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

30:22I 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. So what conclusions can you draw about the genetic predisposition to Alzheimer's and the ability or the agency that one has to, you know, sidestep that genetic predisposition?

31:08Like, in other words, like how much is your genetic predisposition a driver of outcomes? 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 one and two 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.

31:57So 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. So 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.

32:41It does not trigger Alzheimer's, does not cause Alzheimer's necessarily. And these genetic mutations are found in about two, maybe 3 % of all Alzheimer's cases, which means that for the vast majority of individuals with Alzheimer's, other factors are applied. Yeah, it's a non-issue comparatively. So to try and answer your question, depending on the studies that we look at, there's evidence that between 20 and 50 percent of all Alzheimer's cases may be due to lifestyle and medical conditions rather than genetic mutations for sure, probably in combination with some kind of genetic blueprint they were trying to unravel.

33:25But there is a strong lifestyle component that I think has been overlooked in medicine for a long time.

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37:00Drilling 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 because obviously the numbers prove that out.

37:43But with lifestyle, I assume you can opt out. But if you have the predisposition if you have genetic mutations lifestyle can help it can delay the onset of dementia it's hard to avoid dementia once you have that kind of mutations they're causative yeah but if you do not have those genetic mutations lifestyle is more impactful right 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 the Alzheimer's gene. Is this the Chris Hemsworth situation?

38:29Yeah. So there's a genetic risk factor called the apolipoprotein E or ApoE gene, right? We all have this gene and it comes in three forms. There's an epsilon 2 form. There's an epsilon 3, 4. And there's an epsilon 4 form. And each one of us has two copies of 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 or 4-4 carrier, then your risk is higher relative to people who don't have that specific genotype.

39:23But 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 we understand a little bit more what can reduce the odds of developing dementia for people who are carriers of the apoe4 genotype interesting 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 euphoralea. There are plenty of people who have it and do not have dementia.

40:03So 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. Right. I would assume that you would recommend that everybody get tested for that though. We're gonna get to testing later, but... I would not, I would not recommend. Yeah, because it just rents space in your brain in a perhaps not so healthy way. 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.

40:47They 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. So I think what I do recommend is that if you decide to do genetic testing, that genetic counseling 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 23andMe or something similar and they find out that they have this APOE4 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.

41:39That's something that needs to be addressed. Or conversely, if you find out that you are not at risk, then perhaps you're less enthusiastic about upgrading your lifestyle habits. You know what I mean? But that's harmless, isn't it? 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 wanna 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 people have experienced the hot flashes and all that.

42:22Like we're all kind of culturally aware of those things, but there's also some interesting benefits also that certain people experience. With menopause? Yeah. Oh yes. In terms of what's happening cognitively. 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.

43:06And 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. So when you have kids who are, yeah. 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 has to expect. I would expect nothing less from your child. Yes. 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.

43:43It matters in ways that not all parents enjoy necessarily, right? There's the reckless behavior, there's the temper tantrums in some ways, and there can be depressive states and the blues and the brain fog and the sleep 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 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.

44:31whereas 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 those interactions of different regions, which is key to become members of society, to be able to put your needs to the side 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.

45:15Theory Monday 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. 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.

45:59Infants can't speak. So you really have to learn to read minds, quite literally. And the mummy 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 there is a problem before there is a problem. It's 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, but a lot of pregnant women have half flashes as well. So those are very similar symptoms to menopause because it's the same pathway.

46:43It's the same neuroendocrine system that is changing. So you have changes in body temperature at 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 needs to be able to do that. With pregnancy, same thing. You need to activate your thermoregulation because you have a bun 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 risk and the depression 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 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.

47:47But also, they report being happier the day themselves where before they went through menopause, which is quite interesting. And fits in with the notion that happiness follows this sort of U-shape, right? 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 my network that is rewiring and ends up with greater empathy. So postmenopausal women are the greatest empaths. And if you measure empathy levels across, you know, at any age range in between genders, it's really the postmenopausal women that stand up, which is a beautiful way to think about aging and nurturing and just being able to take care of others.

48:32But then there's one thing that I find so sweet. And a lot of women tell me that after menopause, they kind of reach a state where they give fewer. Yeah, they just don't give a fuck anymore. I mean, I think 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.

49:15And 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. Yes, there's a rationale and there's a neurological explanation. or for the giving fewer Fs, 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.

49:55And 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, for anyone who's born with ovaries or anyone who knows women, 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 of being alive is to reproduce a personial genes. So the fact that women stop reproducing at some point and don't die is effectively against these theories.

