Neuroscientist Dr. Lisa Mosconi On Menopause, Hormone Health, & Alzheimer’s Prevention

Menopause, often overlooked yet profoundly impactful, marks a critical juncture in a woman’s life, reshaping the brain for half of the global population. This week I am joined by Dr. Lisa Mosconi, a leading neuroscientist in women's health, who challenges outdated perspectives on menopause, emphasizing its neurological significance and advocating for recognition as a neuroendocrine transition. In this episode, we explore diverse menopausal experiences and factors influencing symptoms and shed light on the link between genetics, Alzheimer’s, dementia, lifestyle, neuro-nutrition, and hormone replacement therapy. Dr. Mosconi’s insights provide a crucial antidote to common misconceptions, making this episode essential for women and equally important for everyone, addressing gaps in education about women’s health. Show notes + MORE Watch on YouTube Newsletter Sign-Up Today’s Sponsors: CamelBak: Unlock 20% OFF with code RICHROLL 👉camelbak.com Seed: Use code RICHROLL25 for 25% OFF 👉seed.com/richroll Birch: Get 20% off ALL mattresses 👉birchliving.com/richroll GoBrewing: Use code Rich Roll for 15% OFF 👉gobrewing.com/richroll Momentous: Get 20% OFF my favorite products 👉livemomentous.com/richroll This episode is brought to you by BetterHelp: Get 10% OFF your first month 👉betterhelp.com/richroll Learn more about your ad choices. Visit podcastchoices.com/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Rich Roll?

  Eating well rarely falls apart because of one big failure. It's the daily question that wears you down, like, what am I actually gonna make tonight? What's in the fridge? And it's exactly why we built the Plant Power Meal Planner. It's a personalized, plant-based meal planning program that matches you with recipes based on your taste, your allergies, your cooking skills, and how much time you actually have. You build, through this program, a balanced, nutrient-dense plan for your entire household in a few minutes. Then it generates a grocery list for you with one click that plugs right into our delivery partners. All the recipes in the program are built by dietitians with culinary training. Plus, you get your own food coach to help you problem-solve along the way.

• 0:44Rich Roll?

  It's kind of an amazing thing. For listeners of the show, all you special people, we're offering an exclusive $20 off an annual subscription right now. To get it, go to meals.richroll.com, take your quick personalization quiz, and enter promo code RICHROLL20 at checkout.

• 1:05Lisa Mosconi?

  Menopause is, in fact, changing your brain. So we started looking at menopause, and I was like, well, what's been done? Let's look at how many brain imaging studies have been published. What did they find? There wasn't a single one.

• 1:19Rich Roll?

  Not one.

• 1:20Lisa Mosconi?

  And so I said, well, let's do it. And we started scanning. This is what we learned.

• 1:28Rich Roll?

  My guest for this discussion is world-renowned neuroscientist Dr. Lisa Moscone. Dr. Moscone's work may very well provide answers as to why 2/3 of all Alzheimer's patients are women.

• 1:41Lisa Mosconi?

  Once you have Alzheimer's disease, there's only so much we can do. Menopause is a riddle, because it goes completely against evolution. When it comes to brain health, quick fixes don't work. They just cannot.

• 2:04Rich Roll?

  So nice to meet you. Thank you for doing this. I'm so excited to talk to you.

• 2:08Lisa Mosconi?

  Thank you for having me.

• 2:10Rich Roll?

  Yeah, I think it would be cool to just learn how you got into neuroscience because there's a really interesting backstory to everything that you do now. Are you open to sharing that?

• 2:20Lisa Mosconi?

  Of course, of course. So I was born and raised in Florence in Italy. And I know you have an affection for my hometown.

• 2:28Rich Roll?

  Very much so.

• 2:29Lisa Mosconi?

  Yeah. I grew up into science. I like to say that half of my family has a PhD and the other half is in the army. So we sit up very straight as scientists. But both my parents are scientists. They're professors in nuclear physics at the University of Florence, which made for an interesting childhood.

• 2:50Rich Roll?

  Yes, very intense, I would imagine, at times. The dinner table conversations must have been interesting.

• 2:55Lisa Mosconi?

  It was interesting. I remember I was maybe six and I had no idea who Cinderella was, but I knew everything about proton decay and, you know, energy states and gravity and relativity. So it was very interesting. But the most interesting part to me is that... So that's in Florence, Italy, in the 80s. And back then, it was a very small university. So a lot of my parents' students would come to the house on the weekends just to ask questions and get some workshops done with my parents. And they were taking turns and they would babysit me in the meantime. So they would talk to me about nuclear physics. And some of them then transitioned to work in nuclear medicine,

• 3:39Lisa Mosconi?

  which is this branch of radiology that uses radioactive isotopes to measure different things inside the brain and other organs of the body. They would talk to me about that. I remember one of the students, Dr. Sandro Passi, who is a professor now at the University of Florence, would, you know, kind of walk me around on his shoulders. He's a big guy, a strong guy, and talk to me about all this different nuclei and isotopes and this and that. So I developed a love for that kind of work from a very young age. But I always wanted to study brains. I was always interested in psychology and people's behavior and why do we do the things that we do and why do we do things that we really should not be doing?

• 4:21Lisa Mosconi?

  And so then I said to my parents that I was going to study neuroscience at the university, which I did.

• 4:28Rich Roll?

  Right, if you had said psychology, how would that have been received? Like, that's a soft science, like.

• 4:33Lisa Mosconi?

  I did say psychology and my grandmother did not talk to me for months.

• 4:38Rich Roll?

  Yeah.

• 4:39Lisa Mosconi?

  She was so terrified, saying, now you're not doing psychology. I was like, what? So it was neuroscience for me.

• 4:46Rich Roll?

  Yeah, that's a hard science way into human behavior.

• 4:50Lisa Mosconi?

  Yes, but it was fantastic. I loved every, every class. Initially, graduating can take anywhere between five years and whenever, and I did it in four because it was so, I just loved it. And I immediately started working on my thesis and I wanted to do a hands-on project. So I started going to the hospital, the clinical research hospital in Florence, and I was working with EEGs and event-related potentials. So immediately, I was 18 and already I was doing my own research that was on the brain.

• 5:26Rich Roll?

  Wow.

• 5:27Lisa Mosconi?

  Oh, it's so good.

• 5:28Rich Roll?

  And what brought you to the States?

• 5:31Lisa Mosconi?

  My PhD. So I graduated, I did my fellowship, my training in nuclear medicine and neurology, and then I applied for a PhD program in neuroscience at the University of Florence, and I got in. It's quite competitive, so I was very fortunate to be able to do that. And then my mentor, who is wonderful, I have been so lucky with my colleagues and my mentors, he said there's an opportunity to go to New York, NYU, NYU Medicine, to work with Dr. Moni De Leon, who's a pioneer in the field of the early detection of Alzheimer's disease. Would you want to go? Now, that was at the same time that my grandmother,

• 6:16Lisa Mosconi?

  who lived right next door to us, started showing signs of cognitive impairment and dementia. And she was informally, back then, diagnosed with Alzheimer's disease. And in just a matter of a couple of years, her two younger sisters also developed cognitive impairment and then Alzheimer's. So that was heartbreaking, but also really scary. And I remember talking to my parents and saying, I want to research this. I want to understand if it's just my family, if it's just us, and what's the actual risk for my mother, for myself? And if it's not just my family, then I think we should really

• 7:00Lisa Mosconi?

  try to understand better what happens in Alzheimer's disease. And it doesn't matter if you're a woman or a man. And so that became my PhD thesis.

• 7:08Rich Roll?

  Right, because curiously, your grandmother's brothers did not develop Alzheimer's.

• 7:13Lisa Mosconi?

  Yes, so my grandmother was born of four siblings, three sisters and one brother, who all lived to the same age. But all three sisters developed dementia and died of it, whereas the brother was spared. So when I asked my professors during my PhD studies, I said, "Does it matter if you're a woman or a man?" And they would say, "Well, so what we know so far is that Alzheimer's disease affects more women than men." So currently, out of every three Alzheimer's patients, two are women, at least in Europe and in the United States, that we had data for. But the thing is, they said, Alzheimer's disease is a disease of old age,

• 7:57Lisa Mosconi?

  and women live longer than men. So unfortunately, it's just aging.

• 8:03Lisa Mosconi?

  But it makes sense, the more women than men end up with a diagnosis of Alzheimer's disease. That never really made sense to me.

• 8:11Rich Roll?

  Right, it doesn't really hold up under investigation.

• 8:14Lisa Mosconi?

  No, because, well, number one, I think that the longevity gap is not that wide. So the difference in lifespan is four years, in the United States, not 10 or 20. And in England, the difference is two years. So women tend to live about two years longer than men. But Alzheimer's disease is the number one cause of death for women and not men, with a difference of two years.

• 8:38Rich Roll?

  And a differential of two-thirds in terms of who gets Alzheimer's and who doesn't on a gender basis.

• 8:46Lisa Mosconi?

  Yes.

• 8:47Rich Roll?

  Or on a sex basis.

• 8:48Lisa Mosconi?

  Yes. And it's unique. You know, there are other disorders that are age-related that do not show their prevalence, like vascular dementia is 50/50. There are other forms of age-related neurodegenerative disorders that do not show the two-thirds, the 2 to 1 ratio. So there's something about Alzheimer's in women that I felt was not being examined as in death as it deserved. And so I did it, and that became my PhD thesis, and I've been researching that forever.

• 9:21Rich Roll?

  And at that time, was that the state of the union in terms of what people understood about Alzheimer's and the XX brain? There was no further investigation or science to support the claim that it was merely a factor of women living longer than men?

• 9:38Lisa Mosconi?

  There was very little research done.

• 9:39Rich Roll?

  That's shocking, actually.

• 9:41Lisa Mosconi?

  I tend to agree, as a woman and a scientist, it's a bit dismaying. But no, back then, it was kind of a dogma, that Alzheimer's disease is a disease of old age, women live longer than men, so who cares?

• 9:53Rich Roll?

  Mm-hmm. Right. So hence begins, you know, your investigation into this world and the many discoveries that you've made. And at the kind of core of that is this premise that women's brains and men's brains are not exactly the same, which is...

• 10:10Lisa Mosconi?

  Any woman can tell you.

• 10:11Rich Roll?

  Yeah, anybody can tell you, but it's also simultaneously a controversial statement that requires a little bit of, you know, nuance to understand what you mean specifically about that.

• 10:22Lisa Mosconi?

  Yes, so I'm talking about sex differences at a very raw biological level.

• 10:31Lisa Mosconi?

  We do not talk about behavior or intelligence as being different or genetically cued in different ways. So I think this is an important distinction because we do have a problem in our field that is called neurosexism. And it's nothing short of the backbone of modern neuroscience, which is to say that for a very long time, actually, since the 19th century, scientists systematically set out to prove that women's brains were inherently inferior to men's brains. And the way that they constructed this hypothesis was obviously

• 11:09Lisa Mosconi?

  flawed, but it was really based on key teachings by Darwin, among other very important scientists. And what they discovered somehow is that women's brains are smaller than men's brains on average. And they weighted all the different brains, they put them on a scale, and found out that on average, women's brains were about five ounces lighter than men's brains. And that immediately, based on the principle the bigger is better, that immediately was taken to reflect the women's brains were weaker, smaller, inferior, less functional, less well-developed than men's brains.

• 11:54Rich Roll?

  How long ago was this?

• 11:56Lisa Mosconi?

  In the 19th century, 1850, more or less. The problem there is that they did not measure head size, right? So if you consider that men on average are also taller and bigger than women, and that their heads are proportionally bigger, then it makes sense that their brains would be bigger as well, because you don't want to have an enormous skull and a teeny tiny brain inside. So your brain is proportional to your head size and overall body size. So once you take that into account, then there's really no difference. But back then, they would use that biased and flawed information to keep women out of universities. You know,

• 12:36Lisa Mosconi?

  it was like reinforcing the status quo that women did not deserve certain rights or certain opportunities, like going to school or holding prestigious jobs. So there was effectively a political weapon to keep women at bay. And the Patriotic Society just loved the kind of research. It was the only research that was done. No, that doesn't happen anymore. But there's still some problems where very often, if I provide evidence that there is a biochemical difference, right, between men's brains and women's brains, that could be

• 13:15Lisa Mosconi?

  used to say that women can't drive, you know, or that men can't do their laundry, so you have to do it for them. So there's still a little bit of overinterpreting biological effects, having whatever effect on behavior, or IQ, or personality, or just making these stupid stereotypes that we still carry with ourselves a lot. And this starts with pink and blue when we're born, but then the consequences that there's, I don't know how many men, sitting on the Supreme Court, deciding what to do with women's health rights, right?

• 13:55Lisa Mosconi?

  So there's a range of problems that can come from the research that we do, that we don't want. For sure, I would never want to do anything that could potentially harm women or men based on a research. But what's important to understand is that there are biological differences between men's brains and women's brains, and that these differences have nothing to do with intelligence, or potential, or opportunities, or preferences, or any such thing. That is biology. What these differences matter for is health. Because they do have consequences in terms of your health, of your risks, of your vulnerabilities,

• 14:37Lisa Mosconi?

  and very often, on the choice of treatment, of course, of the action, they need to be targeting your own biology. And this is missing in medicine right now. It's an approach called precision medicine, and we have it more for other parts of the body, but we're really behind when it comes to the brain.

• 14:55Rich Roll?

  And the differences that you highlight, at least specifically with reference to your work in terms of cognition and women's health, relates primarily to the relationship between the brain- And our hormonal regulation.

• 15:12Lisa Mosconi?

  Yes.

• 15:13Rich Roll?

  And the differences that you're highlighting really have to do with the differences sort of constitutionally that women have with respect to their hormonal landscape versus men and the impact of that on the brain. Because it's a communication between these two mechanisms that, you know, create the differences that are most salient to the work that you're doing.

• 15:35Lisa Mosconi?

  Yes, you said it so perfectly.

• 15:36Rich Roll?

  Yeah, right.

• 15:37Lisa Mosconi?

  I have nothing to add.

• 15:37Rich Roll?

  But what's interesting, I liked, you know, the way that you explained kind of the history of medicine and science with respect to women's health. And I think as much as we would like to believe that that's an archaic vestige of a bygone era, it continues to linger, right? It still sort of persists in this somewhat invisible, but also very palpable way, and continues to show up in the way that practitioners treat women in their offices to this day. And you have a term for it. You call it bikini medicine.

• 16:10Lisa Mosconi?

  It is bikini medicine. I would say that still today, we teach and practice bikini medicine, which is to say that from a medical perspective, what makes a woman a woman is those body parts that we cover with a bikini, so our reproductive organs. And historically, medical professionals and scientists, we've been diagnosing the sexes as if we were all the same person, men. And aside from those body parts that, again, are involved with reproduction, most practitioners would just treat and diagnose the genders exactly the same way, even though we know and we've known forever that there are differences

• 16:53Lisa Mosconi?

  in the ways that our bodies process information, even process nutrients. There are differences in the way that we metabolize different substances, including medications. And most importantly, our brains are just not the same. And the problem with neuroscience is that, for whatever reason, sex differences have not been investigated, really.

