The Alzheimer's Prevention Plan for Women: Hormones, Sleep, and Nutrition with Dr. Lisa Mosconi

Summary

Podcast Summary: unPAUSED with Dr. Mary Claire Haver
Episode: The Alzheimer's Prevention Plan for Women: Hormones, Sleep, and Nutrition with Dr. Lisa Mosconi
Release Date: March 17, 2026

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Episode Overview

This episode of unPAUSED features a deep, evidence-based discussion between Dr. Mary Claire Haver and renowned neuroscientist Dr. Lisa Mosconi about the startling gender disparity in Alzheimer’s risk, the brain’s transformation during menopause, and actionable prevention strategies with a special focus on hormones, sleep, nutrition, and lifestyle. Dr. Mosconi shares both groundbreaking research and her personal story, challenging the inevitability of Alzheimer’s and providing hope and empowerment for women in midlife and beyond.

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Key Discussion Points & Insights

1. Why Alzheimer’s is a Women’s Brain Issue

• Dr. Haver recounts seeing Dr. Mosconi’s brain imaging that documented the transformation of a woman’s brain from pre- to post-menopause:
  • “We literally rewire our brains through menopause... It was proof of what so many of my patients had told me over the years: I just don't feel like myself anymore.” (02:15)
• Dr. Mosconi’s family history, with three female relatives developing dementia but not their brother, became her research motivation: Why are two-thirds of all Alzheimer’s patients women? (00:59–12:15)

2. Types and Genetics of Alzheimer’s Disease

• Early-onset Alzheimer’s (40s–50s): Rare, caused by dominant genetic mutations, accounts for only 2% of cases. If the mutation is present, development is almost inevitable. (13:00)
• Late-onset Alzheimer’s (after 60): Most common. Can be familial (multiple family members affected, no known gene) or sporadic. (14:23)

“98% of people don’t have a genetic mutation... so what is it?” — Dr. Haver (14:23) “In that case, we talk about risk.” — Dr. Mosconi

3. Understanding Brain Fog vs. Alzheimer’s

• Brain fog: Cognitive fatigue, reduced efficiency, not the same as Alzheimer’s; common in perimenopause and menopause.
  • “One of our patients described it as... no matter what you do, your brain just won't turn on.” — Dr. Mosconi (18:03)
• Functional and molecular brain changes observed in menopausal women; altered brain energy metabolism is implicated (ATP production decreases). (19:00–20:56)
• Creatine supplementation is investigational—some preliminary observational support but not yet proven. (20:56–22:20)

4. Emotional Changes & the Menopause Brain

• Estrogen receptors concentrated in the hippocampus (memory), amygdala (emotion), frontal cortex (decision-making, inhibition), and brainstem (sleep/wake cycle).
  • “If estrogen starts fluctuating... the amygdala will glitch in regulating emotions. So you may feel anxiety and fear with no reason for it.” — Dr. Mosconi (29:00)
  • Loss of estrogen leads to “a renovation project on the brain,” with eventual remodeling for a “non-reproductive phase of life.” (30:19–33:10)
• Memory and attention issues: Are these ADHD or menopause symptoms (or both)? Dr. Mosconi emphasizes the importance of understanding the overlapping symptoms. (29:01–29:18)

5. Menopause, Brain Remodeling, and Resilience

• Post-menopausal brain REMODELS:
  • “Postmenopausal women... it’s better than before. Yes.” — Dr. Mosconi (31:24)
  • Remodeling is adaptive, not a pathology, and supports the social and cognitive role of older women. (33:10)

6. When Cognitive Symptoms Signal a Red Flag

• Typical menopausal “brain fog” resolves 2–6 years after the final period.
• Red flag: “If you don't remember what your keys are for, that is a problem.” (37:15–38:19)
• Get a cognitive baseline: Early testing helps identify true decline versus normal fluctuations.