50:43Yeah. I love that. It's some kind of a glitch in the system or vestigial in a way that nobody could make sense of. Nobody can make sense of what people have tried. So men have said, scientists have said. Just go for it. Like speak your mind, come on. So there's a mismatch hypothesis that says that we should die after menopause, but modern medicine is increasing lifespan beyond what nature intended. Artificially keeping all these women alive for no reason whatsoever. Why are we here, right? We're just kind of crowding. But then there's the opposite theory, which is called the grandmother hypothesis that it takes a complete different spin on menopause which I find much more reasonable and says women are helpful.

51:33Even if you're not reproductive, you can still be productive and productive we sure are. And so Dr. Kristen Hawks 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 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.

52:16And at the same time, what she was saying that I think is very smart is that those women back then, we're 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 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.

53:04So that's what she says. Grandmothers are actually evolutionary heroines. It does make sense. Yes, I think it makes sense. I wanna get back to the scans, which you were going to share. And I wanna 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. So these are the brain scans, I'll show you. It's show and tell. Yeah, show and tell. So this is a kind of brain scan that I specialize in. So this is a positive on 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.

53:54And 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. 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.

54:35And 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 singular cortex, which is important for social cognition, 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.

55:14That'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. 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 premenopausal 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.

55:59And 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 going to loop and start again, right? So you see there's a lot of red that just kind of fades away. Not completely, obviously, but there is clearly a shift. And I'm not 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. 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.

56:47Now, 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. 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?

57:25No. 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. 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.

58:06And 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? Premenopausal, perimenopausal. And then for some women, that's it. The brain finds a new normal and stabilizes. And that is your new baseline. at least in terms of metabolic activity. For some women, there is a little bit of a rebound in some parts of the brain.

58:47I have not seen brains that go back to the premenopausal 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 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 attract women over time, starting in midlife, so that we can compare notes.

59:40Right now, all the evidence we have is from, kind of from us. 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? 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.

1:00:20Just 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 it's the gentlest way, it's the most gentle way to go through menopause. Many women, unfortunately, go through menopause for other reasons. 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. 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.

1:01:13And 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 20s, in your 30s, in your 40s, any age before menopause. Because it's a surgery, the ovaries are gone, 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 the menopause can bring about are also more severe. That's very important to consider because we don't do that enough.

1:01:58Is there a study that tracks women who have had hysterectomies and developed Alzheimer's later in life? Yes. And what does that ratio look like? Well, what this study shows 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 that just a little bit higher if only the uterus is taken out. but is 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 in that respect.

1:02:38We're moving in that direction. I definitely have a lot of questions about that. I'm always worried that I'm not going to get to. Yeah, no, no, no, go ahead. 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. It's called amenorrhea. Sometimes it's permanent. So they may end up developing menopause because of that, which is really unfortunate.

1:03:18And they suffer that we don't have 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 care. Yeah, I mean, I do wanna 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 wanna better understand the differences amongst these things. Like what is Alzheimer's exactly?

1:04:03How is it different from what we would call dementia or other forms of perhaps just natural mental or cognitive decline that comes with age? 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 currently based on symptomatology and histopathology. So 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 so the plaques are between neurons and the impaired 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 in synaptic deterioration where neurons can no longer communicate effectively with each other.

1:05:20And 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 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.

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1:07:39On 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 gonna get into that and diet and chronic inflammation and all these sort of things that contribute to heart disease, 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.

1:08:31Yes. 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 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.

1:09:31And 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 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. Nor are they all that efficacious, right?

1:10:11I 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 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 for ourselves. And it's scary. 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.

1:10:56But 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. 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 these diseases are taking root for decades before they truly show up and impact us in negative ways is a call to action, but also encouraging because we do have 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.

1:11:40You've been incredibly prolific with sharing your wisdom, experience, and knowledge. But curiously and interestingly, your first book was called Brain Food. 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, I mean, as everybody should be, we should be deeply mindful of what we're putting in our mouth a couple of times a day.

1:12:18I 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? is something that increases your vulnerability. I apologize if I created that impression. 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.

1:12:59So 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. Right, right, right. I just don't want to scare anybody. Yeah, yeah, yeah. 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. Thank you, that's exactly the point. No, it does not cause dementia. It just increases the vulnerability, I believe.

1:13:33Yeah. Okay, 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. 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? 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.

