Sex Differences in Alzheimer’s Disease

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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: My guest today on Dementia Matters is Dr. Michelle Mielke, professor of epidemiology and neurology at the Mayo Clinic in Rochester, Minnesota. Dr. Mielke studies sex-specific differences in the risk and progression of neurodegenerative diseases including  Alzheimer's disease. Another focus of her work is biomarkers of Alzheimer's disease. Thank you, Dr. Mielke, for taking the time to join us for an episode on Dementia Matters.

Dr. Michelle Mielke: Well thank you. I’m really happy to be here.

Chin: You're a part of the Alzheimer's disease research center at Mayo Clinic and so your ADRC has a very robust research, diagnosis and education program. Many of the National Institutes on Aging affiliated Alzheimer's disease research centers across the country have specialties and focus areas surrounding dementia research. Could you share with us some of the program highlights from the Mayo Clinic ADRC?

Mielke: Sure. Let me first start by just giving a little bit of a background about the Mayo Clinic ADRC. Our ADRC is a collaborative effort between Mayo Clinic Rochester and Mayo Clinic Jacksonville in Florida. This really allows us to capitalize on the strengths of both institutes. Mayo Clinic in Rochester has a larger clinical practice in which we can recruit patients into research including Alzheimer's disease but also other types of dementia such as Lewy body dementia and frontotemporal lobe dementia. Rochester has been more of a leader in developing neuroimaging and fluid markers of Alzheimer's disease and related disorders. Jacksonville is the home site for our department of neuroscience at Mayo Clinic. Rochester has some basic science up here but neuroscience is really located in Jacksonville. That's our hub for any part to do with basic science research genetic research. The brain bank and neuropathology group is down there and that includes brains from the Alzheimer's disease research center as well as the state of Florida’s Alzheimer's Disease Initiative, so it's quite large and covers a variety of dementias. In addition, investigators in Jacksonville have developed a cohort of African Americans to cognitively follow. That's advantageous to our group because – as you know and a little bit more similar to Wisconsin – the population around Rochester, at least at older ages, say 65 and older, is primarily white. It allows us to add a little bit more diversity and to examine differences between whites and Blacks in terms of risk factors. Using this, capitalizing on these different strengths – as you mentioned each center has different focus areas so the theme of our combined Mayo ADRC is to investigate the similarities and differences among neurodegenerative diseases. In addition to enrolling a good number of  Alzheimer's disease patients, we also enrolled several patients with frontotemporal lobe dementia, many with Lewy body dementia and then some patients that are at risk of Lewy body dementia. REM sleep behavior disorder is a significant risk factor for further developing dementia and so we enroll some of those participants as well and follow them. Then the general focus is to try and understand the overlaps between these different dementias with regards to clinical symptoms, neuroimaging measures, genetics and pathological mechanisms.

Chin: In that vein then some of your research is focused on addressing the sort of gap in our understanding of sex and gender differences in the development of the various cognitive disorders that you mentioned, including Alzheimer's disease. Could you start by explaining to us what differences currently exist?

Mielke: Yeah so that's – let me just first start out in saying that while we might say, “Duh,” to ourselves at saying there are differences between men and women, there really is limited understanding of sex differences in the development of any type of cognitive disorders including  Alzheimer's disease. There is starting to be more research in the area so if somebody is interested, this is a great time to get involved or start to follow as new things are coming out. It's certainly been a hole in trying to understand Alzheimer's disease and other dementias. There's a lot of media around sex differences for Alzheimer's disease. Many listeners have probably heard reports that women are at greater risk, but as with all things, with science in general, things are much more complicated than just a simple statement. Different terminology is used which can also make it more confusing, Let me just start out by giving an overview of, I guess, the epidemiology of Alzheimer's disease and sex differences and what we're finding right now. If we look at the frequency of Alzheimer's disease, which is the count or the total number of women affected with Alzheimer's disease and the total of men affected with Alzheimer's disease in the U.S. Roughly two-thirds of all clinically diagnosed Alzheimer's cases are women but it's important to keep in mind that Alzheimer's disease is an aging-related condition and women live longer than men. By simple count, as a result, there's more women at older ages and therefore there are more women with Alzheimer's disease. In fact some of the work we're currently doing in the Mayo Clinic Study of Aging is trying to understand some of these sex differences. We find that men who – if you compare men and women with Alzheimer's pathology, so amyloid and tau in their brains, men are more likely to die before they develop symptoms. Once they're diagnosed with dementia, men are also more likely or at greater risk of dying sooner compared to women. There's certainly a mortality bias there. If we start to look at incidents – this could be defined as, say, we compare a man or woman, let's say, at the age of 75 and we followed them for five years and we want to find out if over those five years more women or more men develop  Alzheimer's disease or other types of dementia – when we look in the U.S. almost every study has not found a difference. There may be slightly elevated increases for women as compared to men but it's not significant and is generally not close, but what's interesting is that although we really don't see a difference in the United States when you look at some countries in Europe and other countries around the world, such as in South America, there does appear to be a greater risk for women. Again, if we're comparing a man or woman at the age of 75 or 80 and follow them for a specific number of years, in those countries women do appear to be at greater risk.