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Prevention Strategies: The Alzheimer’s Prevention Plan for Women

7. Lifestyle Factors for Brain Health

Sleep

• “Sleep is called the wash cycle.” (39:23)
  • Deep (slow wave) sleep activates the brain’s glymphatic system, clearing toxins and Alzheimer’s plaques.
  • “The only time in the day that the brain can actually take care of itself is during sleep.” — Dr. Mosconi (39:31)
  • Chronic sleep deprivation is a modifiable risk factor for Alzheimer’s. (41:34)

Stress & Hormones

• Sex hormones, cortisol (stress), and melatonin (sleep) interact. High stress redirects hormone precursors toward cortisol production, compounding menopause symptoms.
  • “That’s why stress sinks your hormones.” — Dr. Mosconi (42:23)
• Meditation, stress reduction, exercise, and possibly magnesium (anecdotally) may help.

Exercise

• 30% lower dementia risk in midlife-fit women.
  • Exercise increases brain blood flow and produces irisin, which supports neurogenesis and reduces inflammation.
  • “When muscles contract... they produce a peptide called irisin... it supports like estrogen, BDNF production, and reduces... pro-inflammatory cytokines directly in neurons.” (45:46)

Diet & Nutrition

• Brain-healthy diet: Antioxidants (vitamins A, C, E, magnesium), essential amino acids, omega-3s, moderate glucose (for neurotransmitter production).
• Ultra-processed foods: Increase inflammation, indirectly harm the brain.
• Nutrients the brain requires are often lacking in typical diets, especially among former smokers (who should boost antioxidant intake, e.g. vitamin C). (55:16–57:44)

Supplements

• B vitamins (B12, folate, B6), omega-3s, antioxidants have the best evidence for supplementation—especially in deficient individuals.
• Dr. Mosconi: “The brain is completely powerless against oxidative stress. The only way to counteract the effects is by importing vitamin A, C, E, selenium... through the diet.” (55:16)

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8. The Hormone Therapy & Alzheimer’s Debate

• Research gaps: Only one major clinical trial (WHIMS), conducted in much older women using outdated hormone formulations, showed a small increased risk for dementia generally—not specifically Alzheimer’s.
• Modern hormone therapies and treatment at the time of menopause have NOT yet been rigorously tested for Alzheimer’s prevention.
  • “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.” — Dr. Mosconi (65:04)
  • Observational studies suggest estrogen therapy started around menopause may reduce Alzheimer’s risk (~30% in women with hysterectomy), but only a properly designed clinical trial can confirm causation. (63:14)

If Dr. Mosconi had a billion dollars:

“I would redo the Women’s Health Initiative memory study [in midlife women, using biologically-relevant markers and new hormone formulations].” (61:59)

Notable Quote:

“Menopause is a neurological transition, not just a reproductive one.” — Dr. Haver (39:12)

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Practical Advice and Empowerment

9. What Women Can Do Now

• Treat your brain like a muscle: feed it, move it, rest it.
• Prioritize sleep, manage stress, eat nutrient-rich foods, exercise regularly, avoid smoking, control cardiovascular risks, and get sensory impairments treated (hearing, vision).
• Don’t panic if you have brain fog in menopause—it’s common and usually resolves. But get help if you notice profound, progressive impairment.
• “Self-care is not selfish. ... Midlife is a turning point for a woman's health, not just today, but for the rest of your life.” — Dr. Mosconi (67:14)

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Memorable Quotes & Moments

• On brain fog:
  “If you can't remember where you put your keys, that is not Alzheimer’s. If you can't remember what your keys are for, that is a problem.” — Dr. Mosconi (37:15)

• On postmenopausal wisdom:
  “Women have been the wisdom keepers in their older age... it’s kind of beautiful how that played out.” — Dr. Haver (32:51)

• On the state of the science:
  “We need to have more visibility, we need to have a better understanding of brain dynamics. We need to do more work. We need to do work.” — Dr. Mosconi (65:22)

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Key Timestamps

• [06:25-12:15]: Dr. Mosconi and Dr. Haver’s personal family histories with dementia.
• [13:00-16:11]: Types of Alzheimer’s and genetic risk.
• [16:33-22:20]: Brain fog vs. Alzheimer’s, and emerging research on creatine.
• [26:15-35:03]: Emotional symptoms, brain anatomy, and adaptive brain remodeling.
• [39:20-45:25]: Alzheimer’s prevention: lifestyle, sleep, stress, exercise.
• [50:52–57:44]: Diet, nutrition, supplements, and antioxidants for brain health.
• [58:16-66:59]: Hormone therapy and Alzheimer’s—state of the research, what’s lacking, what’s promising.
• [67:04–69:00]: Dr. Mosconi’s empowering closing message to women.

