unPAUSED with Dr. Mary Claire Haver - The Alzheimer's Prevention Plan for Women: Hormones, Sleep, and Nutrition with Dr. Lisa Mosconi

Episode Date: March 17, 2026

In this episode of unPAUSED, Dr. Mary Claire Haver sits down with Dr. Lisa Mosconi, a neuroscientist and associate professor of neuroscience in neurology and radiology at Weill Cornell Medicine, New York Presbyterian Hospital. Dr. Mosconi directs the Alzheimer's Prevention Program, including the NIH-funded Women's Brain Initiative and the Alzheimer's Prevention Clinic, and was recently named director of the $50 million Program in Women's Health, Cutting Alzheimer's Risk Through Endocrinology. She is also the author of the bestselling book The Menopause Brain. This conversation is about prevention. Dr. Mosconi has spent decades building the science that shows Alzheimer's risk in women is neither inevitable nor untreatable and that the choices women make in midlife around hormones, sleep, and nutrition have a direct, and measurable, impact on the brain's long-term health.  Together, they explore why two thirds of all Alzheimer's patients are women and what role menopause plays in that disparity. Dr. Mosconi explains the difference between the rare genetic mutations that directly cause Alzheimer's, found in roughly 2% of patients, and the risk factors that shape outcomes for the other 98%, including the distinction between early and late onset disease and between sporadic and familial Alzheimer's. Both share their own family histories with dementia and what that means for their personal risk. Guest links: Lisa Mosconi Lisa Mosconi (Instagram) Lisa Mosconi (Facebook) Lisa Mosconi Bio (LEAP) Books: “The Menopause Brain: New Science Empowers Women to Navigate the Pivotal Transition with Knowledge and Confidence,” by Lisa Mosconi “The XX Brain: The Groundbreaking Science Empowering Women to Maximize Cognitive Health and Prevent Alzheimer's Disease,” by Lisa Mosconi“Brain Food: The Surprising Science of Eating for Cognitive Power,” by Lisa Mosconi “The New Perimenopause,”⁠ by Dr. Mary Claire Haver ⁠"The New Menopause"⁠ by Dr. Mary Claire Haver To learn more about listener data and our privacy practices visit: https://www.audacyinc.com/privacy-policy Learn more about your ad choices. Visit https://podcastchoices.com/adchoices

What is brain fog? So let's clear it up. Like, what is brain fog? And when should someone be worried? Yeah, it's one of the reasons that actually brain scientists started to look into menopause as a risk factor for Alzheimer's disease. And still today, the vast majority of patients who come to us at the Alzheimer's Prevention Clinic at Walcott Medicine, New York Presbyterian, which have run, come to us because of brain fog, it means. life that can be so severe to really trigger concerns about early onset dementia. So it's really important to clarify what is brain fog and what is Alzheimer's and how one thing could lead to concerns about the others because it's really legitimate to be scared. 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. When I first heard Dr. Lisa Moscone speak, she showed brain imaging that followed a woman from pre-menopause into post-menopause. The changes were distinct and undeniable. We literally rewire our brains through menopause. I remember sitting there floored because in my training and practice, no one had ever shown me us before. To see a woman's brain transition captured on a scan was both validating and life-changing.

It was proof of what so many of my patients had told me over the years. I just don't feel like myself anymore. Dr. Moscone showed us that this isn't just a feeling, it's biology, and it needs to be taken seriously. And then I learned her personal story. She grew up watching her grandmother and two great-a-a-all-developed dementia while their brother did not. That, heart-breaking pattern became her life's work. She turned grief into purpose, asking the question no one else was asking, why are two-thirds of all Alzheimer's patients women? And what role does menopause play in that risk? What struck me the most is that Dr. Mascone has never shied away from those hard questions. She has pushed against the old dogma that ignored women's brains,

and in doing so, she's opened up an entirely new conversation about women's health. She's shown that menopause is not just an ovarian story, it's a brain story. Dr. Lisa Musconi, Ph.D., is a neuroscientist, an associate professor of neuroscience in neurology and radiology at Will Cornell Medicine, New York Presbyterian Hospital. She is the director of the Alzheimer's Prevention Program, which includes NIH-funded Women's Brain Initiative, the award-winning Alzheimer's Prevention Clinic, and the newly launched Alzheimer's Prevention Clinical Trials Unit. Most recently, she was named director of the $50 million program in women's health, cutting Alzheimer's risk through endocrinology,

a groundbreaking initiative placing hormones and midlife at the center of dementia prevention. She's also the author of a number of best-selling books, including The Menopause Brain. What I admire most is that Dr. Mosconi is not only advancing science, she's changing the conversation. I'm Dr. Mary Claire Haver, a board-certified obstetrician and gynecologist and certified menopause practitioner. I'm also an adjunct professor of obstetrics in gynecology 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 welcome to Unpaused.

Thank you for having me. I'm so glad we got to do this. So we have been friends for a long time. Yeah. I want to say the first time I saw you was on stage at my first swell event in Santa Monica. And you stood up and started showing images of the brain of women in premenopause and perimenopause and postmenopause. And the differences in glucose uptake and what's happening. And I stood there in the audience.

I was before or after Avram Blooming and Carewerex. had like dismantled the WHI. So my mind was so blown that day. And then you're talking about how women's brains change through menopause. And I'm like, no one ever, ever, ever in all of my training, talk to me about the structural changes and the biological and that menopause was a neuroendocrine event. And you open that door for me.