Chin: And so what are some of the proposed or even historical explanations for some of these differences that you're seeing, as well as some of the ones that are currently being explored by researchers such as yourself?

Mielke: I think we, at this point, don't fully know what these differences are but the exciting part is that the fact that there are differences by countries suggests that there are probably cultural differences such as diet, societal roles that can cause these differences between the U.S. and other countries. This is particularly exciting to me because a lot of these factors can potentially be modifiable. In terms of cultural roles, education for women, different types of diet, if we can identify those then that is something that we can use for preventive or for treatment efforts. One specific explanation as to what some of the differences might be between the U.S. and some European countries is the impact of World War II. Although the U.S. participated in World War II and many of the men from the U.S. went over and fought in the battles, the experience for women was quite a bit different. It's not to say that women didn't experience hardship here and of course went to work and had a lot of stressors but that it is a little bit different than women who were say in Italy or Germany or some of the other countries in Europe who experienced not only the war itself but also a lot of the political upheaval before and after the war, which also led to less availability for education even beyond the availability for women at the time. That stress could potentially be contributing to the excess risk of dementia in women in those countries. It'll be interesting to see over time if this evens out or if those countries still tend to experience greater risk for women.

Chin: And what role – I mean, when thinking about the biology of men and women, what role do you think pregnancy and menopause play in the development of cognitive disorders and  Alzheimer's disease?

Mielke: So that's a great question and has been a major focus of research for women within the  Alzheimer's disease field. My view on it is that pregnancy and menopause do not cause cognitive disorders or Alzheimer's disease per se. You know, all women go through menopause but not all women are going to end up with developing cognitive impairment or Alzheimer's disease or other dementias down the road. I see the role of pregnancy and menopause more as stress tests to potentially identify the women who are at greater risk. If you think about with pregnancy and, of course, menopause there are certainly hormonal changes but there are also a lot of other synchronous adaptations that the body must go through. With pregnancy, you've got a change in immune response so the body doesn't reject the fetus. You've also got change in the vasculature so the body can take on more fluids and a whole host of other symptoms. As women are going through these, it gives us an opportunity to kind of stress the body system and see if there are any adverse events potentially as a result. In some cases it's kind of similar to undergoing a cardiology stress test, where you might not see differences in heart rate or other heart parameters just by sitting at rest but when people go start to exercise that's when you see differences. I view it a little bit similar with pregnancy and menopause. For example, with regards to pregnancy, one thing we have been examining is whether there's a difference in risk of cognitive impairment for women who develop hypertensive pregnancy disorders or preeclampsia during their pregnancy. One of the the first studies that we published using the Family Blood Pressure Project, which incorporated about half the cohort was white and half the cohort was African-American, we found that those women who did have or did report they had pregnancies with high blood pressure or with preeclampsia, sometimes also called toxemia,  when these women were in their 60s and 70s, they had worse cognition and they also had greater brain atrophy. This suggested to us that maybe hypertensive pregnancy disorders could be a risk factor for dementia. Hypertensive pregnancy disorders have previously been shown to be risk factors for hypertension and cardiovascular disease, and so this research and some of our current studies are trying to figure out what the impact of these disorders on the brain are. I think the positive aspect of this is that once these women are diagnosed and identified, we can follow them up more closely and make sure that their vascular risk factors are properly treated and also conduct cognitive screening, maybe starting in midlife to better assess their risk. It gives us the stress test of pregnancy gives us the early opportunity to better identify those at risk. Similarly with regards to menopause – again all women go through menopause but not all develop Alzheimer's disease. What's apparent is that some women go through menopause and they hardly have any symptoms, whereas other women go through menopause and they experience a wide variety of symptoms, some very severe especially related to mood changes and hot flashes. Some of the new research right now is suggesting that women who experience the most severe hot flashes may be at greater risk of cardiovascular and cerebrovascular disease down the road. Now, while more work is needed, this may be an opportunity, again, to identify those women who are at greater risk of cerebrovascular disease and potentially also dementia and therefore follow them more closely.