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Conclusion

This episode demystifies the link between menopause and Alzheimer’s, debunks outdated inevitability narratives, and arms women with hope, practical strategies, and a reminder of their own agency. Dr. Mosconi’s main message: Women have more power than they realize to support lifelong brain health—and the field is entering an era where the female brain is finally being taken seriously.

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For further information, follow Dr. Lisa Mosconi [@dr_mosconi] and check out her book The Menopause Brain. Dr. Haver’s new book The New Perimenopause is available for pre-order.

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This summary provides a thorough outline and highlights crucial moments from the episode. For more cutting-edge midlife health insights, subscribe to unPAUSED.

Transcript

[Podcast Host / Advertiser]

What is brain fog?

[Dr. Mary Claire Haver]

So let's clear it up. Like, what is brain fog like? And when should someone be worried?

[Dr. Lisa Moscone]

Yeah, it's one of the reasons that actually scientists, 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 Walconut Medicine New York Presbyterian, which I 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.

[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. 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 this 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 aunts all develop dementia while their brother did not. That heartbreaking 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. Moscone 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 us that menopause is not just an ovarian story. It's a brain story. Dr. Lisa Moscone, Ph.D. is a neuroscientist and associate professor of neuroscience in 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 of dementia prevention. She's also the author of a number of bestselling books including the Menopause Brain. What I admire Most is that Dr. Moscone 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 and 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.

[Podcast Host / Advertiser]

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[Dr. Mary Claire Haver]

So welcome to Unpause.

[Dr. Lisa Moscone]

Thank you for having me. I'm so glad we got to do this.

[Dr. Mary Claire Haver]

So we have been friends for a long time. 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 pre menopause and perimenopause and post menopause and the differences in glucose uptake and what's happening. And I stood there in the audience and it was before or after Avrin Blooming and Carol had like dismantled the whi. So like 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 told me this.

[Podcast Host / Advertiser]

No one ever, ever, ever in all

[Dr. Mary Claire Haver]

of my training talked to me about the structural changes and the biological and the, you know, that menopause was a neuroendocrine event. And you, you opened 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.

[Dr. Lisa Moscone]

Let's talk about that.

[Dr. Mary Claire Haver]

You share a similar story to mine.

[Dr. Lisa Moscone]

Yes.

[Dr. Mary Claire Haver]

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 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 MEM. And it's really one of the most painful things I've ever had to do is watch her deteriorate and.

[Dr. Lisa Moscone]

Sorry, it's not. It comes and goes.

[Dr. Mary Claire Haver]

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 talk about my dad being in the room. He passed away seven years ago, and I just realized I don't want this. And so I just kind of grew up thinking this is inevitable for me, but it's not. And you are the one teaching me that. So you were the first person to even say that. This is not your inevitability. There are things that we can do. You're young enough to get ahead of this. So tell me about your family.

[Dr. Lisa Moscone]

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.

[Dr. Mary Claire Haver]

You remember her without dementia?

[Dr. Lisa Moscone]

Oh, yes. Oh, I grew up with my grandmother, mostly. My. 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.

[Dr. Mary Claire Haver]

Know what that would be.

[Dr. Lisa Moscone]

But they did work a lot when I was growing up.

[Dr. Mary Claire Haver]

So your grandmother took on the caretaking?

[Dr. Lisa Moscone]

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 a sign of mixed dementia with some Lewy body components, which was the case for my grandmother as well. And she ended up spending at least years, her final years 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 caregiver, 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, eh, but when three old women express the same genetic vulnerability, that does hit you hard. So my mom and I have been just so up to speed with the research. I obviously do research, but my mom is also really, really participatory and so is 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.

[Dr. Mary Claire Haver]

We do, we'll dig into that.

[Dr. Lisa Moscone]

So yes, that sent me down the rabbit hole of trying to understand first genetics, right. What causes Alzheimer's.

[Dr. Mary Claire Haver]

Was this known? Was the gene known? Or so that's at the time.

