 And most people, I think the general public assumes that men get dementia more than women. But in fact, the opposite, like you say, is completely, you know, it's exactly the opposite. It's exactly the opposite, yeah. The vast majority of people who get dementia, Alzheimer's, are women. And you guys are so much healthier than us men. You would assume, right? You would assume. So what I think is really interesting is that Alzheimer's disease is the only age-related neurodegenerative condition that affects more women than men, like Parkinson's, more men, vascular dementia, 50-50. So there seems to be something specific to women that increases the risk of Alzheimer's. So what is it about women's brains that are so unique that this seems to be a problem more for women than for men? Yes, there are many things that make women's brains really unique. And I think a big determining factor is really hormonal health, because I think it's very helpful to think of brain health as impacted by a number of factors. Like you have your genes, you have your DNA, you have a lifestyle, you have your medical health, you have your environment, you have your hormones. And all these factors really act synergistically to determine a person's risk of Alzheimer's. But at the same time, a person comes with allies. There are things that reduce your risk and other factors that can increase your risk, like the Apolypoprotein E, the ApoE4G, and you mentioned before. And hormones are actually incredibly powerful allies that protect you against Alzheimer's and brain aging at large. The difference is that men have a lot more androgens like testosterone. Women have a lot more estrogens like estradiol. All these hormones are very powerful. They're very energizing and they really keep Alzheimer's plaques at bay. They're anti-inflammatory, they support neuronal growth and plasticity. But they have different lifespans. The testosterone levels don't really decline that much until later on in life, whereas female estrogens really drop pretty dramatically during menopause. And menopause is midlife. So when we started looking into that, we found that women's brains change quite a bit in midlife during menopause. And therefore some women, and we looked at their brains using their brain scans once, twice, over time, over the years. What we found is that for some women, the drops in estrogen levels correlate with the formation of Alzheimer's plaques, which is counterintuitive because we associate Alzheimer's with old age and menopause with middle age. So that is a little bit like a paradox. Sorry to interrupt you about paradoxes, but it is true. And what my work and other people's work have shown is that Alzheimer's disease starts with changes in the brain years, if not decades, prior to clinical symptoms. And for women, that crucial time seems to overlap with menopause. So you don't start worrying about your risk of Alzheimer's when you're 70 as a woman. You better start thinking about it when you're 40 and 50. Okay, so that's the bad news. That's the bad news. So are you saying that let's just generalize that every woman should think about hormonal replacement to prevent Alzheimer's? Or what are you saying? What I'm saying is that there are many things that one can do to reduce risk of Alzheimer's and hopefully prevent it. And what our data is giving us is a timeline, right? So we now know that women tend to develop Alzheimer's earlier than men in their brains and that we can catch the signs of increased risk very early on in life. That we're looking at women who are in their 40s and we can really find signs of an increased risk of Alzheimer's. And then I think that's really the key to prevention. I think it gives us a timeline and it also suggests that perhaps hormonal replacement therapy, which you mentioned, could be helpful. We don't know for sure. We don't know for sure. And I think a lot more research is needed to test the preventative potential of hormonal therapy. Okay, so nobody should go away from this saying Dr. Masconi says I have to get on hormonal replacement therapy when I'm 40 or it's the end. No, no, no. I would not say that. Actually, I'm very cautious in recommending medications for Alzheimer's prevention. I believe in clinical trials. I believe that drugs should be tested very thoroughly for efficacy, but also side effects. And we really need to understand who is eligible for it and who would benefit from these drugs. So something I want to clarify is that not all women who go through menopause develop Alzheimer's plaques. And not all women with the plaques develop dementia later in life. So I think phenotyping is very important. It's very important to have a solid baseline. And it's important to understand our own risks. And like what we were saying before, there are many risk factors for Alzheimer's that we can control. They can also really help improve hormonal health, right? So instead of jumping to a pharmacy with a prescription in hand, there are other things that I would recommend doing first, which really speak to lifestyle, diet, exercise, other things that we know impact our hormone stress reduction is a big one. So that's a good segue into this. Because everyone who comes into my office does not get a prescription for estradiol and progesterone and testosterone, quite frankly. In fact, most don't. And I agree with you, and I actually just did a podcast on this. There are certainly well-recognized effects of estrogen on women, particularly vascular reactivity. And I have a subset of women who, even small amounts of estrogen replacement as a patch, make a huge difference in the way their brain functions. And I was taught this by a gynecologist. He said, believe it, there are women