Chin: In particular with menopause, because there's so much discussion about hormones,  obviously that's a huge hormonal change for women.

Mielke: Right.

Chin: Could hormone replacement therapy be something that might change this course, this risk factor or the trajectory that someone might be on as far as cognitive change?

Mielke: That's a great question. Maybe I’m a little long-winded again, but there's a whole history in terms of thinking about hormone replacement therapy in women after menopause and its relation to dementia. It's also another thing that hasn't been explained fully and there have been a lot of confusing messages regarding the use of hormone replacement therapy, which can also be called menopausal hormone therapy or estrogen therapy. When the original observational studies were out in the 1990s, they suggested that the use of hormone therapy could reduce your risk of dementia, specifically Alzheimer's disease. However, a limitation with just observational studies – which means just following women over a number of years, maybe ten or 15 years, and observing who develops dementia or not – is that you do have a healthy user bias in terms of who ends up taking or using hormone therapy. Typically women who are healthier or those that are more educated and maybe ask more questions to their physicians are more likely to be prescribed to hormone therapy. The first really large randomized clinical trial to examine hormone therapy was the Women's Health Initiative. Actually at the time that was the largest and most costly trial to date that the NIHhad funded. That trial had looked at the impact of oral estrogens – conjugated equine estrogens – versus placebo on risk of dementia as well as a variety of other outcomes. The research was – or the outcomes were published in 2002 and suggested that women who were randomized to the oral estrogens were actually at greater risk of dementia and of cardiovascular disease compared to women that were randomized to placebo. This really threw things up in the air and was opposite of what a lot of people had heard in terms of observational studies. It ended up drastically changing the practice and the number of women that were on menopausal hormone therapy really plummeted after that. However, there was a key limitation to the study, and that is that the mean age of the women at the time of randomization was about 65 years. The average age of menopause for women is about 50 or 51, so they were starting the estrogen therapy on average about 15 years after they had gone through menopause. Women's bodies got used to being in an estrogen deficient state and then, after several years, were given the estrogen. So one thought was that after the re-exposure, that might have actually increased adverse events such as dementia and cardiovascular disease. Since then there have been a couple of other clinical trials that randomized women to menopausal hormone therapy or placebo but started the estrogen therapy within a couple years of onset of menopause. In general, those trials have not found a detrimental effect of the use of estrogen therapy. They have not found really a protective effect either, even with following women over four to seven years. I think, you know long story short,  the initiation of hormone therapy maybe ten to 15 years after natural menopause we think can increase the risk of dementia but if hormone therapy is initiated during the menopausal transition or a few years afterwards, it does not appear to have an effect on estrogen either negative or positive. I wouldn't necessarily go in and prescribe or think about taking menopausal hormone therapy just to prevent dementia but I think women who especially are experiencing menopausal symptoms and its impacting their quality of life, I want them to know that in general it is okay to take menopausal hormone therapy and that it won't directly affect the risk of dementia down the road.

Chin: Now one of the things that you mentioned earlier in your answer was conjugated equine estrogen and so that – equine being horse, correct? – and so I guess I wonder too – and I get a lot of questions from my patients – about what if we didn't use equine and we used a more human-based sort of replacement therapy. Do you think that that would make a difference in some of these results or that that might not actually have an effect?

Mielke: Yeah that's a great question and something that we and others are interested in. There does appear to be evidence that 17-beta-estradiol may be better for brain health as compared to the conjugated equine estrogens which are orally taken. Just to highlight one study, the Kronos Early Estrogen Prevention Study, or KEEPS study, it is a study that randomized women to the oral conjugate equine estrogens, 17-beta-estradiol patch, or placebo within three years of of natural menopause. They followed them for up to seven years. Now, they didn't see any difference in terms of cognition between the two estrogens but two investigators – Dr. Kejal Kantarci from May and Dr. Carey Gleason from the University of Wisconsin–Madison – did a sub-study where they imaged those women that were at the enrolled at the Mayo Clinic site, so there were about 100 women, and they did amyloid imaging, tau imaging, and then also MRI. Within that subset, they found that those women that were randomized to 17-beta-estradiol had lower amyloid levels in their brain compared to the conjugate equine estrogens or to placebo so they now have a large study of all sites that were enrolled in the KEEPS, so there are about 800 women, and they're going back and imaging everybody to see if they can replicate that finding. Of course, as you mentioned if they do, that would suggest that 17-beta-estradiol, at least for brain health, may be more protective and it may actually be a protective factor.