And so I'll forever be grateful in my understanding. But let's back to you. So let's talk about our grandmothers. Let's talk about that. You share a similar story to mine in that my grandmother, who died in her early 90s, mid-90s, spent the last, I didn't know what to call it back then. Of course, I was in early college, maybe starting med school, and she was bedridden at the end. And I know now that she had dementia likely Alzheimer's and was very, very frail and was probably the last two to three years. years in a bed. She was very sweet, but then became very confused and would like call out and thought

people were in the room. She was having a lot of hallucinations at the end. It was just really painful to watch. My mom now has been formally diagnosed with Alzheimer's. She's in her 80s. She's in a facility specifically for memory care. And it's really one of the most painful things I've ever had to do is watch her deteriorate. And sorry. it's not it comes and goes so we have our good days and we have our days where i think oh she's doing better and then she'll say something so outrageous you know or or talk about my dad being in the room he passed away uh seven years ago and and i just realized i i don't want this and so i just kind of grew up thinking this is inevitable for me but it's not no and you are the one teaching me that

So you're the first person to even say that this is not your inevitability. There are things that we can do. You're young enough to, like, get ahead of this. So, like, tell me about your family. My family has also been negatively impacted by Alzheimer's and dementia. And that, for me, also involved my grandmother who, I mean, she was exceptional, extremely intelligent. You remember her without dementia. Oh, yes.

Oh, I grew up with my grandmother mostly. My parents are nuclear physicists. They're professor on nuclear physics, both of them. And they're not like the stereotypical nuclear physicist. They're more the Oppenheimer type person. I don't know what that would be. But they did work a lot when I was growing up. So your grandmother took on the caretaking?

Yes, effectively. I was almost always with my grandmother. And I remember her just being my grandmother. And then at some point when I was about to graduate from university and start my PhD, she started showing signs of cognitive decline. That was shocking because she was always as sharp as attack. But that led to at least a decade of dealing with progressive cognitive decline, Alzheimer's symptoms, dementia symptoms, like you mentioned, hallucinations,

which is usually assigned a mixed dementia with some louis body components, which was the case for my grandmother as well. And she ended up spending at least years, her final ears, in bed, clearly not enjoying her life. And that was the most heartbreaking part, you know, the helplessness. And for my mother, who was the primary care giver, I was already in the United States at that point. that was brutal for the whole family because we did not have the kind of help and support that is available today.

Even more shocking to us as a family was that, so my grandmother was one of four siblings, three sisters and one brother. She was the oldest. So she was the first one to develop Alzheimer's. And then a few years later, the middle sister also started showing the same kind of deterioration

and more progressive memory loss and then ended up with dementia. And then the third one, the youngest sister, also had exactly the same fate, whereas the brother did not, even though they all lived to the same age.

So that was alarming because one person alone, you may be like, but when three, old women, express the same genetic vulnerability, that does hit you heart. So my mom and I have been just so up to speak with the research. I obviously do research, but my mom is also really, really participatory. And so as my father, and we have changed a lot of little things in terms of lifestyle. We know

everything about prevention, whatever we know at this point in the field about prevention. We do. We'll dig into that. Yes, that sent me down the rabbit hole of trying to understand first genetics, right? What causes Alzheimer's? Was this known? Was the gene known? So that's interesting. At the time. So at the time, which is now 25 years ago, there was a long time. We did understand that there are genetic mutations that cause Alzheimer's disease. So there are mutations in at least three non-greens, which are the APP, the amylop precursor protein, and the pre-cineleone, two genes. If you have an autosomal dominant genetic mutation, one of these three genes, that directly causes Alzheimer's disease. And what happens is that it runs in family is genetic

transmission, but it's highly penetrant, an ososomal dominant, which means that if you do inherit the mutation, number one, you have a 50-50 chance or getting the mutation. If you do inherit it, penitrance is almost complete. And for our listeners, penetrance means the, chance that you will express the disease. Yes, so strong this mutation is. So it's so strong. Almost always they're going to develop it if they live long enough. It's close to 100%.

Well, that actually starts in the 40s. Wow. So that's the type of Alzheimer's that is called early onset. Okay. I think this is important because a lot of people think the early onset is 60s. But early onset, when we talk about early onset Alzheimer's, is 40s and 50s. Wow. Certainly before age 65. Now, the sort of good news is that those genetic mutations are exceptionally rare.

Okay. They are found, depending on the country, on average, 2% of all Alzheimer's patients. So if you look at the entire population is actually even less, right? But if you look at all patients with Alzheimer's, no more than 2%, carry these kind of genetic mutations that cause Alzheimer's directly. For everybody else. So the 98% of people don't have a genetic mutation. They do not have a genetic mutation. So what is it?

Right. So in that case, we talk about risk. And we do understand that Alzheimer's is now classified. So first of all, we look at early onset versus late onset. Early onset before, I'm going to say 60, late onset after age 60. Now, in the late onset Alzheimer's umbrella, some people do develop the symptoms of Alzheimer's when they're closer to 60. And a lot of individuals refer to that as early onset. It's early by any standards.

But the right term is earlier. Because early in absolute terms, 40s and 50s. Earlier, yes, it's 60. It's horrible. But the good news is that it's not genetically induced. And then most people develop dementia around the age of 72 on average. And that is late onset. Then we have sporadic Alzheimer's cases and familial.

So like in my grandmother's case, we talk about familiarity because it's not just my grandmother, but also her sisters. So that is familial late onset. It's not a genetic mutation, but it does run in the family. Same for you. Sporadic means to just one person. No other cases of Alzheimer's in the family. And the risk is obviously different to the children and grandchildren. So this is what we talk about when we discuss Alzheimer's disease in terms of characterizing which type of Alzheimer's one has.

