Women and Alzheimer's Disease

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Evidence shows that two thirds of individuals living with Alzheimer's disease are women, and that changes in the brain occur two decades before Alzheimer's disease symptoms develop. In today's episode, we're diving into the risk factors that most impact women diagnosed with Alzheimer's disease and the work being done to prevent onset. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Jessica Caldwell join me for today's conversation. Dr. Caldwell is a neuropsychologist and director of the Women's Alzheimer Movement Prevention Center at Cleveland Clinic, part of Cleveland Clinic's Neurological Institute's Lou Ruvo Center for brain Health in Las Vegas. Jessica, welcome to Neuro Pathways.

Jessica Caldwell, PhD:

Thank you for having me.

Glen Stevens, DO, PhD:

Jessica, just as an introduction, why don't you just tell our audience who you are, how you got to where you are.

Jessica Caldwell, PhD:

I'm a neuropsychologist and I work here in Las Vegas. The way that I got here is I'm a clinical psychologist who always specialized in sex differences in the brain, but I started out looking at adolescence. Then over the course of my clinical training, I got interested in neuropsychology and memory problems. When I came to Las Vegas, it was the first time, seven years ago, that I had the opportunity to really bridge my research and clinical interests, and now I focus on sex differences in Alzheimer's disease.

Glen Stevens, DO, PhD:

Let's start broad. What risks impact men and women when it comes to Alzheimer's disease?

Jessica Caldwell, PhD:

Recent research shows that we know a broad array of risks impact whether or not men and women will get Alzheimer's disease. Some of these things are equivalent across sexes. For example, age is the number one risk factor for getting Alzheimer's disease. Just aging will increase our risk, no matter for a man or a woman, but on the other hand, there are some risks that we have that impact women to a greater degree. For example, our genetics may actually work against women in some ways. If women have a copy of the APOe4 allele, which is the most common risk gene for late onset Alzheimer's, it increases a woman's risk greater than it would a man's risk. There are also risk factors that while they might impact a men and a woman similarly, they're just more common in women. One of those would be physical activity. If you look across men and women on average, women are just less physically active, and that might put us at greater risk.

Glen Stevens, DO, PhD:

Do all women have one copy of APOe4?

Jessica Caldwell, PhD:

No. With the APOe4 gene, we can have a variety of combinations. We each have two alleles, and each of those can be a two, three or a four. The four allele has been shown to increase risk for Alzheimer's disease, and having two copies increases risk more than having one copy.

Glen Stevens, DO, PhD:

About a week ago, I was in California with a friend of mine who I had trained with many years ago. I think he told me he was doing the 23andMe testing, had it done. I don't know if his kids ordered it for him, but he said his APOe4 came back positive and he wished he didn't know it. Are you seeing more of that? People coming to see you just because they do the testing and it's positive, and do you see it more in women than men or not necessarily?

Jessica Caldwell, PhD:

Not necessarily more in women than men, but I do find that it's somewhat common for women to come to my prevention center because they've taken an at home genetic test and found out that they had a risk gene like APOe4 for Alzheimer's disease. On the other hand, many women know that they have a risk for Alzheimer's disease because they have a family history. I think it really varies by person whether or not people want to know about their genetics. For some people, it can be very motivating in terms of changing their behavior. For other people, it feels scary and not quite as helpful for making those behavior changes.

Glen Stevens, DO, PhD:

What are the factors that affect women independent of men?

Jessica Caldwell, PhD:

The big factor that impacts women and really doesn't impact men so much is menopause. Women at menopause lose estrogen fairly rapidly compared to andropause in men, which is losing testosterone, which happens much more slowly and gradually and to a less extent than estrogen loss. With estrogen, we know that estrogen supports memory. It's very active in the brain. It isn't just a hormone related to our reproductive cycles. As women go through menopause, our brains actually have to readjust to not having estrogen at the levels that have been there since we've been through puberty. For some women, and research is trying to figure out exactly which women, it appears that this estrogen loss is really a vulnerability factor for later developing dementia and Alzheimer's.

Glen Stevens, DO, PhD:

I'm a neuro oncologist, and one of the tumors that we see are meningiomas, and meningiomas can be linked with estrogen. They can have estrogen receptors, so we're always very careful about telling women about taking estrogen supplements. Of course, with breast cancer, heart disease, those types things, do you see women asking if they can take estrogen?

