Women’s Health Month: Women and Alzheimer’s Disease

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. May is Women’s Health Month, with May 8th-12th being celebrated as National Women’s Health Week. Across the United States, nearly ten million women are affected by Alzheimer's disease, either living with the disease or serving as a care partner for someone who has it. In honor of the 21st annual Women’s Health Month, we’ll be discussing how women are affected by Alzheimer's disease and preventative strategies to help you prioritize your brain health. Joining us for this discussion is Dr. Jessica Caldwell. Dr. Caldwell is director of the Women’s Alzheimer's Movement Prevention Center at Cleveland Clinic in Las Vegas and an assistant professor of medicine at Case Western Reserve University. Dr. Caldwell, welcome to Dementia Matters.

Dr. Jessica Caldwell: Thanks so much for having me.

Chin: How did you get involved in the field of Alzheimer's disease and with this focus on gender or sex differences?

Caldwell: I came to this field in a roundabout way. When I was in grad school, my area of study and research was brain imaging in adolescence. And of course, adolescence is a time where things that come up – like anxiety and depression, behavior changes – they are impacted or directed by our sex and gender. At the same time, I was training clinically in neuropsychology at the Medical College of Wisconsin, and there I worked mostly with people with memory concerns. Up until the last few years, these kind of proceeded as two separate tracks for me. I had my research interests, I had my clinical interests. And then I came to Las Vegas and had the opportunity to start doing sex differences research in Alzheimer's because we had a philanthropic donor – Maria Shriver – who really wanted to see some work get started here. It's been an amazing experience, just kind of finding my calling.

Chin: Given the importance and predominance of women being affected by Alzheimer's, am I right in thinking that you're still in this unique position of being able to study exclusively the gender differences in Alzheimer's disease and do it clinically too?

Caldwell: Absolutely. Right now we are the only prevention center that's clinically designed just for women. And even though the research world really is getting to emphasize sex and gender effects in multiple diseases, the field is young. Whether you're talking about Alzheimer's disease or cancer or epilepsy, this is an area that unfortunately lags behind a lot of other types of research.

Chin: So then, what are the sex differences? And I'm thinking about this in two parts, Jessica, so in normal aging, normal brain functions – learning, memory, or language – but then also in those who are experiencing Alzheimer's disease?

Caldwell: Overall men and women's thinking – so things like memory, attention, spatial skills – they're more alike than they are different, but there are some sex differences we know about that then can impact disease. So in particular, we know that on average women are better than men are at verbal memory tests. So if you give a man and a woman a story to hear, a list of words to try to remember, women on average perform better on those tests. On the flip side men tend to outperform women on visual spatial tasks. So if you ask someone to mentally rotate a shape and match it or navigate a maze, men tend to perform better there. How could these be relevant to disease? When it comes to Alzheimer's disease, as your listeners know, verbal memory is impacted early. It's really the hallmark of Alzheimer's disease – forgetfulness, forgetting conversations. Women tend to have a steeper decline in their verbal memory after they're diagnosed. Why might that be? There might be two reasons, and this has been really the heart of my research. Reason one is more of a biological reason. Reason two is more of a measurement-error reason. On one hand, women have this reserve as I call it in memory. We outperform men and there's something about that that can really benefit us early on if we have a process like Alzheimer's disease in the brain. We have better memory. We have more to draw from. It takes us longer to show symptoms, which is good until that reserve runs out. Then we have a steeper decline. So that's kind of the biological side of things. The other thing to think about when it comes to sex differences in verbal memory and Alzheimer's disease is that when someone comes into a clinic or a research study to get diagnosed with Alzheimer's disease, the primary test that they're given for that is a verbal memory test. This means that women's advantage in memory – the fact that we can hold on longer before we show impairment – means that we very likely are getting diagnosed at a later disease stage than men are. So while it could be an advantage, it also is a disadvantage at the same time because we are later to get treatment.

Chin: So the tests that you administer in a clinic, those aren't considering gender? They just consider age or education level?

Caldwell: Absolutely. There are many different sorts of neuropsychological tests. What the goal of those tests is is to compare a person who's sitting in your testing room to other people their age, sometimes also of their same education level, sometimes also of the same gender or sex, but not always. Many of the memory tests that are the core standard tests that clinicians and researchers use don't take into account sex. This is changing and so it's something that many researchers are focused on, my groups and others. It's important for us, especially in the clinic, to be able to pick up on women as early as we can pick up on men.

Chin: And you mentioned that – or some of your papers, I should say too, have mentioned that the course of thinking changes looks different and you highlighted that there's a more rapid decline in women because of that resilience, or at least that they perform better on testing in verbal memory. Do you see any other changes in, whether it's aging or disease, how the course looks between men and women?