• 17:19Lisa Mosconi?

  Aside from whatever parts of your brain are involved in reproductive functions.

• 17:25Rich Roll?

  Uh huh.

• 17:25Lisa Mosconi?

  So there's this misunderstanding that a man's brain and a woman's brain is exactly the same. And most of what we know about the brain comes from studies that were focused on men and excluded women. And this is a problem because women have a higher risk of a number of brain conditions. From depression, depressive symptoms and anxiety, the risk is two to one. Stress is high in women as is men. We have three times the risk of developing an autoimmune disorder, including those that attack the brain, like multiple sclerosis. We're four times more likely to suffer from headaches and migraines, as every man knows, right? And we're also more likely to die of a stroke.

• 18:09Lisa Mosconi?

  And we're more likely to develop some kinds of brain tumors called meningiomas, especially after menopause. And like we were discussing before, women have a higher lifetime risk of developing Alzheimer's disease than men do. So if you don't acknowledge that there is such a disparity, and if you don't understand the root causes of this disparity, we will never be able to fix the problem.

• 18:33Rich Roll?

  Hmm. So explain how you characterize that difference. Like, what is it that is specifically different about the woman's brain versus the man's brain? And I'm using those terms, you know, probably incorrectly. Like, I want to be sensitive to, you know, kind of gender.

• 18:51Lisa Mosconi?

  Of course.

• 18:51Rich Roll?

  Identity here and distinguishing that from biological sex.

• 18:56Lisa Mosconi?

  Yes, so when I use the term women, I'm talking to individuals who were born with two X chromosomes, XX brain. And the so-called female reproductive system, meaning if you have two X chromosomes and you have ovaries, that's the biological definition of.

• 19:14Lisa Mosconi?

  Female sex, for lack of a better word, women. But we fully appreciate that there are many individuals who were not born with those characteristics and identify as women. And there are plenty of people who were born with those characteristics and do not identify as women. So, you know, it's hard.

• 19:31Rich Roll?

  Yeah, no, I understand. Yeah, yeah, so we qualified that.

• 19:35Lisa Mosconi?

  Yes. So we preempted.

• 19:37Rich Roll?

  But going forward, yeah, like.

• 19:38Lisa Mosconi?

  This is not universal.

• 19:39Rich Roll?

  Help me understand what those differences are.

• 19:42Lisa Mosconi?

  Hmm. So there are many ways to look into this question. One key finding that we have been developing and that we've been working on is that women's brains age differently from men's brains. And that difference is very, at least in part, related to differences in our reproductive systems and the hormones that drive those systems. So this is actually a nice thing to talk about as, and as a woman and a scientist, is then we are born with a very important and powerful system, which is the neuroendocrine system.

• 20:24Lisa Mosconi?

  It's like a pathway that connects the brain, the neurological system, with the ovaries via the endocrine system that is powered by our hormones.

• 20:34Rich Roll?

  Hmm.

• 20:35Lisa Mosconi?

  And this system we're born with, but is effectively activated during puberty for both men and women. And then for women, is reactivated every time you go through a pregnancy. And then is eventually deactivated, turned off, at least in part, once women reach menopause. Now, what's important about this system is that men have it, women have it, but the hormones that drive the system differ in their types and quantity. So when women are born, our brains come equipped with estrogen receptors. They far outnumber receptors for other hormones like testosterone, for example. For men, it's the other way around.

• 21:18Lisa Mosconi?

  You have a lot of androgen receptors in your brain and some estrogen receptors, which means that women's brains are regulated, for the most part, by estrogen, or the women's brains run effectively on estrogen. Men's brains are more.

• 21:38Lisa Mosconi?

  More heavily modulated by testosterone levels and other androgens. Now, that has consequences because hormonal fluctuations for women occur on a monthly basis for as long as you have a menstrual cycle. Then there's a long period of time that I'm hoping we'll talk about. It's called perimenopause, the menopause transition that can last a decade during which there are strong hormonal shifts that can kind of hijack your brain a little bit. This is what we're going to talk about. And then these hormones effectively recede, at least some of the estrogens recede after menopause, which could be a bit of a shock to your system. Right?

• 22:21Lisa Mosconi?

  This does not happen to men because testosterone levels decline more gradually, usually reaching andropause, which is the male equivalent to menopause in the 70s or 80s. So it's a more gradual decline. There's more time for that to happen. For women is midlife. The average age of menopause is 51, 52, but in reality, if you look across the globe, is 49. You're not even 50 when that happens as the average human being on this planet. But the changes start years prior.

• 22:56Lisa Mosconi?

  And that prompts increased cellular aging at that point, also in your brain. So your neurons become a little bit more vulnerable, can become a little bit more vulnerable to certain things. And there's a whole remodeling that takes place that can have a strong impact on mood, on cognition, on sleep, on stress, on all the things that we usually take for granted.

• 23:27Rich Roll?

  What's interesting in reading your book is this antiquated notion that menopause was seen as a disease.

• 23:35Lisa Mosconi?

  Yes.

• 23:36Rich Roll?

  Which is crazy because it happens to every woman. You know, how could that be?

• 23:39Lisa Mosconi?

  Lots of people say that today.

• 23:41Rich Roll?

  And really not studied in any kind of effective way. But also this idea that

• 23:48Rich Roll?

  It's not an on-off switch, that it is a transitionary phase that has sort of sub-phases within it. It's a process. It's a moving from one state to another that is endocrine-driven, but also has these very real implications in terms of how the brain operates. And understanding that as a pathway towards a little bit more self-compassion. Like, there's this narrative, also something that still persists, that women go crazy, or they lose their minds. And on top of that, that experience of menopause can vary wildly between women.

• 24:33Rich Roll?

  And also, its onset can vary wildly in terms of when it occurs, age-wise.

• 24:40Lisa Mosconi?

  Yes.

• 24:40Rich Roll?

  How do you understand why that experience can be so different for different people? And why it would show up at different stages, you know, age-wise for different people?

• 24:51Lisa Mosconi?

  Yeah. So I think it's really important to clarify that menopause is not just something that happens to your ovaries. As a society, I think that insofar as we have understood menopause at all, it's traditionally or historically been just the half that speaks to the functionality of the ovaries. And brain scientists were really not involved in that definition. So now we understand that menopause is actually a neuroendocrine transition state, which means it's a neurologically active phase during which your brain is impacted just as much as your ovaries are. In some ways, more. Because when your brain is impacted,

• 25:36Lisa Mosconi?

  then you have all these symptoms that... Sometimes really prompt fear in many women who have no clue what is happening to them. And when women talk about having hot flashes and night sweats and depression and anxiety and insomnia and brain fog, which is scary, and memory lapses and forgetfulness or panic attacks, or even skin crawling sensations. If you don't know why you're having those symptoms, it is legit to really worry that that there's something really bad happening to you in your brain. So those symptoms are in fact symptoms of menopause that have nothing to do with the ovaries.

• 26:17Lisa Mosconi?

  Those are neurological symptoms that are prompted by your brain because menopause is in fact changing your brain. When we started looking into this, I come from a different field. I do Alzheimer's prevention. And I landed on menopause, which is an interesting story because some of our patients were having a hard time with cognitive testing. And that's how we kind of made a connection. And so we started looking at menopause and I was like, well, what's been done? Let's look at how many brain imaging studies have been published. What did they find? What can we learn from it? How do we move forward? There wasn't a single one.

• 26:57Rich Roll?

  Not one?

• 26:58Lisa Mosconi?

  No, one. They looked at women's brains.

• 27:00Rich Roll?

  That's crazy.

• 27:01Lisa Mosconi?

  As they are going through menopause. All the studies that were published were looking at menopause as the outcome. So they were all done after menopause, like in women in their 60s and 70s and 80s. But then you're done. At that point, you're in the post-menopausal stage, right? There's not much to learn about how menopause effectively impacts your brain. And so I said, well, let's do it. And that was, there's a bit of a shift. So we called the OB-GYN department and we started working with our colleagues in general OB-GYN and OB-GYN surgery as well, who are wonderful at Walcott and Medicine. And we started scanning women who were all middle-aged women.

• 27:44Lisa Mosconi?

  And midlife is any year, any age between 35 and 65, right? It's a broad definition. And we were, we're trying to characterize them based on their menopausal status. So we had a group of women who were pre-menopausal, a group of women who were perimenopausal, in transition, skipping periods and having symptoms, and a group of women who were post-menopausal. And we age matched them to a group of men, right? Because you want to take age out of the equation as much as you can. And we were doing all these different brain scans that looked at things like brain energy levels and brain anatomy, volume, how much gray matter do you have in your brain? And we looked at connectivity. And we also looked at Alzheimer's plaques. We can do it with brain scans right now.

• 28:29Lisa Mosconi?

  This is what we learned. Before menopause, women, men, no difference. During perimenopause, as you start skipping your cycles and some of the symptoms arise, but you still have a cycle, you're not in menopause. The men are fine at that age, matched one by one. The women start showing changes that are red flag for Alzheimer's disease. And I'll show you the brain scans in one second. And then when we look at the post-menopausal group and age-matched men, the men are still fine, the women are not so great, they start showing red flags even more of things that we want to stop or prevent. And again, I'm not saying that they had Alzheimer's disease back then, but there

• 29:13Lisa Mosconi?

  were signs of trouble in the brain.

• 29:16Rich Roll?

  Those red flags and those signs of trouble being, what, an increase in amyloid plaque deposits?

• 29:21Lisa Mosconi?

  Yes. And reductions in brain glucose metabolism, which is a sign of neurons not working as hard or as fast.

• 29:30Rich Roll?

  Interesting.

• 29:30Lisa Mosconi?

  As prior. And they are localized in some of the same brain regions that are clinically affected in patients with Alzheimer's disease. I need to clarify very clearly. We work with individuals who have a family history of Alzheimer's disease and/or genetic risk factors for Alzheimer's disease. So they have a high a priori risk for developing the condition, which is why we're trying to do early detection. We try to catch the earliest possible signs so that we can intervene right away. Once we look at individuals who do not have a family history of Alzheimer's disease, which we're doing now. We find a little bit of the same things, but not as significantly so.

• 30:11Rich Roll?

  So what conclusions can you draw about the genetic predisposition to Alzheimer's? And the ability or the agency that one has to sidestep that genetic predisposition? Like, in other words, like, how much is your genetic predisposition a driver of outcomes?

• 30:30Lisa Mosconi?

  It's very hard to quantify that. So when we talk about genetics, it's important to clarify what genetic mutations are and what genetic risk factors are, because they're very different. So genetic mutations are errors in your genetic code that lead to Alzheimer's. Currently, we know that there can be genetic mutations in three genes, the APP and the presenilin 1 and 2 genes, that are causative of Alzheimer's disease. These mutations typically run in families. You can track them down. And they prompt the symptoms of dementia quite early on in life.

• 31:12Lisa Mosconi?

  So they're called early onset autosomal dominant genetic mutations, where the affected family members develop dementia in their 30s and 40s, sometimes 50s, but early, usually before age 60. For everybody else, it's called late onset Alzheimer's disease. Even if it's 60, 62, if you do not have a genetic mutations, we refer to that as sporadic or late onset Alzheimer's. You can still have a family history, we just don't know which genes are involved, but not genetic mutations. We can screen that by doing genetic testing, which we do. In that case, genetic background is important, but in terms of higher and lower risk.

• 31:57Lisa Mosconi?

  It does not trigger Alzheimer's, does not cause Alzheimer's necessarily. And these genetic mutations are found in about 2, maybe 3% of all Alzheimer's cases, which means that for the vast majority of individuals with Alzheimer's, other factors are at play.

• 32:15Rich Roll?

  Yeah, it's a non-issue comparatively.

• 32:18Lisa Mosconi?

  So to try and answer your question, depending on the studies that we look at, there's evidence that between 20 and 50% of all Alzheimer's cases may be due to lifestyle.

• 32:31Lisa Mosconi?

  And medical conditions rather than genetic mutations for sure, probably in combination with some kind of genetic blueprint they were trying to unravel. But there is a strong lifestyle component that I think has been overlooked.

• 32:46Rich Roll?

  Right.

• 32:46Lisa Mosconi?

  In medicine for a long time.

• 32:56Rich Roll?

  Drilling down on that a little bit deeper, I gather from that that if you lack that genetic predisposition towards the mutation or otherwise, that does not obviate you from risk. If your lifestyle is a certain way, you can easily find yourself in that two thirds group. But if you are a member of that group, is there clarity around how adopting healthier lifestyle protocols can help you avoid that Alzheimer's manifesting? Like, those are two different things, right? Like, if you're in the out group and you don't have the genetic predisposition, you're still at risk.

• 33:36Lisa Mosconi?

  Yes.

• 33:36Rich Roll?

  Because obviously, the numbers prove that out. But with lifestyle, I assume you can opt out. But if you have the predisposition.

• 33:45Lisa Mosconi?

  If you have genetic mutations, lifestyle can help. It can delay the onset of dementia. It's hard to avoid dementia.

• 33:56Rich Roll?

  Okay, yeah, that's what I was looking for.

• 33:57Lisa Mosconi?

  Once you have that kind of mutations, they're causative. Yeah. But if you do not have those genetic mutations, lifestyle is more impactful.

• 34:06Rich Roll?

  Right.

• 34:06Lisa Mosconi?

  For sure. Also, something that has been on my mind for a little while is that there's a there's a genetic risk factor that's been publicized as being the Alzheimer's gene. And I think it's really important to clarify that it is not.

• 34:21Rich Roll?

  Is this the Chris Hemsworth situation?

• 34:24Lisa Mosconi?

  Yeah. So there's a genetic risk factor called the apolipoprotein E or APOE.

• 34:30Rich Roll?

  APOE.

• 34:31Lisa Mosconi?

  Gene, right? Then we all have this gene and it comes in three forms. There's an epsilon two form, there's a epsilon three, four, and there's an epsilon four form. And each one of us has two copies. Or the alleles, right? One from the mom, one from the dad. So if you have a 2, 2 genotype, that is considered protective against dementia, or the 2, 3 combination is protective. If you have a 3, 3 combination is neutral. But if you have even just one copy of the epsilon 4 allele, if you're a 3, 4 carrier, 4, 4 carrier,

• 35:13Lisa Mosconi?

  then your risk is higher relative to people who don't have that specific genotype. But it is not a genetic mutation. It does not cause Alzheimer's disease. It increases your risk, especially for women. Now, we know that gene has been quite well characterized and well studied. And if nothing else, I think we understand a little bit more what can reduce the odds of developing dementia for people who are carriers of the A P O E 4 genotype.

• 35:46Rich Roll?

  Interesting.