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. So three quarters of women, 75%, are going to. to have brain symptoms during this chaos, during this transition. Yeah. Brain fog, memory lapses, anxiety, depression. So we've got the mental health and what is brain fog.

So let's clear it up. Like, what is brain fog? Like, when should someone be worried? Yeah, it's one of the reasons that actually brain scientists started to look into menopause as a risk factor for Alzheimer's disease. And still today, the vast majority of people, who come to us at the Alzheimer's Prevention Clinic at Walcarnet Medicine, New York Presbyterian, which have run, come to us because of brain fog in midlife that can be so severe to really trigger

concerns about early onset dementia. So it's really important to clarify what is brain fog and what is Alzheimer's and how one thing could lead to concerns about the others because it's really legitimate to be scared. So brain fog is a generic term is a colloquial term that people use to describe what we in neurology referred to as cognitive fatigue or mental fatigue, which is this having a really hard time doing things cognitively. My patients complain. Like, especially the ones who were like cognitive high functioning were teachers, attorneys, you know, their quitting their job, some of them, because they don't feel like they can complete the tasks that they used to, it was mindless for them. And accountants, you know, people who use numbers

are really struggling. Yeah, it's exactly that. It's cognitive fatigue in front of a cognitive effort. It's like things that used to be easy and just seamless now require a huge amount of effort. And it's, I think one of our patients described it as this feeling that, no matter what you do, your brain just won't turn on. There's this feeling of not being yourself, but also of almost being poisoned, if it makes sense. Like if anyone has ever had a bacterial infection, right, I had it once. And I could not find my energy, my mental energy. And I think that's, I don't, I'm not a menopause or close to it. So I don't, I have not experienced that, but I have, I had one experience, one experience of brain fog posthardom.

Okay, in a low estrogenic state, yeah. Yes, and with breastfeeding and whatnot, that I just could not remember where my child was. I was in complete panic. I just, first of all, I knocked on the door of the fridge before opening the fridge, and that was already like, oh, my God. And then I found myself outside with the stroller empty, going so away. No, because the baby was with the nanny. But I had no idea what I was doing.

And that was the only time in my life I could not count on my brain. And that was absolutely petrifying. So if menopause is anything like that, oh my gosh. And they completely sympathize. And that's why we're really trying to help women who come to us. And also by doing the research, obviously. So what we and others have found is that there is an association at this point with brain fog and alterations in brain energy levels.

And other people have used fMRI, functional MRI, to show that the functional connectivity of the brain is altered in women with brain fog relative to those without. We have looked at the molecular mechanisms that may be involved. And what we have shown is that it's a bit technical, but the ratio of phosphocryotene, Creatine? You like creatine. I like creating. To ATP is increased, meaning there is more creatine, phosphocreatine, than ATP being made. So phosphocreatin is what the brain uses to make energy, is the buffer, right? But what you want is ATP, so you want them to be in a one-to-one ratio.

Whereas the ATP production is suppressed in some of the same brain regions that are affected by Alzheimer's disease. Now, I've seen on the Internet, well, I have no data to back this up, I probably should pull the studies, that creatine supplementation could be helpful with brain fog. Is there any data to really support that? There are a small-scale studies, observation of mostly

of creatine supplementation for cognition. I think we're not quite there. There, yeah. Given everything I know about the biology of creatine, how important it is for brain health in the form of phospho creatine, I think that that is really something that's worse starting in part because the rest of creatine is lower in women than in men. And if they are lower in muscle and body, there's also a chance that they're lower in brain to start with. The bigger leg muscles, the more likely to have higher brain volume. Did I read that correctly? Yeah, that's a less, you know, also the smaller your feet and your risk a lot of time, sometimes we find correlations that are interesting.

I don't know. I don't know. But I would love to see those studies. Yeah. I would like that. I think they're doing some observational stuff. The creatine data mostly comes from muscle, right? Yes.

And the bodybuilders. But I think Abby Smith, Ryan and those people out of North Carolina are starting to look and doing the cognitive work. Great. We're doing some measurement there. I think it's something really worth looking into. There are so many things that become a little bit trendy before the research has been done. Yeah. But that doesn't mean...

It's not helpful. It doesn't mean anything. It could be. It could be. Well, you just don't know yet. Hi, my name is Lloyd Lockridge, and I'm the host of a new podcast from Odyssey called Family Lour. In this podcast, I'm going to have people on to tell unusual and sometimes far-fetched stories about their families. I've heard my whole life that she invented the margarita. And then we're going to investigate those stories and find out how much of it is true.

He gets a patent one month before the Wright brothers. Oh, my God. Please follow and listen to Family Lore, an Odyssey podcast, available now on Apple Podcasts, Spotify, or wherever you get your shows. Let's talk about the emotional side of it. So, you know, the occasional outburst in a lot of my patients, they come in and they're completely worried because of rage. and fear and paranoia and severe anxiety and anger and, you know, it's affecting relationships. And at the same time, it's a, it is a hard time of our lives for a lot of us with aging parents and teenagers. You know, we're kind of in the sandwich area.