Jessica Caldwell, PhD:

Yes. One of the biggest hot topics in research for sex differences in Alzheimer's is actually hormone replacement right now. As you are pointing out, this is an area that's had an unfortunate and storied history, starting with the Women's Health Initiative studies, because estrogen is great for memory, folks thought it would be also great for preventing or reversing dementia. Unfortunately, it wasn't. Women who started taking estrogen and hormone replacement years after menopause had really unfortunate outcomes where dementia risk increased, cardiovascular disease risk increased, so that really changed the story about who should be taking hormone replacement.

Jessica Caldwell, PhD:

At this point, in addition to knowing that it's not really beneficial and it could be damaging to start HRT after menopause is over, the research does suggest that women who have very early menopause, so before age 45, might actually have some brain benefit from using hormone replacement around the time of that early menopause, whether it was natural or due to surgery, for example, but the big area that is still an unknown is really around the time of menopause. It's called, at this point, the window of opportunity. The hope is that there are some women, and we have to, again, figure out who they are. Is that people with particular genetics or lifestyles, but that some women may benefit from taking HRT in terms of brain health. At the same time, there isn't a simple answer, because as you pointed out, there are so many other things that estrogen does in the body beyond the brain, beyond reproduction, and the role in cardiovascular disease and certain types of cancers, of course, has to be a priority in discussing those kind of treatments.

Glen Stevens, DO, PhD:

I know this is about women in Alzheimer's, but I'm a man of a particular age, as I like to say, and testosterone decreases in us. Does the decrease in testosterone increase risk for men?

Jessica Caldwell, PhD:

Decreasing testosterone risk, it's one of those things that has been a little bit less of my focus of research, but what I can say is that there's a role for testosterone in women and it might be protective. Knowing that, it's also an area where we should be looking and we should find out. It's definitely not to the same degree as the hormonal changes in women, and that may just be because of the gradual nature versus the more rapid changes in estrogen.

Glen Stevens, DO, PhD:

Now, we may not have data on this, but women that go on anti-estrogen drugs, tamoxifen, that have sometimes low level breast cancer when they're young and will be on it for five years, any data to suggest that they have increased cognitive problems later in life, or are they a little more at risk, or not enough data to know?

Jessica Caldwell, PhD:

I think that there is active research in this area. I don't know if there's enough data to be definitive about long term effects, but there are some studies that are suggesting that aromatase inhibitors do impact memory in the short term for women, and some women may not recover as well. Again, I think this is an area where we have to figure out, who is this most disadvantageous for? Is it a particular age, a particular sort of genetic vulnerability, and so on.

Glen Stevens, DO, PhD:

Yeah. As you can imagine, it gets pretty complicated. There's an entity, I'm sure you're well familiar with, called chemo brain, and often times breast cancer patients are on other drugs as well, and then to try to differentiate one from the other could be quite difficult. Moving on, what about presentation of the disease? Do women present with Alzheimer's different than men?

Jessica Caldwell, PhD:

In terms of the actual symptoms of Alzheimer's disease, men and women both present with a common set of symptoms, and they tend to be forgetting of conversations, of names and also difficulty coming up with words in conversation. That said, every individual may look a bit different, but there's not a different set of cognitive symptoms that women present with versus men. It's more about the timing. Research shows that women do have what we refer to as a verbal memory reserve, or advantage. So on average, women have better verbal memory than men. Unfortunately, we in the clinic often times rely on memory tests, especially verbal memory tests, to diagnose Alzheimer's disease or pick it up early. So what this means is that often times women may be diagnosed later than men. So men may be diagnosed with mild cognitive impairment, or MCI, at an age when a woman may have similar levels of disease pathology in her brain, but just less memory symptoms, so women are showing the memory symptoms a bit later.

Glen Stevens, DO, PhD:

Again, being a man of a certain age, I know a lot of women of a certain age, and I do hear this quite a bit. Oh, my memory's not as good. It's menopause. That's why I'm having the problem, so I suspect that also contributes to the underdiagnosed. People don't go to be seen.

Jessica Caldwell, PhD:

Absolutely. I think that there are a number of issues surrounding menopause that really could impact women's insight into the fact that something's changing, or their willingness to just talk about it and ask questions. There's really still a stigma about talking about menopause, and part of that stigma resulted in most women not knowing that menopause is not just about changes in your reproduction and ending of that fertility time. It really means that there could be changes in your sleep, there could be changes in your mood, you might get anxious or depressed, and you also might have memory problems.