• 35:47Lisa Mosconi?

  Yeah, but I think it's important to say it does not mean that you are going to develop dementia. There are plenty of people who have dementia and do not have the A P O E 4 allele. There are plenty of people who have it and do not have dementia. So I think it's really important to understand that it's not a black and white situation and that you do have power over your genetics.

• 36:07Rich Roll?

  Right. I would assume that you would recommend that everybody get tested for that, though. We're going to get to testing later, but.

• 36:14Lisa Mosconi?

  I would not, I would not recommend, no.

• 36:17Rich Roll?

  Because it just rents space in your brain in a perhaps not so healthy way?

• 36:21Lisa Mosconi?

  I think that what we have learned from clinical practice is that the response to genetic information is very highly individual. Let's say if you find out you don't have it, then you're fine. But if you find out that you have a genetic risk for anything, not just dementia, but any kind of condition, some people take it well. They use it to motivate themselves to make healthier choices and take care of themselves even more. Other people have mixed reactions, maybe panic initially, but then they kind of go ahead and live with that. There are people who really become suicidal.

• 37:02Lisa Mosconi?

  So I think what I do recommend is that if you decide to do genetic testing, that genetic counselling is imperative. And this is the guideline of every professional society. There are a lot of people who come to us really, really in a panic because they did 23ME or something similar. And they find out that they have this A4 genotype. And then they hear on television that that is the bad Alzheimer's gene and that they're doomed, that they don't really understand the nuances. That's something that needs to be addressed.

• 37:38Rich Roll?

  Or conversely, if you find out that you are not at risk, then perhaps you're less enthusiastic about upgrading your lifestyle habits.

• 37:47Lisa Mosconi?

  Yeah, that could be so. But that's harmless, isn't it?

• 37:50Rich Roll?

  Yeah, yeah, yeah. Well, let's get back on track in terms of what you're beginning to discover about the XX brain, specifically with respect to menopause. And then I want to tie that to Alzheimer's as well. So as somebody is progressing into that menopause phase and they're experiencing those endocrine shifts, we've all heard about or, you know, people have experienced the hot flashes and, you know, all that, like, we're all kind of culturally aware of those things. But there's also some interesting benefits also that certain people experience.

• 38:27Lisa Mosconi?

  With menopause?

• 38:28Rich Roll?

  Yeah.

• 38:29Lisa Mosconi?

  Oh, yes.

• 38:29Rich Roll?

  In terms of what's happening cognitively.

• 38:32Lisa Mosconi?

  Yes. So something that I find it's been quite overlooked in medicine and culture is that menopause is not all doom and gloom. There are actually some positives that result from any neuroendocrine transition and I like to think about, especially for women's brains, I like to call them the three Ps, which is puberty, pregnancy and perimenopause, which is again a transitional phase before menopause. And what we have learned is that your brain changes during each one of these three Ps and also if you have multiple pregnancies, every time a woman is pregnant. And what happens is that there's a remodeling that takes place inside the brain.

• 39:17Lisa Mosconi?

  So when you have kids who are...

• 39:19Rich Roll?

  Yeah.

• 39:20Lisa Mosconi?

  My daughter is eight and she already knows everything about puberty and how her brain is going to change and what to expect and what not to expect.

• 39:27Rich Roll?

  I would expect nothing less from your child.

• 39:28Lisa Mosconi?

  Yes, but so what happens during puberty is that the connectivity of your brain really changes. And I'm telling you this because it matters for menopause as well. It matters in ways that not all parents enjoy necessarily, right? There's the reckless behavior, there's the temper tensions in some ways and there can be depressive states and the blues and the brain fog and this late too late and can't quite manage them. But that's the downside of a brain that is in transition and is in transition for a good reason. So the teen brain serves a very important evolutionary function, which is to connect

• 40:12Lisa Mosconi?

  some parts of the primitive brain, which are called hippocampus and amygdala, to the frontal cortex, where the primitive brain regions are more reactive, they're more impulsive, whereas the frontal cortex is in charge of impulse control and reasoning and thinking and planning, besides multitasking and language. And when these different universes collide is when the brain becomes mature enough to develop a strong theory of mind or mentalizing, which is the ability to put yourself in somebody else's shoes. And empathy as well really grows around this, there's interactions of different regions,

• 40:54Lisa Mosconi?

  which is key to become members of society, to be able to put your needs...

• 41:01Lisa Mosconi?

  To decide and prioritize the need of your group in a way, and just being able to work with us and other people and cooperate as well. Theory mind is very important for women's brains, because once you are pregnant, those same brain regions go through another remodeling, where in this case, the primitive brain regions get a bit of an upgrade. So they have more of a saying over your frontal cortex, which is extremely important if you're growing a baby who's physically helpless for years, right, so that they can grow their own big brains. And you, as a mother, number one, you have to protect them, so your aggression, the mama bear behavior can come up.

• 41:45Lisa Mosconi?

  But also, your theory of mind is super strong, because you need to be able to read the mental states of someone who has nonverbal communication only. Infants can't speak. So you really have to learn to read minds, quite literally. And the mommy brain can do that. It's neurologically wired to be able to pick up all these nonverbal signals and clues and just understand your baby's state of mind. And if there is a problem before there is a problem, anyone, you know, anyone can do. At the same time, that comes with some issues. We all know that there are depressive symptoms that can happen during pregnancy and during postpartum. Many women experience brain fog. We don't talk about it,

• 42:29Lisa Mosconi?

  but a lot of pregnant women have heart flashes as well. So those are very similar symptoms to menopause, because it's the same pathway. It's the same neuroendocrine system that is changing. So you have changes in body temperature. Puberty as a woman, because you need to have a menstrual cycle. So you need to increase your body temperature just a little bit around ovulation. So your brain is to be able to do that. With pregnancy, same thing. You need to activate your thermoregulation, because you have a burn in the oven, right? But then comes menopause, and all the system is dismantled. And so that comes with glitches that we know about, the symptoms and the medical risks,

• 43:12Lisa Mosconi?

  and the depressive symptoms and the anxiety and the brain fog. But at the same time, your brain is rewiring in a way that is quite beautiful and we never talk about, because the theory of mind network gets another update, another upgrade as well. And so what happens is then... Number one, life contentment. If you look at the graphs, women who are post-menopausal report greater happiness than women who are pre-menopausal and younger than they are, but also they report being happier than they themselves were before they went through menopause, which is quite interesting. And fits in with the notion that happiness follows a sort of U shape, right?

• 43:56Lisa Mosconi?

  With a little bit of a midlife slump, but then it goes back up, which is interesting. Number two, greater empathy. Again, it's the theory of mind network that is rewiring and ends up with greater empathy. So, post-menopausal women are the greatest empath. And if you measure empathy levels across, you know, at any age range in between genders, it's really the post-menopausal women that stand up, which is a beautiful way to think about aging and nurturing and just being able to take care of others. But then, there's one thing that I find so sweet. A lot of women tell me that after menopause, they kind of reach a state where they give fewer...

• 44:39Rich Roll?

  Yeah, they just don't give a fuck anymore. I mean, I think, I think what's, what's interesting about that is, it's all the more powerful, given our kind of cultural relationship with women as they age. Like, the fact that women post-menopause are actually happier in a culture that discards women at a certain age and has a unhealthy kind of relationship with how we think about older women, to me demonstrates how palpable that kind of theory of mind is at that stage of life. And then on top of it, from an evolutionary perspective, there's this grandmother effect thing, right? So, there is like a rationale behind why this is the case.

• 45:22Lisa Mosconi?

  Yes, there's a rational and there's a neurological explanation. So for the giving fewer F's, there's something very interesting that happens to the amygdala, to this reactive region, that basically just part of that gets turned down so that you do not respond to negative things or upsetting things as reactively as you used to. So you're able to sustain happiness for longer and just don't care too much about things that would have been upsetting otherwise. And this fits in with this theory that menopause is actually a good thing for women and also for humans as a species. So as a scientist, so for anyone who's born with ovaries, or anyone who knows women,

• 46:07Lisa Mosconi?

  I think that menopause is just a fact, that at some point you go through menopause and then you just stay in it for another third of your life or so. But in reality, as a scientist, menopause is a riddle because it goes completely against evolution, right? According to Darwin, who we know didn't love women very much, the only point to being alive is to reproduce a person via genes. So the fact that women stop reproducing at some point and don't die is effectively against his theories.

• 46:38Rich Roll?

  Yeah.

• 46:39Lisa Mosconi?

  I love that.

• 46:40Rich Roll?

  It's some kind of glitch in the system or vestigial in a way that nobody could make sense of.

• 46:47Lisa Mosconi?

  Nobody can make sense of it. Well, people have tried. So men have said or scientists have said.

• 46:53Rich Roll?

  Just go for it. Like, speak your mind. Come on.

• 46:57Lisa Mosconi?

  So there's the mismatch hypothesis that says that we should die after menopause, but modern medicine is increasing lifespan beyond what nature intended.

• 47:08Rich Roll?

  Artificially keeping all these women alive for no reason whatsoever.

• 47:11Lisa Mosconi?

  Why are we here? We're just kind of crowding. Yes. But then there's the opposite theory, which is called the grandmother hypothesis, that it takes a complete difference in menopause, which I find much more reasonable, and says... Women are helpful. Even if you're not reproductive, you can still be productive, and productive we sure are. And so Dr. Kristin Hawkes came up with this theory where she realized that it is effectively better for women to stop attempting childbirth once you reach a certain age because the risk of dying is higher the older you are, and also the risk of birth defects

• 47:56Lisa Mosconi?

  in the children offspring. So it is better to stop reproducing and take on a caregiving role where you effectively help your children have more children because you're still passing down your genes, not directly, but you're still promoting your genes to be passed on. And at the same time, what she was saying that I think is very smart is that those women back then were talking cavemen, their ancestors, those were the fittest women possible. Right? They had genes that number one kept them alive after multiple pregnancies, and they were likely more physically strong because they were able to make it to old age. It was very challenging to do that. And therefore, the genes that were being passed on were like a Wonder Woman's genes

• 48:41Lisa Mosconi?

  and genetic code that perhaps made these women's children also live longer and go through menopause and then take on the caregiving role that allowed their species to really multiply beyond any other animal species. So that's what she says.

• 49:00Rich Roll?

  Yeah.

• 49:01Lisa Mosconi?

  Grandmothers are actually evolutionary heroines.

• 49:04Rich Roll?

  It does make sense.

• 49:06Lisa Mosconi?

  Yes, I think it makes sense.

• 49:08Rich Roll?

  I want to get back to the scans which you were going to share, and I want to better understand the relationship between menopause and these endocrine shifts that are occurring in women and how that connects with the onset of Alzheimer's and other forms of cognitive decline.

• 49:26Lisa Mosconi?

  Mm-hmm. So these are the brain scans.

• 49:28Rich Roll?

  Yeah.

• 49:29Lisa Mosconi?

  I'll show you.

• 49:29Rich Roll?

  It's show and tell.

• 49:30Lisa Mosconi?

  Yeah, show and tell. So this is a kind of brain scan that I specialize in. So this is a positron emission tomography, or PET scans, that looks at the way that the brain takes up glucose and burns it to make energy in the form of ATP. An ATP is the energy currency of all cells. So what we're seeing here is a metabolically active brain, where the red parts indicate very high brain glucose metabolism, high energy levels. And the blue in the middle indicate no metabolic activity because there's fluid inside the brain, which we need to have, right? It's for cushioning, for hydration, for protection.

• 50:15Lisa Mosconi?

  But what we need to look at is the brain. So anything that is red, yellow, or green is brain tissue. And this is a very healthy-looking brain. So this brain belongs to a woman who was 43 years old when she worked with us the first time, when she got her first brain scan. And you want your brain to look pretty much like that. You want this part of the brain, which is the frontal cortex, in charge of thinking and reasoning and planning and language and multitasking as well, to be really in the red range. And this part in the back of the brain, which is back here, to be pretty much as red. So it's like an inverted triangle shape. And this is the precuneus and posterior cingular cortex, which is important for social cognition,

• 51:01Lisa Mosconi?

  for example, has a sort of integrative role and also autobiographical memory. It helps you remember things that you have done. So it's the memory of you that's a little bit in this part of the brain. And then you want the left side, we're looking at the brain from the top, so the nose would be here and the ears would be on the side. And this is the back of the head. You want the left side to be broadly as bright as the right. You want to have symmetry.

• 51:28Rich Roll?

  Symmetry.

• 51:28Lisa Mosconi?

  Beautiful. So this is a beautiful-looking brain for 43 years old. We kept doing brain scans. As this woman got a little bit older, she was pre-menopausal at this stage, so regular menstrual cycle. She went through menopause fairly quickly, sort of, within like eight, nine years, which is not fast by any definition, but biologically it is. And now I think you can see how the intensity changes in different parts of the brain, where the red turns yellow and the yellow turns green and this is gonna loop and start again, right? So you see there's a lot of red that just kind of fades away. Not completely, obviously,

• 52:13Lisa Mosconi?

  but there is clearly a shift. And I'm now going to put this side by side. And they think it's quite clear that the before and after scans are effectively different. You can see there's a lot more green here.

• 52:28Rich Roll?

  Hmm.

• 52:29Lisa Mosconi?

  Now, quantitatively, that's approximately a 20 to 30% reduction in brain glucose metabolism, which is one of the best measures we have for brain energy levels. Now, why is this important? For a couple of reasons. Number one, the people don't take women seriously. When we go through menopause and say, I don't feel well, I don't feel like myself, I feel like I'm losing my mind, right? There is an actual biological correlate to that. So basically, what we're doing is that we're validating what women have been saying for centuries or longer by showing evidence that we're not making things up. It's not your imagination, it's not fiction.

• 53:12Lisa Mosconi?

  There's an actual change that's happening and that can happen inside the brain. Now, you might think, is that just the only woman who shows this? Right? No.

• 53:21Rich Roll?

  Sorry to interject, but quickly, just to clarify, it's also not a situation where there's a change and then it snaps back to some kind of homeostatic state that it was before, which I think is a kind of persistent misunderstanding. Like, you go through menopause and then you reset to some balance point. There's a before and an after where you don't return to the way the brain was before.

• 53:46Lisa Mosconi?

  Yes, there is such a scenario. So this was one of the very first studies that we did, and we only had the before and after, but we keep scanning our participants, those who allow us to do so, of course, we're very grateful, for longer.

• 54:01Rich Roll?

  Hmm.

• 54:01Lisa Mosconi?

  And we did publish this, that it depends. So this seems to be quite the average change, although some women do not show these changes, but just very mild or no changes, and some women show more severe changes. So there's a range already here. But then what happens after that is quite interesting. So this is the typical scenario, right? Pre-menopausal, perimenopausal, and then for some women, that's it. The brain finds a new normal and stabilizes, and that is your new baseline.

• 54:37Lisa Mosconi?