So what's happening? Is it the same biomechanical process that's happening that's leading to the emotional changes? Yeah. So this is really in part at least reflective of the architecture of menopause. in the brain. So estrogen receptors are a little bit everywhere, but they're more prevalent, they're more abundant in very specific brain regions, and especially in the most primitive parts of the brain. And these we know mostly from animal studies, but we also now see with the brain scans that we just looked at, which is the first time in humans and they thought it was really fascinating. They are most expressed in the memory centers of the brain. like the hippocampus and the medial temporal lobes,

but also in the emotion control centers of the brain, like especially one region that's called the amygdala, this sits right on top of the hippocampus and is connected to the rest of the brain, of course, and kind of regulates emotions, including fear, but also empathy. So it's very complex. And then the estrogen receptors are present in the frontal cortex, which is in charge of thinking and reasoning,

and inhibition, very important, and the posterior singular cortex and precunias, which are more about autobiographical memory, which is the memory of places you've been and things you've done. Yes, and then in the brain stem, where we find all the nodes for sleep and wake, the sleep cycle, but also stress.

And then, of course, we have the hypothalamus and the pituitary gland, which is predominantly reproductive regions, by the hypothalamus also both regions, actually, both glands play an important role in autonomic function, which is like control of blood pressure, heart rate. So all the most primitive functionalities are effectively influenced by the presence of estrogen and the way it works with the receptors, which means if estrogen starts fluctuating and is all over the place, then the hippocampus is not activated correctly. And then you don't consolidate memories and

you feel like you have ADHD. Yes, we see. All the time. Patients complain constantly of that. Yes, they become aware that they can't memorize things and they have a hard time paying attention to things. Is it ADHD or is it menopause or both? Or both.

Do we unmask something you were managing? Exactly. It's all this. Unmask. Yes. Amygdala, full of estrogen receptors. Yeah. And if estrogen starts fluctuating or is not there,

the amygdala will glitch in regulating emotions. Right? So you may feel anxiety and fear when there's no reason for it. You may, it's not just the amygdala. It's the whole network, right? But just to explain the anatomy, you may get the rage, right? If you haven't slept because the estrogen hasn't been activated, your sleep cycle and your melatonin is completely out of whack, that will make it worse.

And if your frontal cortex is impacted, you're going to have. a harder time inhibiting this response, this strong response that is not you, is your brain transitioning to work mostly without estrogen. So the same brain regions that were supported by the presence of estrogen before are now finding themselves in a state of remodeling. Yeah, renovation. Yes. So Robbie actually says that that manopause is a renovation project on the brain. I want to show you one slide if I find it. So here we are looking at differences between premenopausal women and age-controlled men. When the women in all those fiber tracks inside the brain show more positive markers of connectivity. So there's more diffusivity. There's more diffusivity. It's just

the brain is basically better connected in those specific parts of the brain relative to men at the same age. So we have better brain function than men up to a sort of connectivity. Yeah. Yes. And then this is what happens at the perimenopausal stage. There are basically no differences. And this, you're going to love this. Whoa.

Yes. Oh, I love that. Wow. This is postmenopausal women. And it's better than before. Wow. Yes. So it remodels. It remodels to make us connect better. Definitely from before. So these parts of the brain are this is a cross-sectional study. We're now doing the same analysis longitudinally over time. It takes a long time to map the transition because it takes many, many years. Seven to ten years and you've got to go postmenopausal. So you're looking at a 15 year. It's going to take a minute. But we do have

six-year data now, so we're doing that. But this suggests, this is a cross-sectional study. Lots of people kind of like give me like a wrinkled nose when something is done cross-sectionally, but you have to start cross-sectionally because you don't want to waste your time longitudinally if there's no differences that are suggestive of a change. These suggests that there are differences to start with, no differences when we're paramedozo and more differences at the postmenopausal stage. Nobody here is taking hormone therapy. So that does suggest a U-shaped change

that we find with other modalities as well. Brain aging is not linear in women. And that is something that is difficult to model and study, but we are doing it. We're doing deep phenotyping and increased sampling, and we're trying to map it really, really carefully. But I thought this was brilliant. It's amazing.

It's amazing. Women have been the wisdom keepers in their older age. The postmenopausal women, the grandmothers, were the wisdom keepers. And that, you know, traditionally, if they lived long enough, you know, they carried their traditions. They taught the younger, you know. It's kind of beautiful how that played out. I think it's beautiful. And I think what we're thinking as a field is that this remodeling is essential.

It's very important because. the link between the brain and the ovaries is a very big pathway in the body and it's very expensive to maintain. So once women are no longer are no longer reproductive, it makes no sense to keep all these connections and all these mechanisms that are necessary to trigger ovulation and to potentially make your body able to host a pregnancy. A lot of what happens in the pregnancy actually comes from the brain, right? And once you no longer have the ability to be pregnant, it's really cost-effective for the brain to say,

you know what? It's duly the sprint cleaning. All this stuff I no longer need is best if I discard it. That's my personal own interpretation, but I think this is what happened. And this is the renovation process where the connectivity is changed, right? We're preparing for a non-reproductive phase of life,

which needs to remain productive. So the brain rearranges itself. But at the same time, that is tricky to do, right? Right. And that can lead to the symptoms of menopause, to the glitches, and unfortunately to a lot of discomfort for a certain amount of time. But it's for, we're hoping, of course, a good reason. Right.

So when something that is genetically programmed and expected to happen, happens that is not a pathology. Yeah. And that's important to say, menopause is no walk in the park, it's certainly no picnic for so many women, but there's a reason for it, and their brains and bodies are equipped to go through it.

Okay. What we can do is to support them during the transition, is to provide our brains with the tools and chemicals that it needs to support us and go through a gentle, Yeah. Menopause. I love that explanation. A lower long-term risk of Alzheimer's and anxiety and depression and Parkinson and whatnot.