[Dr. Lisa Moscone]

So at the time, which is now 25 years ago, that 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 known genes which are the app, the amyloid precursor protein and the pre senilin 1 and 2 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's genetic transmission but is highly penetrant and autosomal dominant, which means that if you do inherit the mutation, number one, you have a 50, 50 chance of getting the mutation if you do inherit it. Penetrance is almost complete.

[Dr. Mary Claire Haver]

And for our listeners, penetrance means the chance that you will express the disease. This mutation is so, it's so strong almost always. They're going to develop it if they live longer.

[Dr. Lisa Moscone]

Yeah, 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, which 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, in on average 2% of all Alzheimer's patients. So if you look at the entire population, it's actually even less. 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.

[Dr. Mary Claire Haver]

So then 98% of people don't have

[Dr. Lisa Moscone]

a genetic mutation, do not have a genetic mutation.

[Dr. Mary Claire Haver]

So what is it?

[Dr. Lisa Moscone]

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. Before, I'm gonna 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, is 60. It's horrible. But the good news is that it's not genetically induced. Okay. 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 Alzheimer's cases. 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.

[Dr. Mary Claire Haver]

So your PhD is in what?

[Dr. Lisa Moscone]

I have a dual PhD in neuroscience and nuclear medicine, which is a branch of radiology. So I do a lot of brain imaging.

[Dr. Mary Claire Haver]

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

[Dr. Lisa Moscone]

And the half life.

[Podcast Host / Advertiser]

What is brain fogs?

[Dr. Mary Claire Haver]

So let's, like, clear it up. Like, what is brain fog like? And when should someone be worried?

[Dr. Lisa Moscone]

Yeah, it's one of the reasons that actually scientists, 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 Weill Cornett Medicine, New York Presbyterian, which I run, come to us based on 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, it's a genetic term, is a colloquial Term that people use to describe what we in neurology refer to as cognitive fatigue or mental fatigue, which is this having a really hard time doing things cognitively. Like, you have a hard complaint.

[Dr. Mary Claire Haver]

Like.

[Dr. Lisa Moscone]

Yes.

[Dr. Mary Claire Haver]

Like, especially the ones who are, like, cognitive high functioning at work. Teachers, attorneys, you know, they're 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. So.

[Dr. Lisa Moscone]

Yeah, it's exactly that. It's. 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 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. I'm not a menopause or close to it, so I don't. I have no experience that. But I have. I had one exam, one experience of brain fog. Postpartum.

[Dr. Mary Claire Haver]

Okay. In a low estrogenic state. Yeah.

[Dr. Lisa Moscone]

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 I was already like, oh, my God. And then I found myself outside with the stroller empty. Going somewhere? 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. Petrifying. So if menopause is anything like that, oh, my gosh. And I 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 function, MRI to show that the connectivity. 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 the. It's a bit technical, but the ratio of phosphocreatine Creatine. You like creatine? Yeah, I like creatine. To ATP is increased, meaning there is more creatine phosphocreatine than ATP being made. So phosphocreatine is what the brain uses to make energy. It's the buffer. Right. But what you want is ATPs. 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.

[Dr. Mary Claire Haver]

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?

[Dr. Lisa Moscone]

There are small scale studies, observational 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 phosphocreatine, I think that that is really something that's worse, starting in part because the reservoir of creatine is lower.

[Dr. Mary Claire Haver]

Right.

[Dr. Lisa Moscone]

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.

[Dr. Mary Claire Haver]

And deficit bigger leg muscles, the more likely to have higher brain volume. Did I read that correctly?

[Dr. Lisa Moscone]

Yeah, that's, you know, also the, the smaller your feet and the higher your risk of all the 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.

[Dr. Mary Claire Haver]

I think they're doing some observational stuff. The creatine data mostly comes from muscle. Right. And the bodybuilders. But I think Abby Smith, Ryan and those people out of North Carolina are starting to look and doing the great cognitive work, doing some measurement there.

[Dr. Lisa Moscone]

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, but that doesn't mean it's not helpful. It couldn't be helpful. It could be. Well, you just don't know yet.