  At least in terms of metabolic activity. For some women, there is a little bit of a rebound in some parts of the brain. I have not seen brains that go back to the pre-menopausal levels. But we're also older at that point. But when there is a little bit of rebound, that also seems to correlate with the fact that the symptoms go away, that your memory is clearer, that you're more like yourself and you feel overall better. Some women keep declining. Those are the people that we really recommend Alzheimer's prevention for. So I think that's a good time to think about prevention and what we can do to make sure that is not going to lead to more serious issues.

• 55:22Lisa Mosconi?

  And I want to preempt it. I'm not aware of any other studies that have shown this yet. So I would love for other scientists to do what we're doing and track women over time, starting in midlife, so that we can compare notes. Right now, all the evidence we have is from, kind of, from us.

• 55:39Rich Roll?

  Is there a sense of what accounts for the differential between and amongst women in terms of symptomology and their experience, you know, through this process? Why it's severe for some and mild for others?

• 55:53Lisa Mosconi?

  There are many indications, and we have some information, that the type of menopause, for instance, matters. Now, we think of menopause as a single entity, but that is really not the case. So women go through menopause for different reasons. Usually, when we talk about menopause, we're thinking spontaneous menopause, which is part of the aging process. Just your ovaries run out of follicles and eventually you stop making these hormones and then you just transition to menopause, which is not a piece of cake necessarily, but is the gentlest way, is the most gentle way to go through menopause. Many women, unfortunately, go through menopause for other reasons.

• 56:36Lisa Mosconi?

  Some women have something called POI, primary ovarian insufficiency, which is when you develop menopause before age 40 or 45. So quite early on in life. That could be due to genetics, to autoimmune conditions.

• 56:53Lisa Mosconi?

  Or to medical interventions that impact the onset of menopause. So sadly, one in eight women in the United States undergoes a hysterectomy, which is the surgical removal of the uterus with or without the ovaries. And about half of those women undergo hysterectomy before menopause. That can prompt surgical menopause at any age. It can happen when you're a teenager, if you have the ovaries removed at that time. Yes, it can happen in your twenties, in your thirties, in your forties, any age, before menopause. Because it's a surgery, the ovaries are gone.

• 57:35Lisa Mosconi?

  Then the onset of menopause is obviously abrupt, is rapid, and the consequences might be more severe. So the symptoms might be more severe and the health risks that menopause can bring about are also more severe. That's very important to consider because we don't do that enough.

• 57:54Rich Roll?

  Is there a study that tracks women who have had hysterectomies and developed Alzheimer's later in life?

• 58:00Lisa Mosconi?

  Yes.

• 58:01Rich Roll?

  And what does that ratio look like?

• 58:04Lisa Mosconi?

  Well, the studies show is that women who undergo menopause because of surgeries have a higher risk of Alzheimer's disease and dementia as compared to women who go through menopause spontaneously. The risk is just a little bit higher if only the uterus is taken out, but it's significantly higher if the ovaries are taken out before menopause. And I'm hoping that we're going to talk about hormone replacement therapy because it is helpful.

• 58:33Rich Roll?

  Yeah, we are. We're moving in that direction. I definitely have a lot of questions about that.

• 58:37Lisa Mosconi?

  Thank you. I'm always worried that I'm not going to.

• 58:39Rich Roll?

  Yeah, no, no, no. Go ahead.

• 58:41Lisa Mosconi?

  One more category of women that really don't get much attention sadly are women who go through menopause, medically induced menopause because of chemotherapy and radiation. Those are women who have a history of breast cancer or ovarian cancer or endometrial cancer. And very often, the endocrine treatments that are used, that we use, stop menstruation. Sometimes it's only temporary, scolddermenorea. Sometimes it's permanent. So they may end up developing menopause because of that. Which is really unfortunate and they suffer that we don't have.

• 59:17Lisa Mosconi?

  A better grasp on how to do things differently or that could lead to different outcomes and what do we do for treatment? So this is something that really needs to it needs to become more of a topic of research and medical.

• 59:31Rich Roll?

  Yeah, I mean, I do want to ask you about studies you'd like to see done that you feel are most pressing or urgent in this field. And that feels like that would be one for you. When we talk about Alzheimer's and dementia, cognitive decline, I want to better understand the differences amongst these things. Like, what is Alzheimer's exactly? How is it different from what we would call dementia or other forms of perhaps just natural mental or cognitive decline that comes with age?

• 1:00:09Lisa Mosconi?

  So dementia is an umbrella term that includes many different disorders that negatively affect cognition. So there are many different forms of dementia that are defined based currently based on symptomatology and histopathology. So define whatever happens inside your brain in terms of lesions is used to characterize one form of dementia from another. Alzheimer's disease is the most common form of dementia and is defined at autopsy by the presence of very specific lesions. Amyloid beta fibrils or plaques, Alzheimer's plaques. Neurofibrillary tangles, which are tau pathology, mediated damage inside the neurons.

• 1:00:54Lisa Mosconi?

  So the plaques are between neurons and impair communication, whereas the tangles disrupt the neurons from the inside. So it's like a double attack on neurons from the outside and the inside. And then there is neuronal loss as a result and synaptic deterioration, where neurons can no longer communicate effectively with each other. And then the symptoms of Alzheimer's are predominantly memory based. So there's severe memory loss, but there's also loss of attention. There's loss of language. There's loss of sense of direction. And in the end, you have a problem with daily living activities where you just can no longer take care of yourself. So Alzheimer's disease is a

• 1:01:38Lisa Mosconi?

  It's a neurodegenerative disorder that is silent, has a silent onset. It's in your brain for many years before the symptoms show up on clinical examination. And that basically makes you become debilitated slowly over time.

• 1:02:03Rich Roll?

  On some level, there's shared DNA between cardiovascular disease and neurodegenerative disease in the sense that these are diseases that build up over decades. We think of dementia as an old age disease, but honestly, it just manifests at that stage of life, and it is the result of things building up over a great period of time. To what extent is dementia a result of circulatory disease in the way that cardiovascular disease is? Because when you think about lifestyle, and we're going to get into that, and diet, and chronic inflammation, and all these sort of things that contribute to heart disease,

• 1:02:46Rich Roll?

  America's number one killer, it would seem that there's an extreme amount of overlap in terms of how that's affecting brain health, for better or worse.

• 1:02:55Lisa Mosconi?

  Yes. So there's a form of dementia that's called vascular dementia, that is more specifically related to cardiovascular and heart issues, and very often overlaps with Alzheimer's disease. We talk about Alzheimer's as being one thing, but in reality, most people have a mixed type of pathology. There's a lot of different things that can happen. And cardiovascular health is extremely important for brain health. And having heart disease and different risk factors for heart disease are in turn risk factors for Alzheimer's disease dementia as well.

• 1:03:34Lisa Mosconi?

  So I think that there's a strong lifestyle component to dementia. And a lot of people in the United States of America live lives that are quite sedentary and include components that are quite pro-inflammatory, like you said.

• 1:03:55Lisa Mosconi?

  And those are all things that are within our power to change and mitigate and work on that could also significantly impact our chances of developing dementia or not. So I think it's really, prevention is key when it comes to Alzheimer's because once you have Alzheimer's disease, there's only so much we can do. So the drugs that are approved right now are mostly symptomatic drugs like acetylcholinesterase inhibitors or memantine. They slow down progression for a little bit. They can alleviate the symptoms for a little bit, but they do not reverse the disease nor do they stop it.

• 1:04:31Rich Roll?

  Nor are they all that efficacious, right? I mean, there's a lot of room for improvement there. I mean, it's a whiplash situation because on the one hand, we're seeing the numbers in terms of Alzheimer's and dementia going through the roof. It feels like everybody, you know, has somebody in their life who's being impacted by this disease. There's a lot of fear amongst people in my age bracket about what might come, you know, for ourselves. And it's scary.

• 1:05:01Lisa Mosconi?

  Yes.

• 1:05:01Rich Roll?

  Also, if you're a woman, knowing that menopause is something that you're going to undergo no matter what, and that there is this connection between what's occurring in the body and how that relates to what's happening in your brain and what may happen later is a frightening prospect. But at the same time, to your point, I think there's been this narrative that this is a genetic predisposition and there's very little that you can do about it.

• 1:05:27Lisa Mosconi?

  Right.

• 1:05:28Rich Roll?

  And the truth is that we have great agency over the extent to which any of these disorders are going to manifest, if at all. And these decisions that we're making now, understanding that that these diseases are taking root for decades before they they truly show up and impact us in negative ways, is a call to action, but also encouraging because we do have

• 1:05:54Rich Roll?

  Control over the arc that our brain is going to take. So let's talk about that. We were talking before the podcast. You've written three books in a very short period of time. You've been incredibly prolific with sharing your wisdom, experience and knowledge. But curiously and interestingly, your first book was called Brain Food. Like, and I was like, shouldn't that be the third book? Like, first you do the neuroscience and then you do kind of like the protocol. But you came out of the gate first to address lifestyle in terms of brain health. Clearly, you know, diet is important, as is exercise. We'll get into all of these, but maybe let's start with diet. Like, if you're concerned about your brain, as everybody should be.

• 1:06:36Lisa Mosconi?

  Yeah.

• 1:06:36Rich Roll?

  We should be deeply mindful of what we're putting in our mouth a couple of times a day.

• 1:06:41Lisa Mosconi?

  I completely agree. And also to look back to Alzheimer's disease and contextualize lifestyle and diet in particular, or other things as well. All women go through menopause, but only, in quote, 20% develop dementia. So I think this is important to clarify because it's not like menopause causes dementia, right? It's something that increases your vulnerability.

• 1:07:05Rich Roll?

  If I created that impression.

• 1:07:06Lisa Mosconi?

  No, you did not. I did. And it happens. And that's why I want to clarify this. That means that there are other factors at play, right? Because if menopause gave you dementia, then that would be it. But in truth, not all women, obviously, develop dementia. So it's important to understand that there are things that you can do to mitigate your risk and make sure that you don't get dementia. I just want to say, because I don't want to be absolute like menopause Alzheimer's.

• 1:07:33Rich Roll?

  Right, right, right.

• 1:07:33Lisa Mosconi?

  I just don't want to care anybody and make it more.

• 1:07:36Rich Roll?

  No, that's a very important point. I guess, would it be fair to say that the endocrine system and neurological shifts that occur as a result of menopause create a greater susceptibility to Alzheimer's?

• 1:07:48Lisa Mosconi?

  Yes, thank you. That's exactly, that's exactly the point. No, it does not cause dementia. It just increases vulnerability, I believe.

• 1:07:56Rich Roll?

  Yeah.

• 1:07:56Lisa Mosconi?

  Okay.

• 1:07:57Rich Roll?

  And.

• 1:07:57Lisa Mosconi?

  Thank you. I always want to make sure it's clear because I don't want people to make choices based on an assumption that I wasn't. Clarifying enough, so, thank you.

• 1:08:10Rich Roll?

  I think we're clear. So, diet. First, let me just say, of all these lifestyle choices and interventions, is there a hierarchy in what's most important? Or are they all working in concert with each other?

• 1:08:22Lisa Mosconi?

  I think it's a combination of things that becomes really important, because you can eat all the broccoli you want, but if you're super stressed, you don't sleep, you don't exercise, there's only so far the broccoli can take you, even though they are very helpful, and the other way around. So I think it's multifactorial, and most preventative efforts are, in fact, based on a combination of different things. In my hands, when we tried to rank different lifestyle factors in terms of outcomes, measurable outcomes in the brain, diet usually comes up on top. Sometimes, exercise.

• 1:09:02Rich Roll?

  Yeah, I thought it was exercise. But I guess it depends on how you look at it.

• 1:09:06Lisa Mosconi?

  In our studies, at least statistically, diet played a big role. And that's what brought me to write Brain Food and really focus on diet more. Exercise is a big deal. And what we tell patients to start with when we talk about prevention, if you only have time for one thing, exercise. Because especially the kind of aerobic exercise, like you do, it really stimulates blood flow to the brain, seems to be almost like an immediate health boost for brain health, so you can get results quickly. However, diet is important, because most people eat at least three times a day, every day, which means that we have at least three chances every single day

• 1:09:50Lisa Mosconi?

  to make a smart decision and nourish our brain in a way that is also protective against Alzheimer's disease, dementia, aging, and whatnot. Or the opposite, and really create problems for your body and brain health at the same time. So diet is powerful. I think it's very powerful. We're constantly bombarded by chemicals that are being released in the environment, including our foods, that we probably don't quite appreciate the kind of damage that can do for you. So I think it's important to-

• 1:10:23Rich Roll?

  Right. There's toxins in our home care products, our cleaning products-

• 1:10:27Lisa Mosconi?

  Postcards.

• 1:10:28Rich Roll?

  And our packaging and all the like, but just to stay on food for a little bit, understanding that there are a lot of battles being waged on the front lines of the diet wars. Choose your words carefully.

• 1:10:38Lisa Mosconi?

  On social media, not in academia.

• 1:10:41Rich Roll?

  What do we know about food and brain health? You call it neuro-nutrition.

• 1:10:48Lisa Mosconi?

  Neuro-nutrition.

• 1:10:49Rich Roll?

  How do we eat to fuel our brains?

• 1:10:53Lisa Mosconi?

  We eat in a way that is based on chemistry, because food is not food. Food is information and food is biochemistry and your brain needs to want the food that you give it. So the brain is a very interesting organ in that some nutrients and some substances can get inside the brain easily by passive diffusion like alcohol and caffeine, but most nutrients cannot. There are very specific gates in the brain that only allow specific nutrients in when the brain needs them. So it's an active choice from your brain to utilize some nutrients or not. And I think this is important in the field of brain nutrition, because I think there's

• 1:11:38Lisa Mosconi?

  a little bit of misinformation sometimes, that when I started writing brain food, I didn't use social media at all back then. So it was a little bit shocking at first. But there was a theory going around that the brain is made of fat, especially cholesterol. Therefore, you need to eat foods that are rich in cholesterol to feed your brain. And I was like, what? Though it's important to understand neurochemistry, the brain makes its own cholesterol. It makes it when we're born. And as soon as possible, it shields the cholesterol away from the rest of your body.

• 1:12:23Lisa Mosconi?

  So no cholesterol from diet will ever get inside your brain unless your blood brain barrier is compromised. And then there are different things to worry about at that point. But for as long as your brain is healthy and self-sufficient, no cholesterol from whatever meat you eat will get inside your brain. So that's one important thing. Fat, same exact problem. Saturated fat can get inside the brain, but the brain doesn't really want it after adolescence. The saturated fat gates do not open as often. And we see with the brain tracers, because we try to make the traces lipophilic, which means that they bind to fat so that they can get inside the brain more easily.

• 1:13:08Lisa Mosconi?