So for someone who's listening, who's having the brain fog or having the anxiety, you know, especially on the cognitive side, but when should the brain fog or the cognitive symptoms be a red flag? When should you worry and say, I need to go get evaluated? Well, I would go regardless because you want to have a baseline. For me, at least in this day and age, we do have the tools, we have the technology, we have the possibility, we have the access often. I think it's a good idea to have a baseline of your own brain and your own cognitive performance

when you're relatively young because you are the best reference for you when you are a little bit older. Now, there is no reason usually to get alarmed if brain fog tends to emerge during the transition to menopause. if you do notice that your period is changing and is getting more irregular and you also experience brain fog, that is most likely to be part of the hormonal transition once, obviously, you go to your and it gets better, right? It should get better. It should resolve within two to six years of the final menstrual period, which I know it's a lot of time. It's a long time.

It's unfortunately a lot of time, but it should get better. But we can support that. We can support it. Yes. through the transition. In our clinic, we offer hormone therapy in these cases, and they usually do very well. And there's more research coming. There are more options. So that is really important to know that help is available. And there are therapies and other things. Also lifestyle. You're a big. Oh, yeah. Let's get into that. I'm excited. Let's do that. If brain fog gets worse, right? And if you

don't remember where you put your keys, that is not Alzheimer's. If you can't remember what your keys are four, that is a problem. I will use that again. That is excellent. But then again, a lot of, a lot of people come to us to get cognitive testing done. And we do cognitive testing. And you can see that, for instance, there's this test that's called the MMSC that we always do as a screening, where the scores go from 0 to 30. And most people, my age, your age, will score 28 to 30. Right. If you are a 30 and menopause brings you down to 28, to you, that is a catastrophe. To as you are within normal range for women, your age and educational level. And that is a huge relief to hear. That, yes, we understand. You are experiencing a change in cognitive performance that we refer to clinically as subjective cognitive decline.

because you feel it, you're aware of it, is not measurable using standardized cognitive tests, which means you do not have dementia at this stage. I love that. If you can't remember where you put your keys, but if you don't know what the keys are for, you need to go get a value it. That's a problem.

Okay. All right, let's talk about our brain plan, our game plan for midlife. Because there's so much hope here. Yes. Yes. You know, there's so much. much we can do. Like Mary Claire's nursing home prevention program is what I like to call it.

You know, preventing osteoporosis is much easier for me, you know, to deal with than how do I hang on to my brain function as long as I possibly can? And so that I really, I won't know the difference, you know, I'll be frustrated, but I don't want to do this to my kids. You know, I don't want them to have to go through this like gut-wrenching decision-making that my family and my husband's family is going through and how to best help our parents, you know, as they traverse this. So menopause is a neurological transition,

not just a reproductive one. Yes. But what can women actually do to protect their brains? So let's talk about the key lifestyle factors involved in brain health. Yes. So we're going to start with sleep.

I would say, yes. I think that's a problem for a lot of us, isn't it? I've heard sleep is called as the wash cycle. Yes. So what does that mean? What that means is that the brain, minute after minute, is always busy supervising the rest of the body. The brain is constantly either thinking, memorizing, feeling is very, very busy. But also supervising the rest of the body.

Even heart rate and breathing and moving, all of that needs to be active at all times. The only time in the day that the brain can actually take care of itself is during sleep. And specifically during slow wave, sleep or deep sleep, which is when your body is completely still. You are not moving, just breathing very quietly. The brain can let go of everything else and activate a system that is called the glymphatic system, which is effectively like a car wash. There's like fluid that starts moving throughout the brain, removing toxins, removing waste, removing Alzheimer's plaques.

That's when a lot of clearance mechanisms are activated. The oxidative stress is removed. The inflammation is flushed out in the same. All the mess we accumulated through the day. All the things that, yeah, well, it's an organ. There's a lot of activity going on. So if you don't sleep, if sleep is fragmented and you sleep, especially your deep sleep is impacted and you lose that window of sleep, that over time has consequences because then all the toxins

will not be cleared out, right? They will accumulate in the brain, the Alzheimer's plaques will stay in the brain, the inflammation may stay in the brain. So sleep hygiene and sleep protection is a very important. just recently discovered protective factor for brain health and Alzheimer's disease, whereas sleep deprivation is a risk factor for Alzheimer's. So now sleep is now in cardiovascular disease, now characterized as a risk factor. How much sleep do we need?

Well, that's a really good question. And why do these middle of the night wakeups, which a lot of my patients complain of, including me? Yes. So one potential mechanism is related to menopause. And of course, stress, anxiety, that is a different story. But for women who are going through menopause, there can be a hormonal component to sleep disruption. And what can happen is that all these different hormones work together. It's a hormonal system that is in a flux.

We're always talking about estrogen and progesterone, but other hormones also are impacted. And in particular, stress hormones and sleep hormones. Cortisol. Cortisone and melatonia. Okay. So for cortisol, the relationship is well characterized in that the body needs a common precursor, which is pregninolone, to make both sex hormones and cortisol, the stress hormone. If you're super stressed out, the body is going to have to use most or more of the pregnolone

to make the cortisol. And that means it cannot make as much of the sex hormones. Wow. Yes. That's why stress. sinks your hormones that women who are really really stressed out may experience more severe symptoms of menopause because you have less availability the perlinolone gets eaten up yes your hormones are on the adrenal pathway to make cortisol yeah yes and for melatonin is a similar problem where if stress and cortisol says the cortisol is high in your body that suppresses melatonin production so what happens is that usually melatonin

