really love about this is that they didn't just give me that money to do the work. They sponsor global international coalitions of scientists who then all work together to address a question that none of us can realistically hope to answer alone. So they really promote collaboration between scientists, whereas usually we're very relaxed. We're very excited. Because you're fighting for the same research dollars. We're fighting for the same, yeah, sort of same part of money. It's terrible. And in this case instead, we now have, I'm trying to find this slide I want to show you, we now have 17 sites with over 70 leading scientists from all over the world. And what is the question you're trying to answer? Well, the question is, can we realistically have the risk of Alzheimer's disease for women by the year 2050 in the next 25 years? And how do we do that? We have estimated, we have done all sorts of calculations and projections, but we have estimated that we're able to do all the work that I designed, all the work that I set we needed to do the next three years, potentially four. Then we can expect to reduce the risk of Alzheimer's disease for an estimated 330 million women all over the world and given current conversion rates to Alzheimer's, hopefully prevent 55 million new Alzheimer's cases among women by the year 2050. What we're doing specifically is that we are looking at menopause and hormonal aging throughout the woman's life. We're looking at pregnancy. We're looking at puberty. We're looking at birth control. We're looking at all the female specific risk factors that are mainly in the neuroendocrine base, but also everything else that impacts a woman's life, everything we have talked about today. And we're going to try and firmly position at least some of these factors as predictors of Alzheimer's risk in women using brain scans and biological markers. And then we're going to test whether hormone therapy can offset the risk of Alzheimer's by using a modern biomarker based approach, which is what I think is missing in the field right now. And then we're going to use all the knowledge to develop sort of like online risk calculators for women. Yeah, we have them for breast cancer. We have them for cardiovascular disease. We have a porousioporosis. Exactly. Yeah. We don't have them for Alzheimer's, especially for women. And we are targeting an easy to use tool that can be implemented in epic and become point of care for women. I must show you this slide. We have now data through care. So we have all the scientists that I mentioned. And care stands for? Care stands for cutting Alzheimer's risk through endocrinology. So when I made this slide, we had 67 leading scientists. We now have 70 investigators from all over the world. These are all the data that we have access to from all over the planet. Six continents, all major continents, except Antarctica. And we're going to leverage data from 100 million women, estimated. If all the data sets come through, which makes care, this program of research, the largest ever global examination of women's health and Alzheimer's risk ever attempted. Amazing. Congratulations. Thank you. I am so happy. I think your new position is less stressful than. Surprisingly enough, it is. You're doing the work you're born to do now, you know, like without the. What, you know, our listeners don't understand is, is the way that research has been set up historically is very difficult and so many hoops to jump through. And that you basically were given the gift of a lifetime for a researcher. Yes. Oh, this is. Build your program. Here's the money. Let us know how it works out. You know, and really, you know, with all the pushback and all the. All the things that people have said to me ever, ever since I started being a scientist. Just hearing, I believe that you know what you're doing. You know, it's like, oh, yeah, we do know what we're doing. Well, congratulations. Thank you. And I'm so glad you came. So glad to hear that. It was lovely that all the papers coming. So it's going to be amazing. As a reminder to our audience, you can follow Dr. Moscone on Instagram at Dr. underscore Moscone. Her book, The Menopause Brain is available now through her website at LisaMoscone.com. You can find full episodes of Unpaused on YouTube at Dr. Mary Claire. I'd love to hear from you about this topic and anything else that's on your mind. You can follow me on Instagram at Dr. Mary Claire and get honest and accurate information on health, fitness and navigation. and navigating midlife at thepawslife.com. My upcoming book, The New Perry Menopause, is available for preorder on Amazon. If you're loving this podcast, I have an important request. Please take a moment to follow Unpaused on your favorite podcast app. Following and listening is what pushes this information to more women who need it. So if this podcast has helped you feel seen, understood or supported, hit follow right now so you never miss an episode. Thank you for being here with me. Let's keep going. Unpaused. Unpaused is presented by Odyssey in conjunction with PodPeople. I'm your host, Dr. Mary Claire Haver. The views and opinions expressed on Unpaused are those of the talent and guests alone and are provided for informational and entertainment purposes only. No part of this podcast or any related materials are intended to be a substitute for professional medical advice, diagnosis or treatment.