  And it's very hard to do it because some fats just don't get in. It's really hard. You can't push stuff inside your brain. The brain needs to want it. And the kind of fat that the brain wants is polyunsaturated. So the omega threes, the omega six. Plant-based foods have a lot of really good building blocks for the omega threes and the longer omega six and omega sixes. So that's the kind of fat that your brain wants that I think we would want to prioritize in our diet.

• 1:13:38Rich Roll?

  Right, the brain runs on fat. You should be eating a high-fat diet, high in cholesterol, because the brain needs that cholesterol. Nonsense.

• 1:13:46Lisa Mosconi?

  Nonsense.

• 1:13:46Rich Roll?

  Okay, thank you for that. You've advocated for a Mediterranean diet approach to nutrition with an emphasis on greens, like a sort of, you know, pro-turbo-green version of the Mediterranean diet, which is really kind of a plant slant focus on the Mediterranean, perhaps a little bit away from the higher fat or the fish and more on the dark leafy greens and...

• 1:14:13Lisa Mosconi?

  Yes, like lean protein as well that comes from vegetables. That's what this kind of greener Mediterranean diet prioritizes. But I... I think it's not about a specific diet or another. It's really about the kind of nutrients that your brain wants and needs. And it's about making sure that you have this kind of nutrients from whatever sources you like. So you're plant-based, right? Great, so let's make sure that your diet includes all these different nutrients that your brain really thrives on. So antioxidants, easy on a plant-based diet. For me personally, the most important nutrient group for brain health is antioxidants. Why?

• 1:14:57Lisa Mosconi?

  Because the brain is the most metabolically active organ in the body, and it runs on glucose. So glucose is the main energy source for the brain. And when you burn glucose to make energy, inevitably oxidative stress is formed. And free radicals can damage your brain. And the only way that you keep them at bay is to import antioxidants from your diet. So the most important antioxidants for brain health, at least the best studied, are betacarotene, which is the precursor to vitamin A, and then vitamin C, and vitamin E, and selenium, which is a rare mineral that's found in Brazil nuts.

• 1:15:38Rich Roll?

  Brazil nuts, yeah.

• 1:15:41Lisa Mosconi?

  So these antioxidant nutrients are found exclusively in plant-based foods.

• 1:15:47Rich Roll?

  So if you're eating a carnivore diet exclusively meat, you're depriving yourself of those nutrients?

• 1:15:54Lisa Mosconi?

  Then it is important to supplement. Meat in general does not include... I think the antioxidant levels would be very low. So in that case, I think it would be really important to supplement when at least the multivitamin.

• 1:16:10Rich Roll?

  But I do have some...

• 1:16:12Lisa Mosconi?

  Antioxidants are important for brain health, no matter your diet.

• 1:16:14Rich Roll?

  So Brazil nuts. But what are some of your favorite high-antioxidant foods that you would recommend?

• 1:16:20Lisa Mosconi?

  So my daughter, I'm very, very lucky. She loves fruits and veggies. She's a high-carb girl spontaneously. So we have all sorts in the house and I like to go seasonal. So right now, persimmons. We found this kind of persimmons that are cross with apples. So they're a little crunchy. The orange, so any orange produce contains beta carotene. Almost don't contain beta carotene or some form of vitamin C. So I would say, you know, lemons are a fantastic source of vitamin C and also citric acid, which is really good for digestion. Oranges, grapefruits, it's winter, at least in New York. So those are the fruits you find. But even apples contain antioxidants and blackberries.

• 1:17:05Lisa Mosconi?

  Most people think about blueberries, but blackberries actually have a higher antioxidant content. The blueberries, goji berries are a great source of vitamin C. Amala, the Indian gooseberry is probably the highest antioxidant capacity of all fruits.

• 1:17:23Rich Roll?

  Oh, I didn't know that. What about meringue?

• 1:17:26Lisa Mosconi?

  Meringue citrifolia, yes.

• 1:17:27Rich Roll?

  Yeah.

• 1:17:28Lisa Mosconi?

  That also is good. Mulberries, and they taste like honey, which is really sweet. It's a good snack. Prunes.

• 1:17:36Rich Roll?

  Prunes?

• 1:17:36Lisa Mosconi?

  Prunes, they have a good amount of vitamin C, antioxidants and soluble fiber.

• 1:17:41Rich Roll?

  So our grandparents and great grandparents, at least in America, drinking their prune juice. They knew what was up?

• 1:17:47Lisa Mosconi?

  Yeah, the juice depends what's left in the juice, right? But the prunes are good. You can soak them in water. We do it. It's a very European thing to do, by the way. You soak them in water and then they're like little dessert. They're yummy. Nuts and seeds and green leafy veggies, leafy greens are also really good sources of vitamin C. So broccoli, kale, cruciferous veggies. The more, the better. I think really you can't go wrong with fruits and veggies.

• 1:18:19Rich Roll?

  What is the efficacy of supplementation? We could start with antioxidants. I mean, you can go and get resveratrol or turmeric in capsule form. I'm always curious, like, is this doing anything? Obviously, it's always better to digest your nutrients within the matrix of the food that they come with. But I'm curious if there's any understanding about the usefulness of supplementation of individual nutrients in that way.

• 1:18:51Lisa Mosconi?

  There's some understanding. And I think, at least in science and academia, we advocate for what you just said, which is that supplements cannot replace a healthy diet. Supplements are helpful once you are deficient in specific nutrients or your levels of some nutrients are low from a clinical perspective. Even if you're not deficient, they could be below average. And you think that they might be helpful in that respect. Oversupplementing does not seem to be helpful. So there's only so much of these vitamins that your body needs. Some are fat soluble, so they store in tissues and fat.

• 1:19:35Lisa Mosconi?

  So you can build a reserve. But high doses can be toxic. I mean, they have to be really, really high. So in general, what we try to do is to establish a baseline. It's really helpful to do labs, right? If there's any indication that somebody might be deficient in some nutrients, because maybe the diet isn't as healthy or there are medical conditions like arthritis, IBS, Crohn's disease, like where you can't really absorb the nutrients as easily because of digestive issues, then you want to run tests and check. The level of specific nutrients with vegan diets as well. It may be helpful to measure some of the nutrients like the fatty acids or,

• 1:20:20Lisa Mosconi?

  you know, whatever you're concerned about. And then if you're low, then it makes sense to supplement.

• 1:20:25Rich Roll?

  Right.

• 1:20:25Lisa Mosconi?

  Otherwise, it doesn't seem to be beneficial.

• 1:20:27Rich Roll?

  What, what?

• 1:20:28Lisa Mosconi?

  For brain health.

• 1:20:29Rich Roll?

  What are common deficiencies that somebody who is menopausal or post-menopausal might experience? And with respect to whatever those common deficiencies may be, is there an understanding of how they might be connected to Alzheimer's?

• 1:20:46Lisa Mosconi?

  Hmm. I do not think the menopause has been linked with nutritional deficiencies, but calcium could be low. And we tend to to recommend calcium and vitamin D supplements for bone health. Has that been related to Alzheimer's? It is not really. But again, we have so little research on menopause that I think this is a little bit. Maybe at some point, there will be research. So, lack of evidence does not mean that there's no benefit, just that the research hasn't been done in that respect. In our hands, I can tell you, we've done some studies and I would love to do more. But we have shown a positive associations between a higher intake of antioxidants

• 1:21:30Lisa Mosconi?

  and these brain scans in women of menopausal age, pre-menopausal, perimenopausal. It seems to correlate. So, the more antioxidants you have, the higher your brain energy levels, which is something that we want to.

• 1:21:43Rich Roll?

  Yeah. And then omega three. If you do nothing else to increase the amount of antioxidants in your diet every day.

• 1:21:49Lisa Mosconi?

  I think that is very, because as you do it.

• 1:21:51Rich Roll?

  I mean, you should do that anyway.

• 1:21:52Lisa Mosconi?

  Yes. And as you do it, it means you're prioritizing foods that are good for you to start with. Right? So, you also get the fiber. I like to say the fiber is like the name of the game in women's health, which is maybe an overstatement, but it is very important for women's health for a number of reasons. Number one, it helps your gut microbiome, right? It's really important for digestive health, as we all know. But also. It modulates the action of the sex hormone binding globulin, which is that protein that regulates how much free testosterone in men and women, and free estrogen we have in the circulation.

• 1:22:32Lisa Mosconi?

  So it helps shuttle estrogen and other sex hormones where they are needed. And fiber has a positive effect on this specific substance. So it also has a positive effect in estrogen levels. And also, eating carbohydrates or plant-based foods is important to support the astrobolome. So, you know, there's the gut microbiome. That is not just one big family of microbes and whatnot, but is the city with many communities living in the city. And one of the communities is the astrobolome, which is made of good, friendly bacteria that are involved in estrogen metabolism.

• 1:23:17Lisa Mosconi?

  They help regulate estrogen levels. There's one enzyme in particular, it's called beta G U S, that's been investigated right now. This seems to have a modulatory effect. So estrogen, like any substance, stays in your bloodstream for a certain amount of time, and then it's either reutilized or is expelled. And this part of your microbiome tends to help decide whether you need more estrogen, so it keeps it in your circulation for longer, or not. And so you want these bacteria to be happy and healthy, because they are helpful to you in return. And the best way to do it is to eat plants, because they feed on plants.

• 1:24:01Lisa Mosconi?

  And especially oligosaccharides, which are a type of carbohydrates that comes from plant foods. They're slightly bitter, like onions.

• 1:24:10Lisa Mosconi?

  And asparagus and beetroot and ginger.

• 1:24:14Rich Roll?

  Yeah, yeah.

• 1:24:15Lisa Mosconi?

  And they're really helpful in that respect as well.

• 1:24:18Rich Roll?

  That's interesting.

• 1:24:18Lisa Mosconi?

  So there are many ways that you can use diet to support hormonal health and of course, phytoestrogens.

• 1:24:24Rich Roll?

  Mm hmm. Most people are fiber deficient in their diet.

• 1:24:27Lisa Mosconi?

  Yes.

• 1:24:28Rich Roll?

  And it's a pretty easy fix.

• 1:24:30Lisa Mosconi?

  Yes.

• 1:24:30Rich Roll?

  All you have to do is just incorporate more plants into your diet and more diversity of those plants. And it seems curative in that regard. But understanding that and the relationship with hormone regulation in your microbiome is kind of fascinating. And it speaks to the emerging complexity and understanding that we're only beginning to develop around the microbiome and its impact on every sort of biological system in our body, not the least of which is the gut-brain access. Like this communication between our microbiome and our gut and what's happening in our brain

• 1:25:11Rich Roll?

  is nothing short of fascinating, dictating everything from cravings and impulses to modulating all of these unconscious systems that were running in the background.

• 1:25:23Lisa Mosconi?

  Mm hmm. Anxiety.

• 1:25:25Rich Roll?

  It's unbelievable, right? That the culture of your microbiome could dictate the cravings that you have, like sending these impulses to the brain about what you would like to eat, thinking, well, my body's telling me I need this. And it's like, well, your microbes are.

• 1:25:41Lisa Mosconi?

  Mm hmm. I think it's fascinating and it really goes against a lot of things that I was taught in school, which is that the brain is in charge of the rest of the body, but is relatively unaffected by what happens from the neck down, which turns out to be completely wrong.

• 1:25:59Rich Roll?

  Yeah, it sort of makes inroads on our degree of sentience, right? Like who's making the decisions up here and why, right?

• 1:26:08Lisa Mosconi?

  Yes.

• 1:26:08Rich Roll?

  Which is humbling, I guess.

• 1:26:10Lisa Mosconi?

  It's humbling, but also I think it gives you power because then you can effectively help your brain. But if you know what kind of factors go from the bottom up, then you can do all the things that your brain could benefit from. And I think this is very empowering. It's much more interesting than just saying it is what it is and you have no power over your your brain health.

• 1:26:36Rich Roll?

  Let's talk about exercise.

• 1:26:37Lisa Mosconi?

  Let's talk about exercise.

• 1:26:38Rich Roll?

  You you sort of referenced, you know, low intensity, consistent movement as the most beneficial.

• 1:26:48Lisa Mosconi?

  Moderate intensity.

• 1:26:49Rich Roll?

  Moderate intensity. That's like hiking.

• 1:26:52Lisa Mosconi?

  It's when you can talk, but you would have a hard time singing.

• 1:26:56Rich Roll?

  We call it zone two around here.

• 1:26:57Lisa Mosconi?

  Oh, my goodness.

• 1:27:01Rich Roll?

  Why do you laugh?

• 1:27:02Lisa Mosconi?

  Thank you, thank you. So, okay.

• 1:27:04Rich Roll?

  Is there a sense that that's really what the focus should be? Like, do we do we know? Or is there something we still need to learn about what high intensity exercise does to our brain? The differences between something like strength training or resistance training versus that low intensity or moderate intensity in terms of what's happening in our brain? Like, do we have scans on that over time that tell us anything interesting?

• 1:27:33Lisa Mosconi?

  No, when I was talking about the moderate intensity exercise, it comes from studies that specifically looked at health outcomes in women in menopause. And what they have shown is that there's an inverted U curve between intensity and gains, but not fitness gains, rather a reduced risk of cardiovascular conditions, a reduced risk of diabetes, a reduced risk of obesity. And what they showed is that, obviously, if you if you don't exercise at all, there's no improvement in health. But as you start exercising and this is intensity, a low intensity, there are some benefits. Moderate intensity, there are more benefits.

• 1:28:16Lisa Mosconi?

  But then, once you start going high intensity, the benefits go down. Now, why is that? I think this, remember, these are observational studies. They're not clinical trials. So what I think they're capturing there is that moderate intensity activity is more sustainable.

• 1:28:34Lisa Mosconi?

  For women who are of menopausal age. Well, obviously, if you don't move, you can't expect benefits. But there is some evidence that high intensity exercise does not work for all women after menopause because of a sort of interaction between the fact that adrenaline would be increased and perhaps cortisol would be increased and that has a negative effect on your sex hormones at the same time. Or maybe just the fact that it's hard to sustain over time. So what I was trying to say at that point is that obviously if you can do more, do more. If it works for you, great. But many women are discouraged by what they hear on social media or television

• 1:29:19Lisa Mosconi?

  that you have to do all these difficult things that are very intense. And they just don't do anything at that point. Or they try and hurt themselves or the recovery takes too long and then you're sore all over and you haven't slept, your muscles don't have the time to rejuvenate. Is that a good word? So if you stay in your zone two, it seems to be more sustainable and more doable. And that might be linked to better health outcomes. So the bottom line is just don't be too hard on yourself. You know, if walking is your thing, do it. If dancing is your thing, do it. If running is your thing, great, whatever works, as long as it's something you can sustain over time.

• 1:30:03Lisa Mosconi?

  Because the truth is, when it comes to brain health, quick fixes don't work. They just cannot. Because from the neck down, our bodies are engineered for change, right? If you think about cellular turnover, blood cells renew every few weeks. Even the skeleton is renewed at the rate of 10% a year. So your body can respond to changes quickly. And if you go on a diet, if you start exercising, you can see the changes relatively fast. Not so much in the brain because the brain is built for stability. Our neurons, the vast majority of our neurons are born with us and stay with us for a lifetime.