peaks around that time of night, but that before day 1 to 3 p.m. window, but then you've remains in the system unless you're super stressed out, in which case cortisol kicks in, around 2 in the morning. Wow. And so it's a whole mechanism. You know, when the sex hormones are disrupted, the stress hormones are disrupted, the sleep hormones are disrupted. So you can start in any of these nodes. The internet is full of all of these wellness cures, you know, some, and I, I have no data, you know. Right. How do we lower cortisol? I know we can do, you know, stress reduction, meditation journaling, you know, but are there supplements, are there, you know. For cortisol. Yeah. Not that I'm aware of. Okay. A lot of claims out there to take this and we'll

lower your cortisol. Oh, God, all kind of internet claims. Oh, really? I do. By my supplement and I'll lower your cortisol. I'm not aware of any supplements that can directly lower cortisol. Good to hear. What has been shown to look. lower cortisol levels, it's like you said, is meditation, stress reduction. If you can sleep, that should also lead to a reduction in stress hormone levels. So prioritizing sleep is so really important. And this is more anecdotal than anything else, but magnesium glycinate may be helpful and do not ask me for clinical trials. We can't do clinical trials for everything, but at least for for several women, magnesium glycinate in particular can help relax the musculature and help you

fall asleep and stay asleep, which then has a differential effect on the cortisol pathway. Melatonin can help you sleep and stay asleep, and that also may help lower cholesterol. So all the things that help you sleep, in other words, may also have a lowering effect on cholesterol. Amazing. It's not direct. I would say it's more indirect. Indirect, right. Relaxing the body. Yeah. It just, it's like. Exercise. Exercise. That's my next question.

Women who are fit in midlife, whatever fit is defined as, have at 30% lower dementia risk. Those are the women who have the highest level of cardiovascular fitness. Okay. In midlife, yes. So what is exercise doing to the brain? Exercise supports brain held through multiple pathways. and the most interesting ones, I believe, are the direct pathways. So the first one is by increasing blood flow to the brain. That is very, very important because that supports oxygenation and nutrient transmission.

So you're effectively feeding your brain. Exercise is also anti-inflammatory and reduces oxidative stress, which the brain is very sensitive to. And then there was really super interesting discovery just a couple of years ago. I came out in science, that when muscles contract as part of exercise, they produce a peptide that is called irisin from like a red goddess of the rainbow, which is very pretty. And iridine can cross the blood brain barrier, right? And once it crosses the blood brain barrier, it supports like estrogen, it supports BDNF production and reduces the amount of pro-inflammatory. motor cytokines directly in neurons. So that's a beautiful way that exercise can directly support

brain health. And look, this is when it comes to Alzheimer's disease. I love this line. I was looking for this the other day. Okay, here we go. Oh, good. All right. So this is what we currently know about the modifiable risk factors for Alzheimer's disease, which cumulatively account for over 40% of all Alzheimer's cases. Okay. These are all lifestyle-based. And I specified what percentage of risk they each account for. And if you look, exercise, actually physical inactivity, which can be obviously offset by exercise, accounts for over 2% of all Alzheimer's cases globally.

And then we have things like excessive alcohol consumption, which excessive means more than two glasses a day. we have social isolation. We have depression in midlife, more of an issue for women than for men. We have air pollution. We have low, they say low education is more like low intellectual stimulation. Right. I would say rather than just ears of schooling, although that is a factor as well. Hearing and vision loss if untreated.

So glasses, hearing aids are becoming important for Alzheimer's prevention as well. Traumatic brain injury, especially with loss of consciousness. smoking, and then the heart disease, risk factors. So obesity, diabetes, hypertension, and high LDL cholesterol. Those are 14 and have been formalized as risk factors for Alzheimer's disease that can be modified, right? Right. Anyone can do any of all these things in necessary to reduce the risk of Alzheimer's.

And now we're looking at other things like sleep, very important, diet and nutrition, obviously important. What about GOP ones? We're not there yet. Everyone's asking. No, no, no, no, no. No, no yet. All right, well, let's talk about food because what I loved in your books is that you spend a lot of time talking about nutrition.

I love chemistry. And nutrition is effectively biochemistry. Well, my daughter's undergrad before med school. Catherine's a third year med student. And so her undergraduate is nutrition science. But she went to a biochemistry program, not the. cooking for a thousand people program. The nutrition science goes two ways, you know.

Yeah, yeah. And she absolutely loved it. And I think it's such a strong foundation for her for medical school. It's so good. I also, I did not study nutrition at school, but I'm kind of self-taught. At some point, it was okay, just get me every chemistry book. Because all the things I'm learning about brain health, all the sodium pumps, you know, serotonin is made of tryptophanine.

And these are all nutrients. that come from food, right? They're not made by the brain. They are imported. So I loved it. I spent a lot of this time. So what should we be eating for our brains? The brain is an interesting organ.

And if you eat healthy for your brain, you're also eating healthy for the body, not necessarily the other way around. So the brain is more specific. Okay. It's a little bit more of a picky eater relative to other organs. And it loves predominant, and it needs, predominantly antioxidants like vitamin A, C, and magnesium, and vitamin E. Specific amino acids, especially the essential amino acids, which come from many different foods,

and omega-3 fatty acids, which are predominantly from fish, nuts, and seeds, and some marine algae, if you wish. And we're not for the fish. That's where the fish get the omega-3 is they eat the algae. Yes. So it's part of the food chain. So if you can't tolerate fish or you're allergic, you can get the algae-based supplement. Yes, absolutely. And obviously, glucose is very important for brain health.