[Podcast Host / Advertiser]

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[Dr. Mary Claire Haver]

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 anger and fear, anxiety and anger. And, you know, it's affecting relationships. And at the same time, 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 this sandwich area. So what's happening? Is it the same biomechanical process that's happening that's leading to this emo. The emotional changes?

[Dr. Lisa Moscone]

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 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 cingular cortex and precuneus, 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 brainstem, 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, but the hypothalamus also really both regions. Actually, both glands play an important role in autonomic function, which is, like, control the 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.

[Dr. Mary Claire Haver]

Patients complain constantly of that.

[Dr. Lisa Moscone]

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.

[Dr. Mary Claire Haver]

Do we unmask something that we're managing before a vulnerability?

[Dr. Lisa Moscone]

Yes. Amygdala full of estrogen receptors. 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.

[Dr. Mary Claire Haver]

Renovation.

[Dr. Lisa Moscone]

Yes. So Robby actually says that menopause 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 tracts inside the brain show more positive markers of connectivity. So there's more diffusivity, there's more. It's just the brain is basically better connected in those specific parts of the brain relative to men of the same age.

[Dr. Mary Claire Haver]

So we have better brain function than men up to a certain connectivity.

[Dr. Lisa Moscone]

Yeah, yeah. And then this is what happens at the perimenopausal stage. There are basically no differences. And this. You're gonna love this. Whoa. Yes. Oh, I love that. Wow. This is postmenopausal women. And it's better than before. Wow. Yes.

[Dr. Mary Claire Haver]

So it remodels.

[Dr. Lisa Moscone]

It remodels to make us connect better, differently 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 10 years.

[Dr. Mary Claire Haver]

And then you got to go postmenopausal. So you're looking at a 15 year.

[Dr. Lisa Moscone]

It's going to take a minute. But we do have six year data now, so we're doing that. But this suggests that 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 perimenopausal and more differences at the postmenopausal stage. Nobody here is taking hormone therapy. So that does suggest a huge shape 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 now. But I thought this was brilliant.

[Dr. Mary Claire Haver]

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 live long enough, you know, they were. They carried the traditions, they taught the younger, you know, it's kind of beautiful how that played out.

[Dr. Lisa Moscone]

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. Is a very big pathway in the body, and it's very expensive to maintain. So once women 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, let's do a little spring 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 has 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.

[Dr. Mary Claire Haver]

Okay.

[Dr. Lisa Moscone]

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 gentler menopause.

[Dr. Mary Claire Haver]

I love that explanation.

[Dr. Lisa Moscone]

Long term risk of Alzheimer's and anxiety and depression and Parkinson's and whatnot.

[Dr. Mary Claire Haver]

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?

[Dr. Lisa Moscone]

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 possibly 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.

[Dr. Mary Claire Haver]

And it gets better, right?

[Dr. Lisa Moscone]

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 be present.

[Dr. Mary Claire Haver]

We can support it.

[Dr. Lisa Moscone]

We can, yes.

[Dr. Mary Claire Haver]

Through the transition.

[Dr. Lisa Moscone]

Exactly.

[Dr. Mary Claire Haver]

In our clinic, we, we offer hormone therapy in these cases and they usually do very well.

[Dr. Lisa Moscone]

And there's more research coming. You know, 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.

[Dr. Mary Claire Haver]

Oh, yeah, yeah. Let's get into that.

[Dr. Lisa Moscone]

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 kids are for, that is a problem.

[Dr. Mary Claire Haver]

I will use that again. That is.

[Dr. Lisa Moscone]

But then again, 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 MMSE 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 30 and menopause brings you down to 28 to you, that is a catastrophe to us. 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.

[Dr. Mary Claire Haver]

If you can't remember where you put

[Dr. Lisa Moscone]

your keys, but if you don't know what the keys are for, that is a problem.

[Dr. Mary Claire Haver]

You need to go get evaluated.

[Dr. Lisa Moscone]

That's a problem. Okay.

[Dr. Mary Claire Haver]

All right, let's talk about our brain plan, our game plan.

[Dr. Lisa Moscone]

Yes.

[Dr. Mary Claire Haver]

I love it for midlife because there's so much hope here.

[Dr. Lisa Moscone]

Yes, yes.