Caldwell: I think the course change – it's not just that it's more rapid in women. It's really that, in men, it seems to be, when you think about how memory and thinking change, men look more continuous or linear over time. With women, what you see is more of a plateau followed by a falling off the cliff. It's not as though women aren't declining to the same level as men. It's just that when that decline hits is a little bit different. If you look at a man's memory when he's cognitively normal but he's going to get Alzheimer's Disease, you can just see over time that start to decline. With a woman, you can't start to see that decline as well until the MCI stage or the time when a person is already starting to have impairment on memory tests and other thinking tests.

Chin: And I know this is probably a question you get all the time but I'm still going to ask it because I think it's important for us to hear your response. Why are women more affected by Alzheimer's disease than men? In your prior answer, you didn't mention anything biologically different between men and women and Alzheimer's pathology, so what do you say to that?

Caldwell: Sure. This is a great question. In, you know, days before about ten years ago, it was pretty commonly thought that women had higher rates of Alzheimer's disease because we live longer than men, and that's true. The most significant risk factor for Alzheimer's disease is just getting older, so there is a part of the story that's told just by our differences in longevity but that is not the whole story. Beyond that we have research evidence that supports that there are some factors that impact women more than men when they come on board as a risk factor. One example of that is diabetes. There's research suggesting that diabetes is a risk factor for Alzheimer's disease. Not only that but that if a woman has it, it impacts the brain more significantly than it does for a man. Another example of that would be genetic risks. ApoE 4 allele is the most common risk factor for late-onset Alzheimer's disease and having a copy of that ApoE 4 allele increases a woman's risk of getting Alzheimer's disease more than it does a man. There are risk factors with that differential impact. There are also risk factors that are more common in women. Here, I would think about something like physical activity. Being physically inactive is a risk for Alzheimer's disease, and on average women are just less active than men are so that could be part of the story. Then finally, there are some things biologically that women go through that men don't that could be part of the story. Here I'm really talking about estrogen loss at menopause. A lot of people think about estrogen as related to menstrual cycles or pregnancy. They don't really understand how critical estrogen is for the brain and for memory. Estrogen directly supports memory; it supports the health of the hippocampus, that region of the brain that's impacted early in Alzheimer's. Research suggests that some women may have a particularly bad time with menopause such that losing estrogen at that time isn't something that they recover well from. It may be true that we the people that that's true for are really the people with other types of Alzheimer's risks on board as well like a genetic risk.

Chin: This is more of a historical question, but I'm wondering if you, in all of your time in this field, are there other disproven theories – or not disproven – but are there other theories that people have speculated that just really aren't true when it comes to the differences between men and women?

Caldwell: Well, I think that one good example of theories that are not true is just the thinking around menopause and around the menstrual cycle. Back in not even that long ago – I'm talking about maybe fifty years ago, forty years ago – researchers thought that the menstrual cycle was essentially damaging and that these hormonal changes really could relate to uncontrollable mood symptoms, dangerous mood symptoms. At the same time, menopause was thought about as, you know, almost – it's the end of your fertility years, but it was also thought of as almost a senescence in a grand form so that women at that point were treated differently in terms of just your cognitive strength, your ability to contribute to society.

Chin: I think a really important change in our field of Alzheimer's disease is truly investigating the life exosome, or this idea of social determinants of health. When I think about some of the age of our participants and our patients who have lived through so many things, I wonder just your thoughts on this idea that women have gone through different things. They went through different discrimination, more discrimination. They were excluded from education and from being a part of some very cognitively stimulating activities, and the stresses I'm sure were different. Do you think any of these things play a role now?

Caldwell: Absolutely. I think women are exposed to differential social determinants of health, especially in the current generation who are being diagnosed with Alzheimer's. Women just had, typically, less educational opportunities, less educational encouragement, significant barriers to advancement in the workplace and to holding the kind of jobs that give the most cognitive challenge, and really a barrier socially that if you did those kinds of things you were looked at differently. It wasn't seen as womanly to be in that kind of a career field. From a clinical standpoint, I think it's important if you're assessing women that are this age to really think about, you know, not just their education but their potential. What did they do in their life? What were their grades like, even if they couldn't go to college? What were their aspirations like? Then, of course, I'm kind of looping stress into all of this. I think that women are exposed to different types of stressors than men. Research supports that women have more relationship and violence-related stressors that they're exposed to on average and definitely being exposed to these gender-related stressors. Then you combine that with our bodily sex-based stress response. Women have a different environmental-biological combination that we face early on and when these things, stressors, are chronic, it could be setting us up for a disease in a different way than men experience.