who absolutely have to have a small amount of estrogen, or their brain will not work. And their vascular reactivity will not work in their brain. Is that what you guys are finding? I think the response to estrogen replacement therapy is variable. For some women is a godsend. Some women really swear by it, other women swear at it. So the response is very highly individualized. And I think that we need better tools and better tests to really predict whether or not each individual woman will benefit from the therapy. And we're working on developing that. And something that is very dear to my heart as a scientist, because we can measure hormones in blood, but there is no correlation between those peripheral hormones and the hormones inside the person's brain. So we need to be able to quantify estrogen levels in the brain to really dose the therapy correctly and to refine the timing so that we can better understand when to start and when to stop. Like, do we want to wait until a woman is menopausal to give her the patch, which is kind of common practice? Or would it be better to perhaps start earlier and see we can delay menopause? Would that be better? So I think there's a lot of research that really needs to happen and hasn't happened yet, which is honestly offensive. We might have been going through menopause forever and everybody's complaining of hot flashes, night sweats, depression, mood swings, brain fog, memory lapses, and we haven't really done the research that we need yet. And that's half of the population. So you say in your book that the idea that women have no control over menopause is a myth. Can you elaborate on that? Yeah, there are many myths surrounding menopause. There are many things that we don't fully understand or that perhaps are not being explained thoughtfully or accurately to women. So many women don't actually know how menopause works. And I find it endearing in some ways when I do explain that menopause starts in the brain. And so many women are not aware of that and they feel so relieved when I mention that because any woman can tell you that, like you were saying before, that something is happening inside their heads and they're worried that they might be going crazy or that maybe it's happening only to them and not to the other 850 million women around the planet who are not going through menopause and they're experiencing exactly the same level of confusion or changes. So that's something that really made a point of clarifying in the book. Then there is a lot of stigma around menopause. In 2020, it's still quite a taboo. But there is so much that we understand now that we really need to talk about and discuss with women and between women and with men, honestly, because it's a family thing in the end. And going back to your point, menopause is partially genetically mediated in that if your mom went through menopause when she was 43, chances are you're also going to menopause at the same age. If your mom went through menopause at 55, then you're very fortunate because there's a good chance you may also go through menopause later than average. However, there are things that are known to precipitate menopause and other things that are known to delay the onset of menopause. The bad things are definitely smoking, which is the number one cause of early menopause and unhealthy diet in the very high level of chronic stress. So if your mom went through menopause at 58, right, but you've been smoking for 20 years, chances are that you'll go through menopause much earlier than she did. And then there are all the good things that actually delay menopause, which are the good things we always talk about. Oh, let's hear it. Like a healthy diet. Let's talk about that. So, well, a healthy diet is a big deal. There are many studies including an examination of hundreds of thousands of people showing that the more fish you have in your diet, the later the onset of menopause as a woman, of course. And on the other side, if you eat a lot of refined sugar and refined grains, that seems to accelerate the hormonal decline that leads to menopause. So it's good to think about diet in terms of something that can actually impact the health of your hormones, as well as the health of your brain. And there's evidence that dietary patterns like the Mediterranean diet, for example, also really promote hormonal health in women, also support fertility, and that associated with fewer hot flashes in the later onset age of menopause, as well as a number of other things. So better cognitive health, reduced cardiovascular issues, reduced depression in women. So a healthy diet is very crucial, I think, for overall health. Everybody's on a different diet, but I think that on average, just staying away from processed foods would be a really good positive change in everybody's life. So let me back up for a second. Is there any evidence, then you're the expert on this, that if you go into menopause early, let's say in your 40s, early 40s, versus going into menopause in your 50s, that you're better off the later you go into menopause? Number one. And number two, if you go into menopause early, do you throw up your hands and say, I'm screwed? Oh my gosh, now what do I do? The first answer is yes. The second answer is no. Ah, okay. Good. So there is increasing evidence that a longer reproductive lifespan is protective against dementia in women, especially in women. And by longer reproductive lifespan is kind of a metaphor for the longer your body is exposed to your estrogen. So women who develop and go through puberty at the average age or a little bit earlier, like when you're 12 and go through menopause later on, like maybe around age 55, 56, they really seem to have the lower risk