[Dr. Mary Claire Haver]

You know, there's so 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.

[Dr. Lisa Moscone]

Yes.

[Dr. Mary Claire Haver]

But what can women actually do to protect their brains? So let's talk about the key lifestyle factors involved in brain health.

[Dr. Lisa Moscone]

Yes.

[Podcast Host / Advertiser]

So we're going to start with sleep.

[Dr. Lisa Moscone]

Yes. I think that's.

[Dr. Mary Claire Haver]

That's probably one of the most important things I've heard.

[Podcast Host / Advertiser]

Sleep is called as the wash cycle.

[Dr. Lisa Moscone]

Yes.

[Dr. Mary Claire Haver]

So what does that mean?

[Dr. Lisa Moscone]

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 overthinking, for sure. Misremembering. But also supervising the rest of the body, even heart rate, the brain 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 like 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 place.

[Dr. Mary Claire Haver]

All the mess accumulated through the day.

[Dr. Lisa Moscone]

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 your 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 body plaques will stay in the brain, the inflammation may stay in the brain. So sleep hygiene and sleep protection is a very important and just recently discovered protective factor for brain health and Alzheimer's disease. Whereas sleep deprivation is a risk factor for Alzheimer's.

[Dr. Mary Claire Haver]

So now sleep is now in cardiovascular disease, now characterized as a risk factor.

[Dr. Lisa Moscone]

How much sleep do we need? Well, you know, and why do these

[Dr. Mary Claire Haver]

middle of the night wake ups, which a lot of my patients complain of, including me.

[Dr. Lisa Moscone]

Yes. So one potential mechanism is related to menopause and of course the 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 the all these different hormones work together is 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.

[Dr. Mary Claire Haver]

Cortisol.

[Dr. Lisa Moscone]

Cortisol and melatonin. Okay, so for cortisol, the relationship is well characterized in that the body needs a common precursor, which is pregnenolone, to make both sex hormones and cortisol, the stress hormone. So if you're super stressed out, the body's going to have to use most or more of the pregnenolone 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. And women who are really, really stressed out may experience more severe symptoms of menopause because you have less availability.

[Dr. Mary Claire Haver]

The prenelon gets eaten up or.

[Dr. Lisa Moscone]

Yes, you're more so. Yeah, yes, and for melatonin is a similar problem where if stress and cortisol, say 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 the 1 to 3pm window. But then it remains in the system unless you're super stressed out, in which case cortisol kicks in around 2 in the morning. 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 at any of these nodes.

[Dr. Mary Claire Haver]

The Internet is full of all of these wellness cures. You know, some, and I have no data, you know.

[Dr. Lisa Moscone]

Right.

[Dr. Mary Claire Haver]

How do we lower cortisol? I know we can do, you know, stress reduction, meditation, journaling, you know. But are there supplements?

[Dr. Lisa Moscone]

Are there, you know, cortisol? Yeah, not as I'm aware of. Okay.

[Dr. Mary Claire Haver]

A lot of claims out there to say, take this and we'll lower your cortisol. Oh, God. All kind of Internet claims. Oh, buy my supplement and I'll lower your cortisol.

[Dr. Lisa Moscone]

If you. I'm not aware of any supplement that can directly lower cortisol. What has been shown to lower cortisol levels is, 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 also 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. Sleep, in other words, may also have a lowering effect on cholesterol. It's not direct. I would say it's more indirect.

[Podcast Host / Advertiser]

Indirect.

[Dr. Mary Claire Haver]

Relaxing the body. And then it just.

[Dr. Lisa Moscone]

It's like exercise. Exercise.

[Dr. Mary Claire Haver]

That's my necklace. So women who are fit in midlife. Yes, whatever fit is defined as, have a 30% lower dementia risk.

[Dr. Lisa Moscone]

Those are the women who have the highest level of cardiovascular fitness.

[Dr. Mary Claire Haver]

Okay.

[Dr. Lisa Moscone]

In midlife. Yes. So moderate to.

[Dr. Mary Claire Haver]

What is exercise doing to the brain?