Chin: I want to transition to biomarkers too, because you had a very interesting publication in 2021 that showed women had more tau protein burden – tau being the second protein in what we think of as Alzheimer's amyloid and tau – more burden than in men. This was most significant at that stage of mild cognitive impairment. There were also differences in how tau affected people with symptoms. It just seemed very complicated. I'm hoping you can summarize some of the key takeaways that you got from that study.

Caldwell: Sure. A lot of the research that I and my colleagues have done is really looking to figure out why women have this different disease and memory decline trajectory in Alzheimer's. So in this particular paper what we were looking at was whether or not tau buildup, in terms of how much is present in the brain and how quickly it builds up across which regions, might underlie some of those memory differences. We looked at people who had normal cognition, MCI, and Alzheimer's disease dementia. Across all of those groups, what we saw is that women had more tau in their brains. How that relates to memory? We went back and looked at folks who are cognitively normal and saw that women had what we expect – even though they have more tau, they've got better memory than men. Then the MCI stage comes – women have a lot more tau than men, and now their memory is about the same as men's. So women have lost something by that MCI stage but even though they have significantly more tau burden, they're performing equally well as men. This is supporting the idea that women's brains have some resilience against the pathology. It doesn't last forever, so beyond MCI we see a decline, but it suggests that women really have a different kind of peak tipping point for cognitive symptoms than men do.

Chin: Now you were a part of a different paper from 2018 showing that women with elevated amyloid and all the other proteins may show more resistance to the pathology than men. This was in terms of more brain size or particularly the shrinkage of the brain. What exactly did you find in this study and why do you think that's significant?

Caldwell: Sure. In this second study that was from 2018, what we did was look at more than 500 people who had either normal cognition or very early stages of MCI. What we wanted to know is when people have amyloid in their brain that we can pick up with a PET study, does their level of neurodegeneration or brain shrinkage differ in men and women. These are folks that we have a pretty good indication that Alzheimer's disease is in the brain at this point. It's years before symptom onset in the case of the folks who are cognitively normal. What we found in this study was that those folks with amyloid in their brain, when you looked at men you could see that the size of part of their hippocampus was already smaller than men without amyloid in the brain. When you looked at women with amyloid in the brain, there was no difference if you compared them to women without amyloid in the brain in the size of the hippocampus. Similar to some of our other studies, it seems like women's brains – even at the level of brain structure – have some resilience to pathology building up in other areas of the brain. In the case of this study if we think about it as a brain reserve, that was gone by the early MCI stage. So again, this isn't something that lasts and benefits women throughout the disease course but it is something that impacts us early and might impact the way that we're picked up and the way our symptoms present.

Chin: Now more recently in February of this year, 2022, you were part of a study showing sex differences in cortical thickness and memory performance. To start, I want you to explain to our audience, you know, what is cortical thickness? Why does it matter? And then, what did your study show about it and gender?

Caldwell: Yes. I'm going to take one step back and just mention that – so in the brain, if you think about it in basic terms, we have two types of matter: we have gray matter and white matter. The outer layer of the brain is highly folded, giving it a bumpy kind of a look, and the outermost layer of that bumpy cortex is the gray matter. What the cortical thickness is the width of the gray matter in that folded cortex. What that is is the neurons. So the width or thickness of that cortex is important because it's an indicator of the health of our neurons in those regions of the brain. In the healthy brain, it might be correlated with your cognitive function, your educational level. Then when it comes to Alzheimer's disease, the cortical thickness can be an indicator of where people have started to have atrophy or shrinkage of those cells, loss of those cells. In this study, what we wanted to do is see whether or not cortical thickness, especially in those regions of the brain that are important in Alzheimer's disease, is different in men and women and whether that's important for memory when someone's on the Alzheimer's disease spectrum. What we found was that when we looked at men and women, especially early on when folks were cognitively normal but at risk because of amyloid in their brain, women had thicker cortex than men in those Alzheimer's disease related areas. When women had thicker cortex, they performed better on memory tests, suggesting that the thickness of the cortex could be another area where we have some resilience.

Chin: So Jessica, we've talked about a lot of your recent publications and so what is your next project? What are you working on currently or will be soon?

Caldwell: Right now, I'm working on a large NIA – National Institute on Aging – funded study that is aiming to look at whether the stressors that women experience throughout their life might meet and interact with estrogen loss at menopause to really impact intermediate factors that we know increase Alzheimer's risk. In particular, do those two things impact peripheral inflammation in our bodies? Do those two things impact the way our brain uses resources when we're trying to remember? I'm really interested in whether or not we can look at these things at midlife.

Chin: I'd like to transition now to your clinical work. How does your research on sex differences and Alzheimer's disease impact your clinical work as a clinical neuropsychologist assessing people's thinking abilities?