Jessica Caldwell, PhD:

We know that we can actually measure in many women a dip in memory around the time of menopause. That dip is actually accompanied by a similar change or recalibration in brain activity, as well as in some cases in brain structure, so the thickness of our cortex even can show a change. It's true that I think women, if they don't know about these things, it's really hard to understand whether or not a concern you have about your memory if it might pass, or if you should take it seriously and really follow up more significantly on it.

Glen Stevens, DO, PhD:

Jessica, you've done a great job outlining some of the problems, but let's move to prevention and the exciting things that you guys are doing in Vegas. The Women's Alzheimer's Movement Prevention Center, tell us how it started, why it started, what you're doing, what your role is.

Jessica Caldwell, PhD:

The Women's Alzheimer's Movement Prevention Center at Cleveland Clinic, we started because at that point in 2018, we were doing research on sex differences in Alzheimer's disease and we knew that there were these issues that we've been discussing, but Maria Shriver, who had been one supporting a lot of my research, came to Larry Ruvo, our philanthropic benefactor here in Las Vegas, as well as to Dr. Cummings and Dr. Saba and said, can we do more than just research? Can we actually start putting some of this research knowledge into clinical practice? I was thrilled to be able to help with that process.

I designed with some mentorship of these folks I'm mentioning, the clinic model, and I've been directing the clinic since 2020 in June, and it really is a place where women can come, have their risks for Alzheimer's disease assessed, and then have their risks directed toward behavior change. I work with women to prioritize how to change their lives and their behaviors in ways that reduce the risks of Alzheimer's that they can control, although there might be ones they can't, like their family history and their genetics.

Glen Stevens, DO, PhD:

I'm sure there's a lower cutoff and there's a higher cutoff of age. Who's your ideal age woman for this? We mentioned at the start it could be 20 years until things show up, and do they have to have a known risk factor to get into the study?

Jessica Caldwell, PhD:

To be a participant in our clinic, and really we are a clinic first, although we do have research embedded, to be eligible, we ask that women have either a family history of Alzheimer's disease or a known genetic risk, such as through a home test that they took or a test at their doctor's office. We also have a restricted age range of about age 30 to 60. The reason for that is because this is around the time where we can really work on primary prevention of Alzheimer's disease. Changes in the brain begin about 20 years, up to 20 years before symptoms start, and symptoms most commonly start around age 75, so we are looking for women who are either before or right around that time when we would expect pathology to start so that we can really make some changes and hopefully preventing the pathology as well as the symptoms.

Glen Stevens, DO, PhD:

Well, I don't know if it's good news or bad news, but I'm over your age 60 cutoff, and the wrong sex, of course, but I would like to believe that there's a lot of interest in your phone is ringing off the hook. How many people can you enroll in this? Is this unlimited, or do you have a set number of people, you've got the number of people? How long are you going to follow them?

Jessica Caldwell, PhD:

The first day we opened, we actually shut down the phone lines here in Las Vegas and shut down the website because we had so many women calling in wanting to be a part of the clinic. We are one day a week clinic, supported almost entirely by philanthropy. What this means is that we have a wait list. Right now, we are going to be continuing this clinic on into the future. We have support for the next few years, and then really what the limit is is the wait list, but the best way to get on the list is to go to our website and get it on our appointment list now.

Glen Stevens, DO, PhD:

It sounds like we need to encourage a little more philanthropy to increase the N.

Jessica Caldwell, PhD:

I agree. Until insurance reimburses prevention, we really are so indebted and relying upon philanthropy.

Glen Stevens, DO, PhD:

Of course, we'd have to duplicate you probably as well.

Jessica Caldwell, PhD:

This is true.

Glen Stevens, DO, PhD:

As it goes through. What types of preventions are we looking at for women? Give us some examples of someone that might have something that you would recommend a prevention for.