[Dr. Lisa Moscone]

Exercise supports brain health 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 a really super interesting discovery just a couple of years ago. It came out in science that when muscles contract as part of exercise, they produce a peptide that is called irisin from iridescent 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 cytokines directly in neurons. So that's a beautiful way that exercise can directly support brain health. And look, this is, this is when it comes to Alzheimer's disease.

[Dr. Mary Claire Haver]

I was looking for this the other day. Okay. Yeah, here we go.

[Dr. Lisa Moscone]

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. 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, account 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, I would say, rather than just years 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 if 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.

[Dr. Mary Claire Haver]

What about GLP ones?

[Dr. Lisa Moscone]

We're not there yet.

[Dr. Mary Claire Haver]

Everyone's out there yet.

[Dr. Lisa Moscone]

No, no, no, no, no.

[Podcast Host / Advertiser]

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[Dr. Mary Claire Haver]

I've watched my daughter try it.

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[Dr. Lisa Moscone]

Why have I asked my H Vac guy I found on angie.com to change my grandpa's trachea tube? I was so amazed at how we

[Dr. Mary Claire Haver]

replaced our air ducts.

[Dr. Lisa Moscone]

I knew I could trust him to change Pop Pop's tube. I think we should call a doctor,

[Podcast Host / Advertiser]

Angie, the one you trust to find the ones you trust.

[Dr. Mary Claire Haver]

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[Dr. Lisa Moscone]

All right, well, let's talk about food

[Dr. Mary Claire Haver]

because what I loved in, in your books is that you spend a lot of time talking about nutrition.

[Dr. Lisa Moscone]

I love chemistry and nutrition is effectively biochemistry.

[Dr. Mary Claire Haver]

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 cooking for a thousand people program. You know, they're kind of the nutrition science goes two ways, you know, and she absolutely loved it and I think it's such a strong foundation for her for medical school.

[Dr. Lisa Moscone]

It's so good. I also, I did not study nutrition at school, but I'm kind of self taught. At some point I was, okay, just get me every chemistry book because all the things I'm learning about brain health, all the, so the potassium pumps, you know, serotonin is made of tryptophan. And these are all nutrients that come from food. Right. They're not made by the brain. They are important. So I loved it. I spent a lot of time.

[Dr. Mary Claire Haver]

So what should we be eating? Nutrition for our brains.

[Dr. Lisa Moscone]

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, It's a little bit more of a picky eater relative to other organs. And it loves people 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 that's where the fish.

[Dr. Mary Claire Haver]

That's where the fish get the omega 3 is they eat the algae. So it's part of the food chain. So if you can't tolerate fish or you're allergic, you can get the supplement, the algae based supplement.

[Dr. Lisa Moscone]

Absolutely. And obviously glucose is very important for brain health, but within reason, 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, but glucose is a number of functionalities and for the brain is the building block of glutamate, which is the most prevalent neurotransmitter in the entire brain and is needed to synthesize gaba, which is the prevalent inhibitory neurotransmitter. So glucose is not just. And then thinking when the keto diets came out, I was a little bit like, whoa. Because it's important not just for energy, but also to synthesize, okay, the most abundant neurotransmitters that we have.

[Dr. Mary Claire Haver]

Why are ultra processed foods so bad for brain health?

[Dr. Lisa Moscone]

They're bad indirectly. So those kind of foods and nutrients should not be able to cross the blood brain 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 then leads to oxidative stress and inflammation. And those sorts 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 processed food is bad for pretty much every organ we have.

[Dr. Mary Claire Haver]

Are there any supplements you think are

[Dr. Lisa Moscone]

hype or are realistic for brain health? Yeah, I wish we had more data. I think there are some nutrients more. The supplements that are 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 B12 deficient and just don't know that. So it's important to have that we

[Dr. Mary Claire Haver]

check B12 levels on all of our patients.

[Dr. Lisa Moscone]

Yeah, the folate, B6, those are 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 minerals 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

[Dr. Mary Claire Haver]

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 gonna do standard, you know, like, what can we tell her?

[Dr. Lisa Moscone]

Well, for instance, if you are a former smoker, which. This is one of the biggest regrets of my life.

[Dr. Mary Claire Haver]

Same, I quit at 23.

[Dr. Lisa Moscone]

Same me too. You know, initially, I was growing up there and everybody 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 counteract 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 using antioxidants.