1:14:13And 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. Yeah, I thought it was exercise, but I guess it depends on how you look at it. 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. 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.

1:15:09Seems 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 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. And 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 they can do for you.

1:15:59So I think it's important. There's toxins in our home care products or cleaning products 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. On social media, not in academia. What do we know about food and brain health? You call it neuro nutrition. Neuro nutrition. How do we eat to fuel our brains? 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.

1:16:42So 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 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.

1:17:26But 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. 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.

1:18:18So 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. 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-3s, the omega-6s, plant-based foods have a lot of really good building blocks for the omega-3s and the longer omega-6s and omega-6s.

1:19:07So that's the kind of fact that your brain wants that I think we would want to prioritize in our diet. Right, the brain runs on fat. You should be eating a high fat diet, high in cholesterol because the brain needs that cholesterol. Nonsense. Nonsense. Okay, thank you for that. You've advocated for a Mediterranean diet approach to nutrition with an emphasis on greens, like a sort of 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. Yes, like lean protein as well that comes from vegetables.

1:19:55That's what this kind of greener Mediterranean diet prioritizes. But 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, is it on a plant-based diet? For me personally, the most important nutrient group for brain health is antioxidants. Why? Because the brain is the most metabolically active organ in the body and it runs on glucose.

1:20:41So 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 beta-carotene, 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. Brazil nuts, yeah. So these antioxidant nutrients are found exclusively in plant-based foods. So if you're eating a carnivore diet, exclusively meat, you're depriving yourself of those nutrients.

1:21:31Then 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. Antioxidants are important for brain health. No matter your diet. So Brazil nuts, but what are some of your favorite high antioxidant foods that you would recommend? 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 they like to go seasonal. So right now, persimmons. We found this kind of persimmons that are cross with apples.

1:22:14So they're a little crunchy. And 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. Most people think about blueberries, but blackberries actually have a higher antioxidant content. The blueberries, goji berries are a great source of vitamin C. Amla, the Indian gooseberry, is probably the highest antioxidant capacity of all fruits.

1:23:00Oh, I didn't know that. What about Moringa? Moringa citrifolia, yes. That also is good. Maldberries, and they taste like honey, which is really sweet. It's a good snack. Prunes. Prunes? Prunes. They have a good amount of vitamin C, antioxidants, and soluble fiber. So our grandparents and great-grandparents, at least in America, drinking their prune juice, they knew what was up? 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 a little dessert.

1:23:36They're yummy. Nuts and seeds and green leafy veggies, leafy greens are also really good sorts of vitamin C. So broccoli, pale, cruciferous veggies. The more the better. I think really you can't go wrong with fruits and veggies. 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.

1:24:28There'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 it might be helpful in that respect over supplementing 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 so you can build a reserve.

1:25:14But 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 astreides, 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, you know, whatever you're concerned about.

1:25:59And then if you're low, then it makes sense to supplement. Right. Otherwise it doesn't seem to be beneficial for brain health. 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? I do not think the menopause has been linked with nutritional deficiencies, but calcium could be low. And we tend to recommend calcium and vitamin D supplements for bone health. Has that been related to Alzheimer's disease? 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.

1:26:48So 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 in these brain scans in women of menopausal age, premenopausal, perimenopausal, it seems to correlate. So the more antioxidants you have, the higher your brain energy levels, which is something that we want to. Yeah, if you do nothing else to increase the amount of antioxidants in your diet every day. I think that is very important because as you do it.

1:27:28I mean, you should do that anyway. Yes. And as you do it, it means you're prioritizing foods that are good for you to start with. 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. 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.

1:28:09So 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 on estrogen levels. And also eating carbohydrates or plant-based foods is important to support the estrobolum. 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 estrobolum, which is made of good friendly bacteria that are involved in estrogen metabolism. They help regulate estrogen levels. There's one enzyme in particular, it's called beta-GUS, that's been investigated right now.

1:29:03This 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. And especially oligosaccharides, We showed a type of carbohydrates that comes from plant foods that are slightly bitter, like onions and asparagus and beetroot and ginger.

1:29:51Yeah, yeah. And they're really helpful in that respect as well. So there are many ways that you can use diet to support hormonal health and of course, phytoestrogens. Most people are fiber deficient in their diet and it's a pretty easy fix. 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.

1:30:41Like this communication between our microbiome and our gut and what's happening in our brain is nothing short of fascinating, dictating everything from cravings and impulses to modulating all of these unconscious systems that were running in the background. And that idea. 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. 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 it's relatively unaffected by what happens from the neck down, which turns out to be completely wrong.