But within reason, you know, you don't need to eat a ton, but a little bit is important for brain function. Also for the synthesis of glutamate. A lot of people just look at glucose as a sugar. Right. But glucose is a number of functionalities. And for the brain, is the building block of glutamate, which is their most prevalent. neurotransmitter in the entire brain and is needed to synthesize GABA, which is the prevalent

inhibitory neurotransmitters. So glucose is not just, and I'm thinking when the keto diets came out, it was a little bit like, whoa, because it's important not just for energy, but also to synthesize the most abundant neurotransmitters that we have. Why are ultra-processed foods so bad for brain health? They're bad indirectly. So those kind of foods are not. nutrients should not be able to cross the bloodstream barrier, but they do increase inflammation in the rest of the body, and they do have almost like a sort of toxic effect in your gut, for sure, that then leads to widespread negative effects throughout the body and brain. There are a lot of chemicals that are used in the synthesis and making of ultra-processed foods

that our bodies are just not equipped to handle, which should. then leads to oxidative stress and inflammation and those sort of medical issues, really, that then also negatively impact brain health. What's good for your heart is good for your brain. What's bad for your heart is bad for your brain. And ultra-process food is bad for pretty much every organ we have. Are there any supplements you think are hype or realistic for brain health? Yeah. I wish we had more data. I think there are some nutrients, more the supplements. they're clearly beneficial for brain health. And it makes sense that if you are deficient or subclinically deficient

in some nutrients, then supplementation might help. I'm thinking B vitamins. So we do know, especially B12, is an issue for a lot of people because as we get a little bit older, it becomes more difficult to absorb it from the foods that we eat. And almost all elderly individuals are B-12 deficient and just don't know that. So it's important to have that measured. We check B-12 levels in all of our patients. Yeah, the solid, B-6. Because of really important brain vitamins as well. Clinical trials have shown mixed results. I think that the supplement that we have the best

evidence for is omega-3 fatty acids. And I am 100% partial to antioxidants. Full disclosure. I have no conflicts of interest. I don't sell anything. I love antioxidants because I think that the brain is exceptionally prone to oxidative stress is actually the major cause of cellular and neuronal aging. And the brain is completely powerless against oxidative stress. The only way to counteract the effects is by importing vitamin A, C, E, selenium, and the antioxidant mineral. through the diet. And very few people eat enough fruit and vegetables and some nuts and seeds to really ensure adequate levels.

And then it depends. And I do believe in a precision medicine approach. I know you do too. But not everyone has access to that. So like for the lady on the couch in Ohio listening, you know, who just has a primary care doctor who's going to do standard, you know, like what can we tell her? Well, for instance, if you are a former. smoker, which this is one of the biggest regrets in my life. Same. I quit at 23. Same. Me too.

You know, in Italy, I was growing up there and every body was smoking. Everyone smoked. Oh my God. And so did I. And I really wish I hadn't, but I did. I'm aware. And we know that smoking is a major risk for ovarian function and for brain health. How do you counter the negative effects of reactive oxygen species that are caused by smoking and the possible epigenetic modifications that then lead to more oxidative stress being produced. Antioxidants. So I understand that people want clinical trials of supplements. I'm not sure how feasible that is financially and in terms of commitment, but I would say

if you are a former smoker, there is no downside to use an antioxidant supplements. For example, what would an antioxidant be just for our listeners? Vitamin C. Yeah, that's the number one. Even Dr. Pauling, you know, who's the one who discovered vitamin C and then won the Nobel Prize for the discovery. He took very high doses of, I'm not saying anyone should take high doses. He did until the day he died. And he was as healthy as anyone can be.

Now, that's one person, Nobel Prize, that's still one person. I was a regular amount of vitamin C, especially liquid. Liquid vitamins are really good in terms of being absorbed. Absorption. It's good to know. All right. So elephant in the room, lots of talk, worries, the Metapause Society meeting had a whole section on this. Let's talk about hormone therapy and dementia.

Yes. What do we know? What do we know and what we do not know yet? And I think both are really important. And this is the perfect situation to talk about the fact that language matters if it's okay. Absolutely. In both directions. Yes.

So what do we know? We know that we have not done all the work that we could have. That is a fact. There is only one clinical trial that ever looked at hormone therapy for dementia prevention, which is the Women's Health Initiative that we mentioned before. They were way ahead of their time, fantastic study in women who were postmenopausal by decades. There's a part of the Women's Health Initiative that is called the Women's Health Initiative Memory Study, where they specifically tested hormone therapy, which in this case is high-dose,

oral, conjugated equine estrogen and MPA as the progestin, with or without. an NPA and placebo. And they followed these women first to the number of years. And what they showed is two things. Number one, they could not use Alzheimer's disease as the endpoint because two few women developed Alzheimer's disease. So they had to switch their endpoint to dementia. No, dementia is not Alzheimer's.

Right. Alzheimer's is the only form of dementia that shows the female to male disparity. The other forms of dementia that the women, in the Women's Health Initiative, memory study developed, was predominantly vascular, where there is a lower hormonal component

relative to Alzheimer's as far as we know, and some had mixed dementia. So that was an important finding. Nonetheless, when they looked at the rates of how many women developed dementia, they found in the conjugated equine estrogen and MPA group, there was an increased rate double, the rate of dementia, in women who were taking the hormones as compared to placebo.