• 1:30:47Lisa Mosconi?

  And they are very, very protected from changes in the environment, from changes in the diet, from changes in your exercise activity. Because if every time we went on a different diet, that had an immediate impact on our brains, we would all be crazy.

• 1:31:00Rich Roll?

  Yeah, we'd be lunatics.

• 1:31:02Lisa Mosconi?

  We would be lunatics. Can you imagine? It would damage our brains very easily. That can be. So lifestyle changes are important and are impactful, but they only, they have a gentle effect on your brain, which means that you have to build up the effects over time. And that's why consistency is key. Right? You can go to the gym two weeks.

• 1:31:26Rich Roll?

  The best exercise is the one you're actually going to do.

• 1:31:29Lisa Mosconi?

  Yeah.

• 1:31:30Rich Roll?

  Yeah, time and time again. Is there an idea around, I mean, it's never too late, but I'm imagining the person who's listening to this or watching and thinking, well, you know, I don't know, I've just never done anything and now I'm 65 and like, it's kind of said and done. Like, is there a sense that if you could pick up these habits later in life, even if it's a situation where these amyloid plaques have been building up, where you can, through lifestyle, slow it or hit the brakes on it? Or is there a point of no return? Obviously, it's going to depend individually and all of that, but...

• 1:32:05Lisa Mosconi?

  But honestly, exercise helps also patients who have Alzheimer's disease. It really has a positive effect on their mental health for sure, but also on cognition. You can see that in patients with dementia who work with a trainer sometimes. I know quite a few, and it really has an impact. So if you don't have dementia, the impact is much more obvious, I would say. And it is true that it's never too late. It's never too late to start. I would love to see more clinical trials that really are done by age. But I also think that exercise and the type of exercise you decide to do can help your brain in different ways. So we know, for instance...

• 1:32:50Lisa Mosconi?

  Aerobic exercise is really good for cognitive health. It seems to be giving the strongest boost to neuronal health because it stimulates so many different parts of your brain in different ways. But it's also important for thermal regulation. So for instance, when women are having hot flashes and night sweats, then aerobic activity can really help mitigate those symptoms, which I think is really important. There are studies showing that women who are physically active in midlife have almost up to 50% fewer hot flashes than women who are sedentary.

• 1:33:26Rich Roll?

  Oh, wow.

• 1:33:26Lisa Mosconi?

  And also, there are studies that followed hundreds of women for many, many years, up to 40 years. And they showed that women who were physically active in midlife more with a cardiovascular fitness style of exercise had a 30% lower risk of dementia later in life as compared to those who were sedentary.

• 1:33:49Rich Roll?

  Wow.

• 1:33:49Lisa Mosconi?

  Midlife is up to 65, right? But there's no

• 1:33:52Rich Roll?

  That's massively significant.

• 1:33:53Lisa Mosconi?

  It is really important. And then if you add strength training to that, that's been linked with better mood as well and fewer depressive symptoms and less anxiety, as well as a more resilient metabolism, which slows down sometimes after menopause. And then there's yoga and mind-body techniques and flexibility and balance exercises that are also important for better sleep and to reduce stress. So there are so many different ways that we can impact brain health by moving our bodies that, just out of common sense, you know, if you can do different things, that can help different aspects of brain health.

• 1:34:36Lisa Mosconi?

  So if we all had time to do it, that would be wonderful.

• 1:34:39Rich Roll?

  Yeah, but the point being like, get off your butt and start moving if you're not already, right? It is really important and perhaps the most important thing. Yeah. Can we talk about hormone replacement?

• 1:34:51Lisa Mosconi?

  Oh, yes.

• 1:34:53Rich Roll?

  Yeah, we're getting into it now. Yeah, it's gonna get, it's gonna get controversial. So as you know, there was this Danish study that came out recently that, that seemed to say on the surface that hormone replacement Therapy was associated with a 24% increased risk of dementia. Now, this created a lot of discourse out there because it sort of upended what people thought about HRT. So what say you? Like, what's really going on here? And how do you think about HRT as an advisable protocol?

• 1:35:29Lisa Mosconi?

  Yes. So that study was interesting because everybody started calling me. And that prompted a thorough examination of the effects of hormone replacement therapy on the risk of Alzheimer's disease and dementia, because I really wanted to not just give opinions, but actually come up with numbers, because I'm a scientist and opinions really don't matter to me, but numbers do. And so, here's the thing. There's biology and then there's pharmacology, and they don't always go hand in hand. So what we know about estrogen is that estrogen is the master regulator of women's brain health.

• 1:36:11Lisa Mosconi?

  It's like the orchestra conductor in women's brains. It's involved in a number of functionalities that have nothing to do with having kids and everything to do with having a healthy brain. That's endogenous estrogen. It's the estrogen your body makes for a reason. The reason being that the system, the neuroendocrine system, is active and responds to estrogen. So the way the estrogen works is that estrogen alone doesn't really matter. What matters is the system. And the system is the estrogen plus an estrogen receptor, which is a compound that you find throughout the body, in the brain, in the ovaries, in many, many tissues, everywhere in organs, that is like a lock.

• 1:36:58Lisa Mosconi?

  And the estrogens are the key. So the estrogen has to bind to the receptor, activate the receptor, and then the receptor triggers a number of transcriptional pathways that lead to high energy levels, glucose consumption, immunity, and more neuroplasticity, and more blood flow, et cetera. Exogenous estrogens, the estrogens that we introduce in the body, are not the same as the estrogen we make. They could be, molecularly speaking, the same, but we also need to understand when to use them and when to stop using them, and who benefits from them, and why, right?

• 1:37:42Lisa Mosconi?

  So, just for history, because it's frustrating to me. Estrogen was discovered in the 1930s. And as soon as it was discovered, two things happened. One, it was immediately linked to sexual behavior and reproduction and fertility. And so it was dubbed a sex hormone, and we've been stuck with that definition since. So, number two, pharmaceutical companies realized that there was also a link between estrogen and menopause. And so, boom! Estrogen replacement therapy became the number-one drug in the United States until 2002, pretty much. Now, what happened in between? 1992, scientists realized that the same hormones,

• 1:38:26Lisa Mosconi?

  estrogen, testosterone, progesterone, they were so important for fertility and reproduction, actually had a huge impact on the brain. They were just as important for the functioning of our minds. 1996 is when the scientific community really bought into this idea that sex hormones, actually not sex hormones, they're neuroendocrine hormones, right? They serve multiple roles. What's the problem? When do we get to the moon?

• 1:38:57Lisa Mosconi?

  Three years prior.

• 1:38:58Rich Roll?

  Hmm.

• 1:38:58Lisa Mosconi?

  Hmm. When did the biggest clinical trial of hormone replacement therapy begin? 1993.

• 1:39:10Lisa Mosconi?

  That's the Women's Health Initiative. It is, to this day, the largest clinical trial investigating hormone replacement therapy for prevention of cardiovascular disease and dementia, also relief from menopausal symptoms. That trial started before anyone had any clues of how estrogen actually worked in the brain. So what they did, they powered their study based on outcomes. They said, "We need to know if giving estrogen to women can prevent heart disease and dementia." When do you start getting heart disease and dementia?

• 1:39:52Lisa Mosconi?

  When you're older, after menopause, right? Especially.

• 1:39:56Rich Roll?

  Well, that's when it shows up. You start getting it when you're in your teens, probably.

• 1:40:01Lisa Mosconi?

  But the measurable outcomes, like heart attacks and dementia, those are things that happen later on in life, usually. So they said, "Well, I only have 10 years to do this trial, so I'm going to start enrolling women who are 65 and older." What's the problem with that?

• 1:40:17Rich Roll?

  They're already post-menopausal.

• 1:40:18Lisa Mosconi?

  They're post-menopausal by a decade, at least. The system has shut down. You can't just push stuff inside your brain, right? So what happened in these trials is that they were interrupted earlier on, ahead of time, because the investigators were concerned that they noticed that a lot more women that they estimated were getting heart disease, they were getting heart attacks, they were getting strokes, they were getting blood clots. And so they interrupted the trials and they also noticed an increased risk of breast cancer for the women who were taking hormones as compared to those who were not.

• 1:40:58Lisa Mosconi?

  And they noticed a double risk of dementia, so twice as high rates of dementia among some hormone therapy users as compared to placebo. And then the media jumped on it and they, I think everybody says that, so I think it's okay to say that they really inflated the risks to the point that a ton of women just decided to stop hormone therapy.

• 1:41:23Rich Roll?

  Right, the risk to both cancer and dementia.

• 1:41:26Lisa Mosconi?

  That's enough to scare, right?

• 1:41:28Rich Roll?

  Sure.

• 1:41:29Lisa Mosconi?

  Yes. And pharmaceutical development also stopped and so the research. So that was a problem because we know that hormones are meant to be taken as you go through menopause, not after, right? They're supposed to replace the hormones that your body is no longer making, but it's a sort of supplement really, although you do need a prescription. But if you start too far or too long after this window of opportunity has closed, then we now know that the effects could be either neutral or not so great.

• 1:42:06Rich Roll?

  Mm-hmm.

• 1:42:07Lisa Mosconi?

  Okay. Ever since, there have been many studies published, mostly observational studies because clinical trials are hard to do, they look at hormone replacement therapy use in some women as compared to women who decide not to take hormones and then what happens later on in life, do you get Alzheimer's, do you not get Alzheimer's? Now it's becoming more of a thing, so every couple of months, there's a new study that comes out where in July, hormone replacement therapy will completely vanquish any chance of getting dementia and then in September, I don't remember when it was, but in the

• 1:42:47Lisa Mosconi?

  fall, another study comes out showing that actually it's going to give you dementia. What do we do? We cannot look at one study and assume that that is the reality for all women. That's one piece of the puzzle. What we need to do is to take all the available evidence and do something called the meta-analysis, which is a statistical integration of all different findings from different studies all over the world. That will give us greater confidence of whether or not taking hormones is bad for you or good for you when it comes to Alzheimer's prevention. So I don't usually do meta-analysis, to be honest.

• 1:43:29Lisa Mosconi?

  I do brains, but I said to my team, "We have to because this is just too confusing." So I'll show you where we found. All right, so so far, as far as I know, this is the largest meta-analysis done, including, I believe, close to 6 million women from all over the world and over 50 studies, including the Women's Health Initiative, but also everything else that came after the Women's Health Initiative, which I think is just as important. And this is what we found. Two things. When you take hormones matters. If you take them for menopause, as you go through menopause,

• 1:44:09Lisa Mosconi?

  is different than if you take them later on in life when you're done with your transition. Number two, the type of hormones that you take also matters. So if you have a uterus, you need to take estrogen with a progesterone or progestin. So there are different types of hormones. They can be bio-identical, which is what people talk about a lot, which are molecular replicas of what our hormones actually look like, more or less exactly like the hormones that the ovaries make. Or you can take slightly different versions that we refer to as synthetic or progestins. Okay, turns out that matters.

• 1:44:53Lisa Mosconi?

  For women who do not have a uterus, because they've had a hysterectomy, then you don't need to take the progesterone, you only take the estrogen. So we have estrogen-only formulations and estrogen-progestin formulations. We're going to look at them separately, because the outcomes are different based on what you take, at least as far as we know at this point. Estrogen-only, these are women who no longer have a uterus. Okay? If you take estrogen-only within 10 years of the final menstrual period, that is associated with a significant reduction in the risk of dementia later in life. It's about 32%, which is good.

• 1:45:38Rich Roll?

  Significant, yeah.

• 1:45:39Lisa Mosconi?

  Yeah, significant. And the important thing is that the data was quite, I mean, it was variable, but it reached statistical significant, which means that the vast majority of studies showed the protective effect. If you start taking estrogen-only more than 10 years after the final menstrual period, that has neutral effects on the risk of Alzheimer's disease and all-cause dementia. Does it increase it? Does it make it better?

• 1:46:08Rich Roll?

  Hmm.

• 1:46:09Lisa Mosconi?

  Estrogen and a synthetic progestin. If you take it before menopause or within 10 years of menopause onset, there is about a 23% reduced risk of dementia. However, the data here is a lot more variable, so this is a trend. So there's a trend towards reduced risk of dementia, which means the data is not conclusive, because some data, some studies show an increase in risk, like the Danish, I believe, and some studies show a reduction in risk. So what determines what different studies find?

• 1:46:51Lisa Mosconi?

  It's an interesting conversation, but then if you start taking estrogen and progesterone more than 10 years after menopause, that is linked with a possible risk increase. Now, the tip of the iceberg here is the Women's Health Initiative that we know was really a bit of a problem. But there are studies that show protective effect even then. Only when you combine them all together, it looks like there's a possible increase in risk. If you start taking hormones at that point, not if you start in midlife and keep taking that, that's a good thing.

• 1:47:27Rich Roll?

  Right.

• 1:47:28Lisa Mosconi?

  But if you start too late, there's an increase.

• 1:47:30Rich Roll?

  It looks like more than just a risk. I mean, that's a pretty steep curve there.

• 1:47:34Lisa Mosconi?

  Yes, the point is that is a trend. Again, it doesn't reach significance because some studies show protective effects and some studies do not. And a sub-analysis, which is something you do after, shows that the studies that really show an increase in risk use a type of synthetic progesterone that is called MPA that is no longer in use today. Whereas other forms of synthetic progestins do not increase risk nearly as much. And the most important thing, I think, is that bio-identical progesterone, which is what most people use now, has never been linked with a higher risk of Alzheimer's.

• 1:48:16Rich Roll?

  So the takeaway really is, timing is super important. We need more research, yes. Timing and type and like really being with a practitioner who understands this landscape well, right?

• 1:48:30Lisa Mosconi?

  Yes, also, these studies are observational, which is a problem from a clinical perspective. You want clinical trials.

• 1:48:35Rich Roll?

  Right.

• 1:48:36Lisa Mosconi?

  Right? Because you can control a lot of variables, you can standardize, they're more conservative, it's better. The problem is, you cannot physically run a clinical trial for 20 years. So to my mind, we should stop trying to correlate, because at that point is a correlation, use a hormone in midlife with something that happens 20 years later. What would be better is to take hormones at the right time and use brain imaging as the outcome. Makes so much more sense.

• 1:49:11Rich Roll?

  Right, right, right, right.

• 1:49:12Lisa Mosconi?

  Right, so this is what we're doing now.

• 1:49:14Rich Roll?

  So this is what you're doing at your lab?

• 1:49:15Lisa Mosconi?

  Yes, we just started a clinical trial that uses brain scans as an endpoint and also uses a very interesting type of estrogen, it's called-

• 1:49:25Rich Roll?

  Phytoserm, is this what you're gonna-

• 1:49:27Lisa Mosconi?

  Is it phytoserm?

• 1:49:28Rich Roll?