1:31:35Yeah, it sort of makes inroads on our degree of sentience, right? Like who's making the decisions up here and why, right? Yes. Which is humbling, I guess. It's humbling, but also I think it gives you power because then you can effectively help your brain, right? 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 brain health. Let's talk about exercise. Let's talk about exercise. You can talk about it.

1:32:16You sort of referenced, you know, low intensity, consistent movement as the most beneficial. Moderate intensity. Moderate intensity. That's like hiking. It's when you can talk, but you would have a hard time singing. We call it zone two around here. Oh my goodness.

1:32:38Why do you laugh? Thank you, thank you. So, okay. Is there a sense that that's really what the focus should be? Like, 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? No, when I was talking about the moderate intensity exercise, it comes from studies that specifically looked at health outcomes in women in menopause.

1:33:20And 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 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. but then once you start going high intensity, the benefits go down. Now, why is that? I think, remember these are observational studies, they're not clinical trials.

1:34:03So what I think they're capturing there is that moderate intensity activity is more sustainable 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.

1:34:48If it works for you, great. But many women are discouraged by what they hear on social media or television 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, you must don't have the time to rejuvenate. Is that a good one? 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.

1:35:32If 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. 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? So 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.

1:36:16Our neurons, the vast majority of our neurons are born with us and stay with us for a lifetime. 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. Yeah, we'd be lunatics. 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.

1:36:58And that's why consistency is key. Right, you can go to the gym two weeks. The best exercise is the one you're actually going to do. 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?

1:37:37Or is there a point of no return? Obviously it's gonna depend individually and all that. 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.

1:38:24So we know, for instance, Since 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. Oh, wow. And there are studies that followed by hundreds of women for many, many years, up to 40 years.

1:39:09And 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. Wow. Midlife is up to 65, right? But there's no clear limit. That's massively significant. 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.

1:39:58So there are so many different ways that we can impact brain health by moving our bodies that just out of common sense, if you can do different things that can help different aspects of brain health. So if we all had time to do it, that would be wonderful. 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? Oh, yes. Yeah, we're getting into it now. Yeah, it's gonna get controversial. So as you know, there was this Danish study that came out recently that seemed to say on the surface that hormone replacement therapy was associated with a 24 % increased risk of dementia.

1:40:49Now, 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 a advisable protocol? 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.

1:41:36There'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. 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.

1:42:17What 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. And the estrogen is like 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. 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 and why right so just for history, because it's frustrating to me, estrogen was discovered in the 1930s.

1:43:25And 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, estrogen, testosterone, progesterone, they were so important for fertility and reproduction actually had a huge impact on the brain.

1:44:11They were just as important for the functioning of our minds. 1996 is when the scientific community really bought into this idea that sex hormones are actually not sex hormones. They're neuroendocrine hormones, right? There's multiple roles. What's the problem? When did we get to the moon? 30 years prior. When did the biggest clinical trial of hormone replacement therapy begin? 1993. 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 for menopausal symptoms.

1:45:01That 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? when you're older after menopause, right? Especially Alzheimer's. Well, that's when it shows up. You start getting it when you're in your teens probably. 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.

1:45:47So I'm going to start enrolling women who are 65 and older. What's the problem with that? They're already post-menopause. 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.

1:46:34And 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 hormon therapy by then to stop. Both cancer and dementia. That's enough to scare, right? Sure. Yes. And pharmaceutical development also stopped and so did research. So that was a problem because we know that hormones are meant to be taken as you go through menopause, not after, right?

1:47:23They'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. 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?

1:48:04Do 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 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.

1:48:53that 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. 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're from. 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.

1:49:34And this is what we found. Two things. When you take hormones matters. If you take them for menopause, as you go through menopause 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 progestogen. So there are different types of hormones. They can be bioidentical, that's 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.

1:50:17Or you can take slightly different versions that we refer to as synthetic or progestins. Okay, turns out that matters. 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 and progestogen 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.

1:51:11It's about 32%, which is good. Significant. 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 show 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. Doesn't increase it, doesn't make it better. 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.

1:52:00However, 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 is 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.

1:52:46But 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. Right. But if you start too late, there's an increase. It looks like more than just a risk. I mean, that's a pretty steep curve there. 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.