Caldwell: I think because of the work that I've done on sex differences in Alzheimer's disease, I ask about some different things in my clinical interviews when someone comes in for a memory assessment than I might have before. One of those is menopause and hormone replacement therapy. I think it's so important to take that piece into context when you have someone sitting in front of you saying their memory is different, because we know menopause can impact memory in a short-lived way. So if you don't ask about that, you don't have that context to help you understand why memory could be changing. I also do ask more in-depth questions about a woman's education, about her activities throughout her life. This is really because women that are being diagnosed with Alzheimer's disease at this time – I think that not only can they be missed on some memory tests but I think a lot of folks might be underestimated because women didn't potentially have the same potential achievement opportunities, whether that's in jobs or education, as men did and you really want to take that all into account. Then finally I do ask a lot about stress levels. So folks who are worried about their memory right now are often part of the sandwich generation, so they might be caring for elderly parents with Alzheimer's, they might have young kids at home, and they might also be working or balancing other responsibilities. A lot of the time those stressors by patients, they kind of see them as just, ‘Oh, this is what everyone does,’ not realizing that having that level of stress in your life could impact anybody's memory.

Chin: I think a really important question that comes up in memory clinics and certainly during your neuropsychological evaluations is hormone replacement therapy in women who have just gone through menopause or in perimenopause – and I want to preface for our audience,  as a nonphysician you're not encouraging or discouraging one way or the other. I just want to hear your opinion on hormone replacement therapy as a potential when it comes to cognition.

Caldwell: So something that I really like that you said is people are asking about it. Hormone replacement therapy is a hot topic in research and it's an area where we don't have all the answers yet. This is why people should be asking about it. We know some things about hormone replacement therapy and memory risk. There were large studies done that showed that women who are long past menopause should not be on hormone replacement therapy, should not start. It can be damaging. On the other hand, women who have very early menopause, for example in their 30s, might benefit from being on hormone replacement therapy because they're going through that menopause so much earlier than than expected. The middle they call the window of opportunity. Around that time, the perimenopause, the menopause, we don't know yet who should take hormone replacement therapy 100% and who should not. This is the time when I encourage women to talk to your women's health provider. The most important thing that you can do is advocate for yourself, tell your provider if you're having symptoms, and work with your provider one on one to figure out your risk factors related to hormone replacement and what potential benefits you might have. I think that maybe in five to ten years I would be able to give a more straightforward answer, but what research is doing right now is figuring out who should take the hormones at that perimenopause and exactly what hormones we should be taking.

Chin: So given your focus when you assess a woman's risk for Alzheimer's disease and dementia, what types of prevention approaches do you discuss in your clinic?

Caldwell: In the prevention clinic, we talk about a lot of different strategies that women can use to reduce risks for Alzheimer's. Some of those strategies are really medical in nature. We talk a lot about avoiding things that run in your family, like diabetes or high blood pressure, or treating them if they're there. We also talk about habits. Quitting smoking is key for dementia risk reduction, the same thing with moderating alcohol use. Some of the things that we talk about are more psychosocial, so we talk a lot about staying socially connected, getting enough sleep, and making sure that you have enough cognitive challenge out of your life. Not just staying busy, but really actively learning is what is best for brain health. Then, of course, we have some things that we talk about with respect to exercise and nutrition, which is probably what most people think about when you think about lifestyle prevention.

Chin: Well into that end then one of my questions – one of my favorite questions that I ask my guests is what do you do to keep your brain as healthy as possible and, in particular, what do you think is the most important for yourself?

Caldwell: For me in keeping my own self healthy and my brain health protected, my top three are sleep. Even when I have a lot on my plate, I prioritize sleep so that I know that I'm getting that optimal kind of rest and healing time for my brain. I prioritize exercise. It's a huge multitasker when it comes to brain health and mood, so I make sure five to six days a week I'm exercising. And then the last one for me, personally, is really being mindful of the stress on my plate and how I'm responding to it because if I personally or anyone gets into a stress cycle where you're wrapped up in it, it's going to be so difficult to really complete the other activities that we know are important for brain health because stress can really be such a barrier.

Chin: Well thank you, Dr. Caldwell, for being on Dementia Matters and we do hope to have you on in the future.

Caldwell: Thank you so much.

Outro: Thanks for listening to Dementia Matters. Be sure to follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you get your podcasts to be notified about upcoming episodes. You can also listen to our show by asking your smart speaker to play the Dementia Matters podcast. And please rate us on your favorite podcast app — it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Rebecca Wasieleski and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu. You can also follow our Facebook page at Wisconsin Alzheimer’s Disease Research Center and our Twitter @wisconsinadrc. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.