  Yeah, I wanted to ask you about this.

• 1:49:29Lisa Mosconi?

  Okay.

• 1:49:30Rich Roll?

  Yeah.

• 1:49:30Lisa Mosconi?

  Do.

• 1:49:31Rich Roll?

  So it's like a plant-based, plant-derived version of estrogen that you're currently testing?

• 1:49:40Lisa Mosconi?

  Yes, it's called the designer estrogen. So it's a SERM, it's a selective estrogen receptor modulator that's been specifically engineered to go straight into your brain and support cellular function in the brain, but has either a neutral or inhibitory effect on reproductive tissue. Why? Because there are different types of receptors for estrogen, there are three different types. The most important ones are alpha and beta. So the alpha receptor is more expressed in reproductive tissues, breasts, ovaries, uterus. The beta receptor is more expressed in the brain.

• 1:50:23Lisa Mosconi?

  So what this specific SERM, phytoserm, does is that it binds only to the beta receptor. So it leaves your breasts alone and is not being linked with a higher risk of breast cancer.

• 1:50:37Rich Roll?

  That sounds promising.

• 1:50:38Lisa Mosconi?

  I think it's very interesting. Yes, and it was developed by my mentor, Dr. Roberta Diaz-Brinton at the University of Arizona, and she's amazing. She's a rock star in the field and she-

• 1:50:49Rich Roll?

  That's exciting.

• 1:50:49Lisa Mosconi?

  Yes, she's so good. So preventing dementia is one thing, and it's complicated to do, but there are things that hormone replacement therapy can do for you that are important immediately as you go through menopause. And this is reducing hot flashes and night sweats, improving sleep in some women to some extent, reducing the risk of osteoporosis, and also-

• 1:51:17Lisa Mosconi?

  Helping with vaginal dryness, vaginal atrophy and painful sex or painful intercourse, which is very prevalent after menopause. So these are FDA approved indications. Sleep is not yet, but the hot flush reduction and the osteoporosis and these genitourinary symptoms are all FDA approved indications for HRT. And according to professional societies, taking hormones is actually recommended for women who have a hysterectomy and oophorectomy before menopause. So I just want to mention that because it is very controversial whether or not hormones are helpful to you.

• 1:51:57Lisa Mosconi?

  And these are things that the FDA says these are good indications, these are on-label indications. And then there's more evidence that taking hormones may also help some women with depression due to perimenopause and sleep and possibly also brain fog and memory lapses. So just to say, they may be helpful no matter what happened 20 years ago. That is still driving most women's decisions to not try the hormones in the first place. There are women who are not eligible to take hormones, we understand that, but most women

• 1:52:37Lisa Mosconi?

  are, only they choose not to do so, not because they don't want to try, but because they're worried about the risk of breast cancer.

• 1:52:47Rich Roll?

  There's a fear or a distrust.

• 1:52:48Lisa Mosconi?

  Yeah. So I think it's important that women have the information they need to make a decision that is not based on fear, but is based on facts and updated information.

• 1:52:58Rich Roll?

  Are there other pharmacological interventions that you would recommend somebody who's on the precipice of going through menopause explore?

• 1:53:09Lisa Mosconi?

  Well, I think hormone therapy is the best one that we have. Some antidepressants can help, and especially women who are not eligible to take hormones could safely consider some antidepressants that have been shown to reduce hot flashes. There are some new formulations. There's one drug for medicine for menopause that was just recently approved that does not increase the risk of breast cancer because it's not estrogenic, physolinatant, but we still need to see.

• 1:53:47Rich Roll?

  More studies.

• 1:53:47Lisa Mosconi?

  Yes, we need to see more studies. We need to see how it actually works in clinical populations. Testosterone, for some women, is something that's been considered, especially for low libido. That's the primary indication at this point.

• 1:54:02Lisa Mosconi?

  And then there are supplements, and then there is lifestyle. And I think it's important to talk about those solutions because they can really improve the heart flashes, like diet, just one second to go back to diet. Women who follow this Mediterranean-style diet, just a healthy diet that is plant-centric, and there's all the good nutrients and the good foods, have, at a minimum, 20 to 30% fewer heart flashes than women on Western diet.

• 1:54:31Rich Roll?

  Wow, that's a lot.

• 1:54:32Lisa Mosconi?

  Yes.

• 1:54:33Rich Roll?

  That's more significant than I would have thought.

• 1:54:35Lisa Mosconi?

  Yes.

• 1:54:35Rich Roll?

  Yeah.

• 1:54:36Lisa Mosconi?

  Yes, and I think it's important to know that, that you can change your outcomes. And, you know, even women with breast cancer can safely go on a healthy diet and reduce the risk of heart flashes and menopausal symptoms that way, along with exercise and other techniques. In some studies, women who didn't start out on a Mediterranean-style diet, but they were on less healthy, as they way, diets, and then they changed their diet pattern, showed a significant reduction, not just in the number, but also in the severity of heart flashes, which really supports a role for dietary interventions in that case.

• 1:55:18Lisa Mosconi?

  And then another study with thousands of women showed that consuming more fiber-rich foods, in that study fish as well was part of the pattern, also was associated with the later onset of menopause, as compared to women who eat a lot of processed foods and refined grains and refined sugar and sugary beverages, who tend to experience an earlier onset of menopause, which really, nobody needs.

• 1:55:47Rich Roll?

  That's wild. So if you're dining out consistently on ultra-processed foods, you're looking at an earlier menopause.

• 1:55:55Lisa Mosconi?

  Mm-hmm, which is really a pity.

• 1:55:57Rich Roll?

  Wow.

• 1:55:57Lisa Mosconi?

  Yes.

• 1:55:58Rich Roll?

  That's interesting. Sleep. We talk about sleep all the time here. Like, I don't want to reinvent the wheel. Like, we all know we need more sleep than we think, and that it should be a priority, and that our hygiene around sleep is of paramount importance. But I do think it would be worth spending, you know, a few minutes just talking about the importance of sleep and brain health from a neuroscience perspective, and perhaps like what the scans show you or what you know about what happens when we sleep that is reparative and restorative to our brains and protective against these cognitive, you know, declining diseases.

• 1:56:38Lisa Mosconi?

  So, sleep really is the only chance that your brain has to take care of itself. Because when you're awake, or even when you are at the early stages of sleep, your brain still needs to supervise your entire body. When you go through deep sleep, that's when your body's fully still, and the brain has a chance to have a little me-time. And what happens is that there's a system inside the brain that is very specifically activated during slow wave sleep or deep sleep, that is like a little bit like a dishwasher in a way, where all the fluid comes out, and the brain takes a shower, quite literally. And that is very important,

• 1:57:23Lisa Mosconi?

  because that's how it flushes out toxins and waste products and Alzheimer's plaques and all the enzymes and substances that have been degraded throughout the day. So, it's effectively a cleaning service that the brain is able to activate that is very important for brain health. Because if you think about it, in the rest of the body, we keep flushing out stuff. Every time we go to the bathroom, it's effectively a waste removal mechanism. And the only way that the brain can do that is by flushing out the substances in the cerebrospinal fluid and then release it outside of the brain itself. And that can only happen during a very specific time that we're sleeping. So, why is that important?

• 1:58:08Lisa Mosconi?

  Because so many people experience fragmented sleep.

• 1:58:12Lisa Mosconi?

  Right, we don't sleep soundly through the night. Many people wake up multiple times. And the way the sleep works, it's in cycles. So you always start from cycle one before you reach cycle four and five, which is where you really get this good, uh, brain healthy sleep. And so if you keep waking up, you just have to go back to baseline. And you don't give your brain a chance to really take care of itself. And that's been linked with an increased accumulation of Alzheimer's plaques. It's been linked with inflammation. It's been linked with a reduced ability to withstand infections, as well as a higher risk of infections and a brain fog

• 1:58:55Lisa Mosconi?

  and other negative things that can impact your brain. And for women in particular, I would say that menopause can disrupt sleep significantly. More than half of all women who appear menopausal in post-menopausal age had trouble sleeping. And at least one in three has trouble not only falling asleep, but also staying asleep through the night. So this is something that deserves a conversation because it doesn't just sink your energy

• 1:59:24Rich Roll?

  Right.

• 1:59:25Lisa Mosconi?

  has a really negative effect on everything else. Also, all hormones work in tandem, right? So when you go to sleep, it means that your body needs to produce melatonin that helps you regulate sleep and wake cycles. But if that cycle is disrupted and your melatonin production is impaired, then your cortisol production, your stress hormone production will be increased. And that in turn reduces or suppresses your production of estrogens, for example.

• 2:00:00Rich Roll?

  Uh huh.

• 2:00:01Lisa Mosconi?

  So it's all related.

• 2:00:01Rich Roll?

  This is a cascade of the whole thing. And chronic sleep deprivation or lack of adequate healthy sleep on a consistent basis leads to a buildup of these things that need to get consistently flushed out to the point where even if you then are getting periodic good restful sleep, it's not enough to really flush and drain that system out

• 2:00:26Lisa Mosconi?

  Who knows.

• 2:00:26Rich Roll?

  in a restorative way.

• 2:00:27Lisa Mosconi?

  Yeah.

• 2:00:28Rich Roll?

  But it is a very common thing. You reach a certain age and you wake up in the night. You gotta go to the bathroom a little bit more. My wife, she'll wake up at like two. She's like, I'm up. And then she'll start her day. And I'm like, I don't know how you function.

• 2:00:41Lisa Mosconi?

  Oh, wow.

• 2:00:42Rich Roll?

  And she seems fine.

• 2:00:42Lisa Mosconi?

  Wow.

• 2:00:43Rich Roll?

  Yeah, I mean.

• 2:00:44Lisa Mosconi?

  That's amazing.

• 2:00:45Rich Roll?

  It's wild. She'll have a super productive day. And I was like, I don't think this is good, though. But she's like, I can't go back to sleep. So what do you say to that person who is having their sleep disrupted consistently? But is, you know, the idea of like finding a way to get back into a restful state is elusive.

• 2:01:05Lisa Mosconi?

  Oh, that is, that is rough. And that happens a lot. And I'm not a sleep expert, but what people say is that there are a few things that you want to watch out for, which, you know, number one is the amount of stimulants that you introduce in your body, such as alcohol and caffeine. For instance, if I switch to decaf and preparing for not sleeping, because my sleep is not great to start with, but I don't have the energy that your wife has.

• 2:01:31Rich Roll?

  Yeah, and she, I mean, you know, she, her body is her oracle. Like she doesn't put, you know, that's not an issue with her. I don't know what's going on. I think she's, you know, I don't know.

• 2:01:40Lisa Mosconi?

  It's just the way it is.

• 2:01:41Rich Roll?

  She's, you know, channeling energies from the beyond or something.

• 2:01:45Lisa Mosconi?

  And that's so good. And that's so good. For common women, I think it's more really about watching stimulants they introduce in your body and stress levels and whether or not you have moved your body during the day. Because at some point, your body will wake you up if it's ready to go, even if your brain doesn't want to.

• 2:02:08Rich Roll?

  Yeah.

• 2:02:09Lisa Mosconi?

  So these are things that are important. And especially, I find a lot of people drink so much coffee without realizing the half-life of caffeine. Right? So if you drink a cup of coffee at noon and the half-life of caffeine is five to six hours, it means that by 6:00 PM, you still have half of that caffeine going around your blood and inside your brain. But also means then.

• 2:02:40Lisa Mosconi?

  You know, three hours later, you still have 25% of that going around. So by midnight, you're still caffeinated. And that is not helpful if you're trying to sleep. And the same thing with alcohol and things that have a dehydrating effect. That can negatively impact sleep and your ability to fall asleep and stay asleep as well. So it's something to watch out because sometimes, you know, it happens after menopause. I hear, I'm told that sometimes a lot of women would be like, well, you know, I really, I'm going to maybe have a glass of wine to just try and help myself go to sleep without realizing that that can wake you up later in the middle of the night.

• 2:03:23Lisa Mosconi?

  So that's something to consider. Other than that, stress. Stress is a very pervasive issue and it does increase with the menopause transition, where our ability to de-stress are reduced in part because you're too tired and you have every reason to be tired, but in part also for physiological reasons, which is that stress hormones and sex hormones all come from the same precursor. So your body needs a hormone, it's called pregnenolone, the mother of all hormones, to then either make cortisol, the stress hormone, or make sex hormones.

• 2:04:08Lisa Mosconi?

  So if you're under chronic stress and your production of cortisol is elevated, your body can do that by reducing or suppressing production of other hormones. So effectively, too much stress also sinks your estrogens, which is one more reason to think about stress reduction as a, also as a brain protective strategy besides something that can help with menopause as well.

• 2:04:34Rich Roll?

  Testing, I want to talk about testing as we kind of begin to wind this down a little bit. If somebody is listening to this or watching this and thinking, I really need to take stock and inventory of where I'm at right now from a health perspective, from a brain health perspective, from a hormonal perspective. We touched on your thoughts on APOE, but what would you recommend that person do to get a clearer picture of where they're at and what the near future might hold for them?

• 2:05:06Lisa Mosconi?

  Well, in general, it's good to have a really good baseline. So, blood work is helpful.

• 2:05:12Rich Roll?

  And which blood markers do you think are most critical to pay attention to? Is it total cholesterol and HDL?

• 2:05:20Lisa Mosconi?

  LDL, HDL, low-density lipoproteins as well, total cholesterol, triglycerides for the lipids. For metabolic markers, usually it's insulin, glucose levels, hemoglobin A1C. If you want to go fancy, there are other things. But these would be the key metabolic markers. I would look at thyroid function as well. So, TSH, T3 and T4. And then iron, iron levels and B12. Because so many people are anemic and many people are B12 deficient and don't realize that. It's very common as we get older. So, this is something I would measure.

• 2:06:02Lisa Mosconi?

  I would measure nutrients as well, but I know that this is now standard of care. So, these are important to look at. What I would really love is to do a cognitive evaluation.

• 2:06:14Rich Roll?

  Right, and what does that look like? That's what I wanted to ask.

• 2:06:17Lisa Mosconi?

  It depends, of course. But I would say at the minimum, there are tests that measure global cognition. That's a good first step. And then we have more specialized tests. They look at memory, attention, language, executive function, fluency and processing speed. I would do them all. It takes two hours at the most and you get a really good sense of where you are. Because then you get Z scored in two percentiles. So, you can get a sense of where you are relative to other people at your age and with your same educational level. But most importantly, that's you when you're feeling good. So then...

• 2:07:00Rich Roll?

  You have a baseline.

• 2:07:01Lisa Mosconi?

  You have a baseline that you can refer back to. So let's say you're 40 or 50 or 60 and you come to us and we do this nice cognitive testing battery. And then you come back five years later because you may be a woman going through menopause and you're scared that you might be experiencing early onset dementia because you can't remember things, you have trouble coming up with words, so you just feel weird. Or you are older and maybe you're 65 or 70 and you start forgetting things and you get concerned about dementia, which is very, very common. Then we do the test again. We can compare you with you, which is every doctor's dream, right?