Chin: Yeah, I'm glad you clarified that for us. I think that is an important finding. I didn't realize it was Mayo and UW, so that seems kind of biased that I asked it but I think that's a great – (laughs) 

Mielke: (laughs)

Chin: – it's a great finding. I'm also wondering about genetic risks, in particular the risk factor of ApoE e4. Are there differences in the development of Alzheimer's disease for people with ApoE e4 based on gender and sex?

Mielke: Yes, there does appear to be a difference. ApoE e4 is the strongest genetic risk factor for Alzheimer's disease. If you have one e4 allele of the ApoE e4 gene, you're at two- to three-fold increased risk and those with two alleles are at about an eight- to ten-fold increased risk. It's not a deterministic gene, meaning that not all individuals with the e4 allele actually develop dementia. There have been several studies, even recently, that have suggested that women with an e4 allele are at greater risk of developing Alzheimer's disease compared to men with an e4 allele. Now although we see this again in several studies, the reason for this is not yet well understood and there's a lot of ongoing research trying to understand that. 

Chin: Then in regards to biomarkers, like we mentioned with amyloid and tau, do those differ for women compared to men in regard to risk of disease or threshold for diagnosis or even predictive value?

Mielke: Yeah, when you compare levels of amyloid and tau, either looking in the blood, in the cerebrospinal fluid after doing a lumbar puncture, or in the brain after autopsy, there really is not a difference in the amount of these proteins for women versus men. However, there may be prognostic differences. A couple studies highlight this. One recent study had reported that, for the same level of brain amyloid measured via amyloid PET imaging, women were more likely to accumulate tauand accumulated faster than men were. This would potentially suggest that women would be at greater risk of developing dementia because tau is – the accumulation of tau, it causes neurodegeneration and that is more closely tied to clinical symptoms. Other studies, including looking at this in the Mayo Clinic Study of Aging, has not replicated this finding. That's still a little bit questionable there in terms of prognosis. There have been quite a few studies, both pathological and clinical studies, that have shown for the same level of amyloid and tau pathology, women are more likely to show memory impairment and other cognitive symptoms. Again, the reason behind this is not fully clear. One thought has been that women have smaller head sizes than men, and so therefore for the same level of pathology women have less resistance and therefore show more clinical symptoms. You know, again that's an ongoing area of research and something that we are interested in.

Chin: Well really, I would like to end our interview today with a question I ask a lot of my guests. For someone like you who's so knowledgeable in the field of  Alzheimer's disease, I really like to understand what do you do in your personal life to maintain that brain health and to minimize your own risk for Alzheimer's disease?

Mielke: Yeah, that's a – that's a great question. For me, I guess my focus, I do try and get enough exercise and I do try to eat the best I can. Those are the two main things. Actually for me exercise is really important in terms of stress. I can tell you that if I don't exercise for a couple days, my family will tell me to go to the gym, you know, “You're getting irritable and go do something.” I feel better afterwards. Certainly in terms of my mood it helps and other things, so that's something that I am very religious about. I probably work out five or six times a week. With diet, of course, in the current situation too, with working at home and you've got the refrigerator right there, that's a little bit harder but I still try and eat more fruits and vegetables. I really don't eat red meat, not to say that that's a specific risk factor for Alzheimer's disease but more of a personal choice in terms of family history and cardiovascular disease. I think those are the two things that I tend to focus on.

Chin: Well, I thank you for sharing that personal information on the podcast but we do appreciate learning from our experts in the field and what they're doing on a day-to-day level. And thank you for sharing all of the historical and ongoing context for sex differences, gender differences in Alzheimer's disease. With that, we would love to have you back on the show in the future time when you have more to share with us.

Mielke: Well, thank you so much it's been great to have an opportunity to talk with you. 

Outro: 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 was produced by Rebecca Wasieleski and edited by Bashir Aden. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. Check out our website at adrc.wisc.edu. You can also follow us on Twitter and Facebook. If you have any questions or comments email us at dementiamatters@medicine.wisc.edu. Thanks for listening.