1:53:36Whereas other forms of synthetic progesterone do not increase risk nearly as much. in the most important thing, I think, is that bioidentical progesterone, which is what most people use now, has never been linked with a higher risk of Alzheimer's. 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. Yes, also these studies are observational, which is a problem from a clinical perspective. You want clinical trials. Right. Right, because you can control a lot of variables, you can standardize, they're more conservative, it's better.

1:54:19The 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 the hormones 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. Right, right, right, right. Right, so this is what we're doing now. So this is what you're doing at your lab. 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 - Phytocerm, is this what you're gonna - Yeah, yeah, yeah, I wanted to ask you about this.

1:55:06Okay. Yeah. Do. So it's like a plant-based, plant-derived version of estrogen that you're currently testing. Yes, it's called the designer estrogen. So it's a CIRM, 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.

1:55:57The beta receptor is more expressed in the brain. So what this specific CIRM, FIDOSERM does is that it binds only to the better receptor. So it leaves your breasts alone and it's not been linked with a higher risk of breast cancer. That sounds promising. 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'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.

1:56:42And this is reducing half-flashes and night sweats, improving sleep in some women to some extent, reducing the risk of osteoporosis, and also helping with vaginal dryness, vaginal atrophy and painful sex or painful intercourse, which is very prevalent after menopause. So these are FDA approved. 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.

1:57:33And 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. They're 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 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.

1:58:23So 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. Are there other pharmacological interventions that you would recommend somebody who's on the precipice of going through menopause explore? 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.

1:59:17a physiognitant, but we still need to see. More studies. 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 being considered, especially for low libido. That's the primary indication at this point. 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 half lashes. Like diet, just one second to go back to diet. Women who follow this Mediterranean style diet, it's just a healthy diet and it's plant centric and there's all the good nutrients and the good foods have at a minimum 20 to 30 % fewer half lashes than women on Western diet.

2:00:08Wow, that's a lot. Yeah. That's more significant than I would have thought. Yes. Yeah. Yes. And I think it's important to know that you can change your outcomes. And even women with breast cancer can safely go on a healthy diet and reduce the risk of hot 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, let's put it away, diets. And then they change their diet pattern, show the significant reduction, not just in the number, but also in the severity of half lashes, which really supports a role for dietary interventions in that case.

2:00:54And 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 a 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. That's wild. So if you're dining out consistently on ultra processed foods, you're looking at an earlier menopause. Just really a pity. Wow. Yes. That's interesting. Sleep. Sleep. We talk about sleep all the time here.

2:01:38Like I don't wanna reinvent the wheel. Like we all know we need more sleep than we think and 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 declining diseases. So sleep really is the only chance that your brain has to take care of itself.

2:02:22Because 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 is 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 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.

2:03:10So 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? Because so many people experience fragmented sleep, right? We don't sleep soundly through the night.

2:03:52Many 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 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 higher risk of infections and brain fog and other negative things that can impact your brain.

2:04:36And for women in particular, I would say that menopause can disrupt sleep significantly. More than half of all women of perimenopausal and postmenopausal age had trouble sleeping. and at least one in three has trouble not only falling asleep but also staying asleep through the night. This is something that deserves a conversation because it doesn't just sink your energy. Right. It 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.

2:05:37So it's all related. This is the 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 in a restorative way. Yeah. 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.

2:06:16And I'm like, I don't know how you function. And she seems fine. Wow. I mean, 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 our restful state is elusive. Oh, 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.

2:06:59for instance, which is why I switch to decaf and preparing for not sleeping. That's my sleep is not great to start with, but I don't have the energy that your wife has. Yeah, I mean, you know, she, her body is her Oracle. Like she doesn't put it, 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. It's just the way it is. She's, you know, channeling energies from the beyond or something. But anyway. 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.

2:07:39Because at some point your body will wake you up if it's ready to go, even if your brain doesn't want to. 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 p.m. you still have half of that caffeine going around your blood and inside your brain. But also means then, 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.

2:08:29And 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. 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 tired and you have every reason to be tired.

2:09:23But 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. 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 brain protective strategy besides something that can help with menopause as well.

2:10:11Testing, I wanna 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? Well, in general, it's good to have a really good baseline. So blood work is helpful. Which blood markers do you think are most critical to pay attention to?

2:10:53Is it total cholesterol and HDL? LDL, HDL, lower density lipoproteins as well. Total cholesterol, triglycerides for the lipids. For metabolic markers, usually it's insulin, glucose levels, hemoglobin A1C. 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. I would measure nutrients as well, but I know that this is now standard of care.