• 2:07:42Lisa Mosconi?

  Rather than saying, well, you know, relative to other people you've never met who have, who are your same age and also completed a high school degree or something, you're fine. That's not nearly as reassuring. It's good, it's good. It's a great thing to know, but it's not nearly as reassuring as saying, well, look, you scored 28 over 30 when you were doing so good and now you scored 26 over 30 and it's fine because this is consistent with an age-related change, right? If you were below 24, then that could be a problem because we have different thresholds for cognitive impairment and then dementia.

• 2:08:24Lisa Mosconi?

  But at least standardized, you know what's happening and you know what is common during aging and what is not. And then you can get a better sense of where you are. And I strongly advocate for brain scans.

• 2:08:39Rich Roll?

  Yeah. Well, just to put a pin on the cognitive testing, basically if you feel great, go do it and then you have that baseline for the future.

• 2:08:48Lisa Mosconi?

  Yeah, also if you don't feel good, yes.

• 2:08:49Rich Roll?

  Which is a great idea.

• 2:08:50Lisa Mosconi?

  I think it's a great investment. I think it's a great investment. I have seen so many people come to us, really, I'm not exaggerating, terrified that I'm losing my mind, I'm going crazy, maybe I have dementia, maybe I have this, maybe I have that. And we do cognitive testing, we're like, look, you're fine. You're effectively fine. Let's talk about what may be happening that makes you feel that way.

• 2:09:17Lisa Mosconi?

  But the relief, the relief of seeing some objective measure of your own cognitive performance and looking at the numbers and seeing, I am not losing it. This actually happens. And I'm just one of the many people who go through this for this reason or that reason or that reason. The relief is just like palpable.

• 2:09:41Rich Roll?

  Yeah, I think I need to do this. Because I do that like every once in a while. I was like, I can't remember the name of that actor in that movie. And I freak out. I'm like, it's beginning, it's beginning, you know? And it haunts me.

• 2:09:53Lisa Mosconi?

  Of course. I completely, completely relate.

• 2:09:58Rich Roll?

  But talk about these brain scans. I want to have my brain scanned too. Will you, will you scan my brain if I come to New York?

• 2:10:03Lisa Mosconi?

  Of course, absolutely. And bring your wife. I need to know where she gets all the energy.

• 2:10:07Rich Roll?

  I would love to see what her brain scan looks like.

• 2:10:10Lisa Mosconi?

  Yes, we would be delighted to. So I run the Alzheimer's Prevention Program, a well-known up medicine in New York City. We're on the Upper East Side. So it's 72nd and York, just for context. It's easy to get there. And we're NIH funded to do research where we do a lot of tests, of course, that include the blood work that we mentioned before. We also do hormones. So we measure hormones as well, including cortisol, the stress hormone, which is interesting to look at. We do cognitive testing and we do a number of brain scans. They are done for research, obviously. There's currently no easy way to get this kind of brain scans

• 2:10:55Lisa Mosconi?

  for prevention unless you're part of a research program. And so what we do, we start with an MRI scan and we do seven different sequences, which means that we look at seven different things in about 45 minutes to an hour. So we do volumes, we do volumetrics. We measure your gray matter, white matter in every part of your brain. We look at whether or not there is evidence for any sort of damage. We screen for so many things because the brain can get...

• 2:11:32Lisa Mosconi?

  Affected, obviously. So you may have cysts, you may have tumors, you may have a brain tumor. There could be aneurysms, there can be malformations, there can be vascular damage, there can be gliosis, there can be inflammatory disease, there can be demyelination. So we screen for everything. I have a really long list of stuff that we screen for. And if there's anything that we find, an incidental finding, we manage that. So there are different things that one can do to address what we find, anything that we find. Is it common to have incidental findings? No, it's not common, but it does happen. So we do that. And then we look at the connectivity inside the brain, which is actually kind of pretty.

• 2:12:16Lisa Mosconi?

  You see all the different fibers and tracks that connect your different brain regions to each other. And we do blood flow, and we also measure ATP production directly in the brain. And that we do using something called spectroscopy. It's a different technique, but it's still MRI, MRI-based. And then, if you'll let us, we also do the brain scans we were looking at before, where we look at the way that your brain uses glucose to make energy, but we also do Alzheimer's plaques as a screening for prevention.

• 2:12:51Rich Roll?

  Hmm, it's kind of scary, though, too. It feels very vulnerable.

• 2:12:55Lisa Mosconi?

  Um, I guess.

• 2:12:58Rich Roll?

  Yeah.

• 2:12:59Lisa Mosconi?

  But it's good to have a baseline, let me tell you, because at this age, it's very unlikely.

• 2:13:04Rich Roll?

  You are doing the work that you're meant to be doing because you just light up when you talk about this stuff. So, you know, I can tell that it's very authentic and genuine, like your love for this field. And the last thing I wanted to ask you before we close it down. We talked about hygiene in many different ways, sleep hygiene, just, you know, brain hygiene in general. But I think it would be instructive to share a little bit of media hygiene because, to your point, and our conversation around the Dutch study and hormone therapy, et cetera.

• 2:13:37Rich Roll?

  The health pages of, you know, whatever magazine you're reading, or newspaper, or social media channel that you're on, there's so much coming at us about what this study says, and what that study says, and how these studies get interpreted in the media and fed to us through titling and synopsizing that isn't necessarily accurate, that creates a level of confusion and at times paralysis and can drive unhealthy, real-life choices that we're making in the world. So how do you think about the media's relationship to this world that you're in? Because you're there and you understand it better than anybody. And then I'm sure you pick up the newspaper or turn on the TV

• 2:14:22Rich Roll?

  and see, you know, strange interpretations of your field.

• 2:14:27Lisa Mosconi?

  I suffer. Then that's... I think that's the short of the puzzle. I suffer.

• 2:14:34Rich Roll?

  You could become a full-time social media warrior on this.

• 2:14:37Lisa Mosconi?

  No.

• 2:14:37Rich Roll?

  You know, can you imagine?

• 2:14:39Lisa Mosconi?

  No, I cannot. Newspapers, I really appreciate The New York Times and The Wall Street Journal. We were mentioned, they're featured, they're reviewed often these past years. And their fact-checking is superb. At least with me. Maybe because I drive everybody crazy with fact-checking because I'm terrified of being misquoted. But they were extremely, extremely thorough. I never had a bad experience. And I learned to always read, ask for the read-back whenever some learning. Social media is harder for me. It's really, I don't really know how to address it because, you know,

• 2:15:23Lisa Mosconi?

  we're all entitled to our own opinions, obviously. What is... Shocking to me sometimes is, we were talking about that before, but it's just the level of confidence that people have in sharing information that is not accurate. And that, I don't know what to do with.

• 2:15:42Rich Roll?

  That they have no expertise in whatever field they're talking about.

• 2:15:46Lisa Mosconi?

  Expertise is tricky to qualify in some ways because there are people who are very qualified and they're just not up to speed with the research. And there are people who maybe have, don't have the same degrees, but really read and pay attention and inform themselves. You know, education is a lifelong process. So it is hard to know who do I trust and up to which point. And also, something that is very strange for me about social media is they really have twenty to hundred words or characters to explain something complex. So there's an oversimplification that must happen.

• 2:16:24Lisa Mosconi?

  And it's really hard to be clear and be interesting and be accurate at the same time. So I appreciate enormously people who can do it and who also take the time to really talk and use their platforms like you do to bring good information to a lot of people. And other than that, I don't, I don't, do you, do you know what to do?

• 2:16:49Rich Roll?

  No, I mean, there's no real easy answer. But I think the solution isn't do your own research or just casually consume information passively through your social media feed. I think because of the kind of climate that we're in in terms of how we consume news and information, it's incumbent upon us. We have to shoulder the responsibility for taking that seriously and, and, and really kind of vetting our opinions and what we're consuming against other sources.

• 2:17:24Rich Roll?

  Have some legacy or credibility of trust to stress test all of this stuff that's coming at us before we just digest it and make assumptions about its veracity. And that's hard. And I feel like we shouldn't have to do that. You know, and I'm old enough to know where this wasn't a thing, where, you know, there was there's legacy media that's trustworthy, that earned that trust. And for some reason, or for a lot of reasons, I guess, like trust has been eroded in certain media outlets. And that creates an environment where there's a receptivity to other ideas. And sometimes that's good, and sometimes that's toxic and not so good.

• 2:18:06Rich Roll?

  But all of it creates confusion. And I think in terms of health and the choices that we're making every single day, like there are real world implications, immediate implications in terms of behavior that's occurring. And so I'm always curious around sourcing and, you know, where the experts in their given field go to get their information in a trustworthy way.

• 2:18:32Lisa Mosconi?

  Yeah, it's a really good, it's a really good point. I get my information from scientific publications.

• 2:18:37Rich Roll?

  Yeah.

• 2:18:38Lisa Mosconi?

  And calling.

• 2:18:38Rich Roll?

  You're going to sell in nature and science and all these things that like, none of us are gonna read.

• 2:18:43Lisa Mosconi?

  Nobody can read.

• 2:18:44Rich Roll?

  But we trust you to read them and interpret them for us, Lisa. And then to write great books about the stuff that you know best.

• 2:18:52Lisa Mosconi?

  It's tricky. So there's, there's something called peer review in academia that I, I never appreciated as fully as I do now, which is that when you write a paper, when you write up your work, then you send it to a journal and they send it out to peer review. So there are other scientists in your field who are qualified to review your work and they can weigh in. So you really shouldn't, I think the process is conservative enough that everything is being checked. Right? And you cannot make strange claims. Everything has to be backed up either by your

• 2:19:32Lisa Mosconi?

  own data or by referencing other people's work. And there's also this thing that I find on social media that is very funny, that people just. Hear something somewhere, but they never cite their sources. Right? You never say, oh, this person said this, and now I'm going to say it again. It always sounds like you came up with those things and make you also sound a lot smarter than perhaps you are in some cases. Whereas in academia, you just cannot do it. You know, you always have to cite your sources and give credit to whoever's done stuff before you.

• 2:20:09Lisa Mosconi?

  It is, I know that this is not possible to do outside of academia, but something that I, I think could be helpful is if books were checked a little bit, maybe more thoroughly sometimes. And for social media, I don't know. I think in part, the problem is that scientists and doctors don't really have much of a voice. And we are under a lot of stress to do research if you're a scientist and to see patients if you're a doctor. And there are standards to meet, like you're being evaluated in terms of billing. Really, not just how happy your patients are, how they feel better or not, but how many patients you bring in, how fast,

• 2:20:54Lisa Mosconi?

  and how much money you bring into your hospital. The same for scientists, we're basically like CEOs of a startup we know exit. And we're being evaluated not just based on productivity, but based on how much money we bring in, which is beyond stressful. I mean, it's not, it's not a good system to my mind. So we don't really even have the time to talk to people. We're put in a position, we're just constantly working around the clock and we stay within academia. And it would be wonderful if more scientists and more doctors were out there explaining things to people, but they have no idea how to make that happen.

• 2:21:36Rich Roll?

  Well, I think it takes a very certain type of individual. Like you're a very effective. Science communicator, but communication skills don't necessarily go hand in hand with the skills that drive a great researcher.

• 2:21:51Lisa Mosconi?

  Absolutely.

• 2:21:52Rich Roll?

  And being a public face of an idea or a corner of the science world is its own vocation, you know, with its own pressures and responsibilities. And, you know, I think people go into science mostly because of their interest in the science itself.

• 2:22:10Lisa Mosconi?

  Yes.

• 2:22:11Rich Roll?

  And I think that's one of the reasons why I think what you're doing is so laudable, because you are an effective communicator. And I know that you have your own stresses running your lab, and you've got all these other things going on in your life. And you write these books so that you can share with us what you've learned and, you know, relate what's important about these topics so that the public has an understanding. And then you go out and you sit down with people like me to communicate around it. And I know that's a

• 2:22:39Lisa Mosconi?

  It's a stretch.

• 2:22:40Rich Roll?

  Yeah, it's a lot.

• 2:22:42Lisa Mosconi?

  It's an honor.

• 2:22:43Rich Roll?

  But I think that is, you know, an antidote to the perils that we just addressed. So that's probably as good a place as any.

• 2:22:51Lisa Mosconi?

  Thank you.

• 2:22:52Rich Roll?

  But I appreciate it. Yeah.

• 2:22:54Lisa Mosconi?

  I hope it's helpful.

• 2:22:55Rich Roll?

  No, it's great. And the books are wonderful. So the latest is The Menopause Brain, which just came out as of the date that we're releasing this, or is coming out imminently. And The XX Brain, and then you have Brain Food. So all three of them. It's great. Thank you very much.

• 2:23:12Lisa Mosconi?

  Thank you.

• 2:23:13Rich Roll?

  Come back and talk to me some more. I could talk about neuroscience all day.

• 2:23:15Lisa Mosconi?

  Oh, thank you.

• 2:23:16Rich Roll?

  Yeah, thanks. And I do want to get my brain scanned.

• 2:23:18Lisa Mosconi?

  Oh, good.

• 2:23:19Rich Roll?

  So I'm going to follow up with you on that.

• 2:23:21Lisa Mosconi?

  Great.

• 2:23:22Rich Roll?

  Okay, cool. Cheers. Peace.

• 2:23:24Lisa Mosconi?

  Cheers. Blas.

• 2:23:35Rich Roll?

  That's it for today. Thank you for listening. I truly hope you enjoyed the conversation. To learn more about today's guest, including links and resources related to everything discussed today, visit the episode page at richroll.com, where you can find the entire podcast archive, as well as podcast merch, my books, Finding Ultra, Voicing Change, and The Plant Power Way, as well as The Plant Power Meal Planner at meals.richroll.com.

• 2:24:05Rich Roll?

  If you'd like to support the podcast, the easiest and most impactful thing you can do is to subscribe to the show on Apple Podcasts, on Spotify, and on YouTube, and leave a review and/or comment. Supporting the sponsors who support the show is also important and appreciated. And sharing the show or your favorite episode with friends or on social media is, of course, awesome and very helpful. And finally, for podcast updates, special offers on books, the meal planner, and other subjects, please subscribe to our newsletter, which you can find on the footer of any page at richroll.com. Today's show was produced and engineered by Jason Camiolo. The video edition of the

• 2:24:48Rich Roll?

  podcast was created by Blake Curtis, with assistance by our creative director, Dan Drake. Portraits by David Greenberg. Graphic and social media assets courtesy of Daniel Salis. Thank you, Georgia Whaley, for copywriting and website management. And of course, our theme music was created by Tyler Pyatt, Trapper Pyatt, and Harry Mathis. Appreciate the love, love the support. See you back here soon. Peace. Plants.

• 2:25:16Lisa Mosconi?

  Namaste.