of dementia as compared to women who have a shorter reproductive lifespan. So they start menstruating later in life and to go through menopause earlier, whether genetically or because of medical interventions. And I would like to mention hysterectomies and operectomies are the number one cause of early menopause for American women. And those are surgical procedures in which the uterus and or the ovaries are removed. And unfortunately, there is evidence that having the uterus and more so the ovaries removed prior to menopause correlate with a much higher risk of dementia later in life for women. So I think it's really important to talk about this and it is depressing news and it is upsetting news, but it's really important that we talk about it because so many women are not aware and so many doctors are not aware. So many OBGYNs just don't know. And so if you go to your doctor because you have fibroids and they're like, well, you know, you're suffering so much, maybe we should take out the uterus. Let's talk about keeping the ovaries because one of the major reasons for removing the ovaries is that they just happen to be there. Well, we're in there, yeah. Yeah. So I think it's really important to raise awareness of the fact that reproductive organs are there for a reason and they can't just be taken out that easily because there's a connection with your brain that is not the inner conversation material, but it's true. Your brain is in constant interaction with your ovaries as a woman and the ovaries talk back to the brain influence in brain health in return. So it's a network that we really need to nourish and that's a big part of my book because it's really about understanding the system and these interactions and how to really nurture them. Now, another part of that is, okay, so what about pregnancy? Where does that come in in the picture? It's a very good question. It looks like the number of pregnancies is just not associated with Alzheimer's risk. There are some studies that show that the more children you have, the higher your risk of Alzheimer's, whereas other studies have shown absolutely opposite. So at this point, we don't know. What we do know is that the number of pregnancy does not correlate with your age and menopause. It doesn't seem to... Because some people think, well, I haven't had my cycle for nine months so I'm going to catch up later. It's going to be... Menopause is going to be delayed by at least nine months, but that doesn't seem to happen. Ah, interesting. So is there any correlation between pregnancy or no pregnancy and developing Alzheimer's or dementia? I think the research is not clear on that. And this is something that we're looking into right now, clearly at the women's brain initiative because it's such a big deal for women's brains. And then my friend, one of my friends, she's a psychiatrist, and she got pregnant years ago when having kids was not even a thing for me, not even on the radar. And she was telling me that she felt like she had postpartum dementia, that she couldn't... She could not remember things. She was having such a hard time just getting through the day mentally. She's one of the smartest, the most capable women on this planet. And that was like, yeah, yeah, yeah. You just need to sleep. Then I had my baby. And it was like, oh my God, what is happening to me, to my head? And so I think this is something I really want to look into. There's this beautiful study in nature neuroscience that came out just a few years ago showing that women's brains, after pregnancy, throughout pregnancy and after pregnancy, really go through remodeling where the brain kind of loses gray matter that you can see on MRI scans, which sounds like a negative thing, right? I'm losing something inside my head. But a lot of people believe that these changes reflect a maturation process, like something that like, what happens in puberty, that the brain just starts going through this pruning phase where a lot of connections are discarded because you don't need them anymore and it's much more efficient to have a very efficient, very compact brain. And it looks like something similar might happen to women's brains as we become moms because all the attention needs to be on the baby. That is better from an evolutionary perspective. And that leads to discarding other connections that are no longer needed. And I find it to be very insightful and I wonder if something like that can also explain menopause because women, we actually humans, we're just one of the very few species that go through menopause at all. There are just two species on the entire planet that go through menopause and these are women and killer whales. And I find that so cool. But if you think that all other species, in all other species, the female dies when she's no longer fertile. Whereas for us, is an advantage to become grandmothers at some point or at least that's what nature intended for us. And no longer be fertile but still be around and help the family really thrive and grow. So I find it very, I find it beautiful in some ways. Okay. So let's talk about exercise. Since we've been talking about food, how important for women is working out for brain health? It is very, very important and I think there's quite enough convincing research showing how women don't exercise nearly as much as they could or should. And they most certainly exercise less than men do for a number of reasons which is not to blame women for it but it's really a number of reasons that go from just being a mom and holding full-time jobs and taking care of the family and taking care of your parents and your husband's parents perhaps there's just so much that's going on in a woman's life and the men's life as