2:11:44So these are important to look at. What I would really love is to do a cognitive evaluation. Right. And what does that look like? That's what I wanted to ask. 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 that 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 your age and with your same educational level.

2:12:29But most importantly, that's you when you're feeling good. So then... You have a baseline. 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 or 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.

2:13:11Then we do the test again. We can compare you with you, which is every doctor's dream, right? Rather than saying, well, you know, relative to other people you've never met 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 score 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.

2:14:00But at least a 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. 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. Yeah, also if you don't feel good, yes. Which is a great idea. 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 and going crazy.

2:14:41Maybe I have dementia. Maybe I have this, maybe I have that. If 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. 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. 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 an actor in that movie and I freak out.

2:15:26I'm like, it's beginning, it's beginning, you know? And it haunts me. Of course. I completely, completely relate. But talk about these brain scans. I wanna have my brain scan too. Will you scan my brain if I come to New York? Okay. Absolutely, and bring your wife. I need to know where she gets the energy. I would love to see what her brain scan looks like. Yes, we would be delighted to. So I run the Alzheimer's Prevention Program, a wild coconut medicine in New York City. We're on the Upper East Side. So it's 72nd New 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.

2:16:12We 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 just currently no easy way to get this kind of brain scans 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.

2:16:57We look at whether or not there is evidence for any sort of damage. We screen for so many things because the brain can get affected, obviously. So you may have cysts, you may have tumors, you may have a brain tumor. There could be aneurysms that can be malformations, that can be vascular damage, that can be gliosis, that can be inflammatory disease, that 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, any incidental finding, we manage that. So there are different things that one can do to address what we find, anything that we find.

2:17:42Is 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. 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 based. And then if you 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.

2:18:28It's kind of scary though too. It feels very vulnerable. I guess. Yeah. But it's good to have a baseline, let me tell you. Because at this age, it's very unlikely. You are doing the work that you're meant to be doing because you just light up when you talk about this stuff. So, 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 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, the health pages of whatever magazine you're reading or newspaper or social media channel that you're on, And 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.

2:19:48So 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 and see strange interpretations of your field. I suffer. Then that's, I think that's the short of possible. I suffer. You could become a full-time social media warrior on this. No. Can you imagine? No, I cannot. newspapers I really appreciate the New York Times and the Wall Street Journal we were mentioned their feature 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 I'm learning.

2:20:51Social media is harder for me. It's really, I don't really know how to address it because we're all entitled to our own opinions, obviously. What is shocking to me sometimes is, and 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. But that they have no expertise in whatever field they're talking about. 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 don't have the same degrees, but really read and pay attention and inform themselves.

2:21:40You 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 2 ,200 words or characters to explain something complex. So there's an oversimplification that must happen. 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. But other than that, do you know what to do? 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.

2:22:40I 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 really kind of vetting our opinions and what we're consuming against other sources that 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. Yeah. 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.

2:23:27And 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, 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 where the experts in their given field go to get their information in a trustworthy way.

2:24:08Yeah, it's a really good point. I get my information from scientific publications. Yeah, you're going to sell in nature and science and all these things that like none of us are gonna read. 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. It's tricky. So there's something called peer review in academia that I never appreciated as fully as I do now, which is 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.

2:24:54So 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 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 that make you also sound a lot smarter than perhaps you are in some cases.

2:25:34Whereas 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.

2:25:45I know that this is not possible to do outside of academia, but something that 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, and how much money you bring into your hospital.

2:26:34The same for scientists. We're basically like CEOs of a start that will not 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'm telling you, 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. You know, 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. Well, I think it takes a very certain type of individual.

2:27:16Like 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. Absolutely. And being a public face of an idea or a corner of the science world is its own vocation, with its own pressures and responsibilities. And I think people go into science mostly because of their interest in the science itself. Yes. 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.

2:28:10And then you go out and you sit down with people like me to communicate around it. And I know that's a - It's a stretch. Yeah, it's a lot. It's an honor. 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. Thank you. But I appreciate it. Yeah. I hope it's helpful. No, it was 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.

2:28:49Come back and talk to me some more. I could talk about neuroscience all day. All right, thank you. Yeah, thanks. And I do wanna get my brain scanned. Oh, good. So I'm gonna follow up with you on that. Yeah, let's do that. Okay, cool. Cheers. Peace. Bless.

2:29:11That'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 in the Plant Power Way, as well as the Plant Power Meal Planner at meals.richroll.com. 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.

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2:30:36Thank 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. Namaste.

2:31:16Thank you.