The absolute difference in case it was small was about 12 more than in the placebo group. In the group of women who were taking only the estrogens, there was a 50% increased risk that was not significant. These results are not generalizable to meet life women. Right, because these patients were much older. Yes, and that's what we were talking about before, that the system may no longer be there, right? The estrogen receptor binding may not be working the way that it does

once you still are reproductive, once you're still transitioning to your non-reproductive life. When you're, you know, 20 years past. Right. It may just not work. You're bouncing off of a closed door. Yeah, that's the way to put it. And also, those are different formulations to what are.

Right. Then we would use now. Yes. And the new one, the newer formulations have never been tested this way. So we cannot generalize. And we also cannot generalize to Alzheimer's because that was not the end point. The end point. All right.

Lisa, if I gave you a billion dollars. Yes. Good. Right now. What study would you? What would be the study? I would redo the Women's Health Initiative memory study. I would do it using biological markers of Alzheimer's where we work with women who are in midlife, are going through menopause, and they're taking hormone therapy, especially extraneous estradiol and progesterine, which are closer to what their body is naturally produced,

dosed using brain scans, so that I can know what kind of dosed. you actually need, not just for symptom relief, but for brain health and support. And I would use biological markers of Alzheimer's because that I can track as you get treated. What is a biological marker? So these are... It's the brain scan. So we can look at plaques in the brain. We can look at tango formation in the brain. We can look at estrogen and how the therapy modifies estrogen binding in the brain. What's your hypothesis? of this study. Your hypothesis is. But my hypothesis is optimistic, of course. But I would also have also plan B in place because there is a chance that they may not work out. But I think we need to

give it a fair chance because why don't you have a billion dollars for this study? I have 50 million. But let me show you the observation of reason because we have 20 years worth of evidence from pre-clinical studies, that hormone therapy started around the time of menopause is brain protective. And we have observational data showing something similar. And observational data cannot prove cause and effect. You need to have clinical trials, which is what we are missing. But nonetheless, we do see that estrogen-only therapy is associated with a 30% reduced risk of Alzheimer's disease among women with a hysterectomy and or oopherectomy. Whereas estrogen with a progestogen, we can't yet separate like progestogen, sorry, progesterone to progestin with observational

data, but there's still a trend towards a risk reduction. This does not mean that every woman is to take hormones to reduce the risk of Alzheimer's. It means that we do need to do the research. And something that we showed just recently that I think is really, interesting is that also was replicated. There's a strong effect of geographic location. So if you look at all the studies, like in North America, everything is blue. It means that the vast majority of studies show a protective effect. Northern Europe is red. Not protective. Not protective. Why? We don't know. But there's something there. It could be the kind of hormonal formulation that was used, the diagnostic criteria could be a number of reasons. But the studies in North America,

America are consistently protective in Canada, which really suggests that we need to look at what different people are doing clinically when they use these formulations. So good. I just want to say this. When people say blanket statements like you need to go on hormone therapy to prevent dementia, we don't know. We need to do the research. But when people say, which I hear, there is no evidence the whole.

hormone therapy prevents. I believe this was set at a national meeting just a month ago. Oh, yeah? I heard it on social media, actually. It could be misinterpreted. It's kind of saying the same thing that we need to do the research. We need to do their work. But what people understand, I believe, correct me, English is my third language, but what I would understand is that the right research has been done and there was no benefit. This is what I understand. There is no evidence that it works. What we could say that I think is more accurate is that we have not done the right research yet. We don't know if it works, but we also really don't know that it doesn't. And that's important because it's something we can test. For instance, we can check whether it works for some

women and not others. We can check if it works by age. Genetics. Thank you. And now we have the brain scans as well, you never had them before. We give women therapeutic standardized doses of estrogen that are for symptom reduction. We don't give women doses of hormones that are brain protected because we don't know what the doses would be. So this is what we're trying to do now. We need to have more visibility. We need to have a better understanding of the brain dynamics. We need to do more work. We need to do work, but I think it's important to do the work. I think it's important to maintain an open mind. And just because the women's health initiative didn't work out, it does not mean that we can't.

We stop all meaningful research in menopause. Exactly. So for a woman who's sitting at home right now, listening to this and feel scared, what do you want to say to her about her brain health and moving forward? I would say that we all have more power, not over our brains, but we do have the power to support the health of our brains. And that if you make the right choices in life, it takes consistency, it takes work. But really, the benefits are for life. There are also new studies done specifically on menopause, showing that the symptoms can be milder, the experience can be gentler.

if you take care of yourself. So I would encourage everyone to think more of their brains like a muscle. There are things that you can do to support your brain health. Like when you exercise your muscles, right? When you eat carefully to promote your cardiovascular fitness or your fitness overall, the same principles apply to brain health. You can feed your brain properly. You can exercise your brain properly. You can take care of your brain properly. And your brain will just perform. so much better for you. And it's really, it's a long-term insurance policy. And you want to start as soon as you can. Because there's always the idea that it doesn't matter how old you are. If you start taking care of yourself, it will show, you will feel it. But the sooner that you start, the better. Because midlife

really is a big turning point for a woman's health, not just today, but for the rest of your life. So this is the time what most women really have no time for themselves. But I think it's really important to take a step back and say, I also need time for me. Right. Self care is not selfish. You want to take care of yourself so that you can give so much more to your family, to your job, to your friends, and to yourself as well. Well, this feels like this has been a life-changing conversation. Always, every conversation I have with you. and I'm so excited for our listeners to hear this episode. As a reminder to our audience,

you can follow Dr. Mosconi on Instagram at Dr. underscore Muskoni. Her book, The Menopause Brain is available now through her website at Lisa Mosconi.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 navigating midlife at the Pawslife.com. My upcoming book, The New Perimenopause, is available for pre-order 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, 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 pod people. 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.