well but for some reason women and I think any woman would acknowledge that we're just so good at putting everybody else and everything else before us and then the downside is that we don't get to move our bodies as much as we could but there's a lot of evidence that exercise is not just good for overall health is also specifically helpful for your brain and is really a well-established preventative against Alzheimer's and dementia so the fact that women don't exercise as much as they should raises concerns because that could also be one of the reasons that more women than men end up with dementia later in life right and there is very encouraging research showing that exercising reduces the risk of dementia for both men and women but more so for women than for men there was just this wonderful study published with it was over 200 women that were they were followed for over 40 years which I found was incredible and they showed that your cardiovascular level your fitness level in midlife is really predictive of future risk of Alzheimer's disease so the women with the highest level of fitness basically did not decline to Alzheimer's disease that the current rate close to 0% whereas women in the lowest percentile of fitness declined to Alzheimer's at the rate of 30% which means of every three women who don't exercise at least one is going to get Alzheimer's disease so it does not convincing enough I don't know what could be and I also want to mention because I don't want anyone to feel bad about not exercising we have so much guilt around not doing every single thing we could which is clearly unsustainable you know you only have that much time in a day or a week but there's very encouraging evidence that you don't have to to run a marathon you know we we think about outside about exercise mostly in terms of running jumping aerobic exercise and a lot of women just can't do them maybe they're too tired or they're going through menopause they're going there's so much else going on but there's a lot of evidence that lower intensity exercise if done consistently is just as good as high intensity exercise done once in a while and is also less likely to cause inflammation in the body for women who are going through menopause or perimenopause and have a lot of cortisol and have trouble sleeping so slow and steady wins the race as long as it's consistent yeah I agree in fact I write prescriptions for many of my patients to get a dog because dogs actually make you exercise twice a day whether you want to or not and I yeah that's a lovely idea yeah I actually write a prescription and don't say they keep you company yep lower your stress level yeah it's really interesting I have a number of people who come back with that prescription frame that it was the best prescription a doctor had ever written for them so I'm gonna keep doing it I love that if it's okay I'm going to mention that you do that because it's such a good idea yeah no it really is so can you reverse dementia reverse is an interesting word for a scientist you know I know that's been used with books yeah podcasts and magazines for me reversing Alzheimer's means that you're getting rid of the symptoms and you're getting rid of the pathology so the Alzheimer's plaques are gone the tangles are gone the inflammation are gone your neurons are growing back and your symptoms are gone so far I haven't seen that happen the hope is that it will right now I think we are as a field that the Alzheimer's field is coming together in finally accepting that prevention is feasible we got so much pushback for so long that we couldn't even publish a paper with the word prevention in it just recently we had to cross it out of the title really switch yeah absolutely there were I think we had six reviewers which is a lot of reviewers and at least three raised concerns about the word prevention and so we had to cross it off and just replace it with risk reduction you know you do what you're gonna do but the point is a lot of people still don't believe that prevention is feasible the risk reduction is more you know it's more like oh okay it's not a strong award but obviously I'm the associate director of the Alzheimer's prevention clinic while Cornell which I thought was kind of brave so obviously I believe the prevention is feasible and there's a lot of data shown at the very least one-third of all Alzheimer's cases are potentially preventable so I do believe in prevention and I most certainly hope that Alzheimer's disease will be reversible all right well that's a good place to end all this as we're getting in touch with me I'm on Instagram I'm not big on social media but I am on Instagram at drmasconi dr underscore masconi and I have a website which is lisamasconi.com and I actually answer direct messages wow for now no I really do my best to really respond and make friends and it's really be in touch with everybody because it's so informative I find that all the questions really inform my research because as a scientist there are a lot of questions that I have on my mind and a lot of things I wouldn't think about all right well thanks for joining us good luck with the book I know it's going to be great and thanks for you know bringing this attention to women for some obscure reason we've got to get the word out that you know women are the main sufferers of Alzheimer's disease yes all right thank you so much thank you for having me thanks so much for watching this episode but don't go anywhere I think you're going to love this next one now you might think okay if glucose is energy I should eat as much glucose as possible to give my body as much energy as possible makes sense makes sense well actually that's not the way it works and you have