[Dr. Mary Claire Haver]

For example, what would an antioxidant be, just for our listeners? Vitamin C. Vitamin C, yeah.

[Dr. Lisa Moscone]

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 vitamin. I'm not saying anyone should take high doses and tear their stomach up until the day he died. And he was as healthy as anyone can be. Now, that's one person. Nobel Prize Festival, 1%. I would say regular amount of vitamin C, especially liquid. Liquid vitamins are really good in terms of being absorbed, absorption quickly.

[Dr. Mary Claire Haver]

Good to know. All right, so elephant in the room, lots of talk, worries. The Menopause Society meeting had a whole section on this. Let's talk about hormone therapy and dementia. Yes.

[Dr. Lisa Moscone]

And this is what do we know? What do we know and what we don't? 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 MPA 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 too few women developed Alzheimer's disease. So they had to switch their endpoint to dementia. Now, 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 cases was small. Was about 12 more women 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 midlife women.

[Dr. Mary Claire Haver]

Right. Because they were. These patients were much older.

[Dr. Lisa Moscone]

Yes. And as 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.

[Dr. Mary Claire Haver]

You're bouncing off of a closed door.

[Dr. Lisa Moscone]

Yeah, that's a good way to put it. And also, those are different formulations to what. Right.

[Dr. Mary Claire Haver]

Than when we use.

[Dr. Lisa Moscone]

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

[Dr. Mary Claire Haver]

The end point. All right, Lisa, if I gave you a billion dollars right now, what study would you. What would be the study?

[Dr. Lisa Moscone]

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 that micronized estradiol and progesterone, which are closer to what their bodies naturally produce, dosed using brain scans so that you can know what kind of dose 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.

[Dr. Mary Claire Haver]

So these are.

[Dr. Lisa Moscone]

It's the brain scan. So we can look at plaques in the brain, we can look at tangle 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?

[Dr. Mary Claire Haver]

Your hypothesis is.

[Dr. Lisa Moscone]

But my hypothesis is optimistic, of course. But I would also have all sorts of 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

[Dr. Mary Claire Haver]

you have a million dollars for this study?

[Dr. Lisa Moscone]

I have 50 million. But let me show you the observational research 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, with a hysterectomy and or oophorectomy, whereas estrogen with a progesterogen. We can't yet separate, like progesterogen, sorry, progesterone to progestin with observational data. But there's still a trend towards a risk reduction. This does not mean that every woman needs 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 protected. Why? We don't know. But there's something there. It could be the kind of hormonal formulation that was used, the diagnostic criteria. It could be a number of reasons. But the studies in North 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.

[Dr. Mary Claire Haver]

So good.

[Dr. Lisa Moscone]

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 hormone therapy prevent.

[Dr. Mary Claire Haver]

This was said at a national meeting just a month ago.

[Dr. Lisa Moscone]

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 the 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. Genetics by Age, genetics. Thank you. And now we have the brain scans as well, which we 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 protective because we don't know what 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, 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

[Dr. Mary Claire Haver]

that we can't we stop all meaningful research in menopause.

[Dr. Lisa Moscone]

Exactly.

[Dr. Mary Claire Haver]

So for a woman who's sitting at home right now listening to this and feels scared, what do you want to say to her about her health, her brain health and moving forward?

[Dr. Lisa Moscone]

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 where 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 your, and to yourself as well, this feels like this

[Dr. Mary Claire Haver]

has been a life changing conversation.

[Podcast Host / Advertiser]

Always.

[Dr. Mary Claire Haver]

Every conversation I have with you and I. I'm so excited for our listeners to hear this episode. As a reminder to our audience, you can follow Dr. Moscone on Instagram Dr. Moscone. Her book the Menopause Brain is available now through her [e-mail] you can find full episodes of Unpaused on YouTube at Dr. Maryclaire. I'd love to hear from you about this topic and anything else that's on your mind. You can follow me on Instagram Dr. Maryclaire and get honest and accurate information on health, fitness and navigating [e-mail] 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 or supported, hit follow right now so you never miss an episode. Thank you for being here with me. Let's keep going. Unpaused Unpause 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.

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[Dr. Mary Claire Haver]

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