Jessica Caldwell, PhD:

So in my clinic, we focus on two categories of behavior change. One is we're working directly on what are termed modifiable risk factors for Alzheimer's disease. This comes from work published in the Lancet over the past five or six years that shows right now we think up to 40% of current cases might have been preventable if we had known about changing behavior, you know, 20 years ago. Things on that list include medical conditions, like high blood pressure and diabetes. So if women come in at risk for those things due to a family history, we talk about really watching to avoid those things, taking more care even than other women on diet and exercise. The list of modifiable risks also includes things like getting enough physical activity. While we work with every woman on physical activity, there are some women who really need to get moving to a higher degree. It also includes things like reducing alcohol intake. There's a particular level of alcohol above which you're actually increasing your risk for Alzheimer's disease. So if a woman comes in that range, then we would work together on how to get that reduced.

Jessica Caldwell, PhD:

In addition to those modifiable risks, of which there are 12, we still know a lot about different behaviors that support brain health that aren't on that list. Just a couple of examples that are very common in the clinic, one be sleep. We know that sleep is important for memory consolidation. We clear amyloid out of the brain during sleep, but that's that protein that builds up in Alzheimer's, and menopause could disrupt sleep, so very frequently we're working with women in the clinic to change their routines around sleep, or if it's a more chronic sleep problem to work with a therapist to really routinize that sleep and change some of those dysregulation. Another thing that's not on that modifiable risk that's so important for our overall health is of course our nutrition. Women may come in with great, great diets, or they may come in with a lot of processed food, so we'll work individually with each woman to try to change things in a way that's sustainable over time.

Glen Stevens, DO, PhD:

I know in the brain tumor area, for exercise for high grade tumors, there's been some data to support that five days a week, 30 minutes at a time at a brisk walk pace or more, patients with some high grade tumors live twice as long. Do you have any specifics with exercise? Is it aerobic, anaerobic? Is there a timeline? Is there a minimum amount that they need to do?

Jessica Caldwell, PhD:

With women, we try to really meet them where they are, so there's a couple of different things we talk about. One is similar to what you just mentioned, which is the CDC and the World Health Organization for brain health recommend about 150 minutes a week of moderate intensity exercise. Some women might not be exercising at all and we might be working towards that goal. On the other hand, research right now is looking into what kinds of exercise best support brain function. One of the types of exercise that has a lot of accumulated evidence behind it is high intensity interval training. For younger women, women in that 30 to 60 range, we talk a lot about incorporating intervals and high intensity intervals into their routine to potentially best maximize brain derived neurotrophic factor release both in the short term and the long term.

Glen Stevens, DO, PhD:

Very interesting. I guess I'm going to have to start doing some interval training, just in case. Just in case. Something I'm curious about, I hear a lot of women tell me through menopause their cholesterol goes up. Do you guys aggressively treat cholesterol?

Jessica Caldwell, PhD:

This is something that isn't as much in my area of expertise, so I should say within the clinic, I do work with a medical provider as well. In the beginning, we work with a family medicine doctor, and now we're working with a physician assistant to do more of the medical side of things. Our clinic, we don't prescribe, but what we do if someone came in with cholesterol issues is really aggressively recommend through diet and exercise that they continue to attempt to reduce that, but in terms of any prescribing, that's not something that we would do.

Glen Stevens, DO, PhD:

I always hate to ask this question, but compliance. Very motivated patients, they're going to do what you tell them to do, or tell me about the population.

Jessica Caldwell, PhD:

We have a population or group of women that's really extraordinary. These are folks who are highly motivated to change their health, to reduce their risk. I think that motivation comes from having watched a parent or a grandparent or multiple relatives decline with Alzheimer's. These are folks coming in who they ask for what to do, and then they do what you recommend. I think that in the first two years of us running this clinic, we certainly have learned some lessons. We've changed our model a bit to give women a little bit more exposure to our providers over the course of a year so that they have more chances to get that motivational boost and ask questions, but I would say on the whole, these women are honestly extraordinary with their adherence.

Glen Stevens, DO, PhD:

Franchising, push it out to the rest of the country. Any thoughts about that, or sort of see how you do over the first few years?

Jessica Caldwell, PhD:

I would love to bring prevention education and prevention practice to more places in the country, more places in Cleveland Clinic. I think that, as I said before, there are some limitations related to not being reimbursed by an insurance, so it creates a cost around this type of service, but that in my mind really means that I need to be creative. I need to work with my partners to really make sure that we're thinking of different ways to bring prevention out there, because I think that although prevention and long term outcomes, we will have to wait to get those numbers, we have enough data now to bring information on behavior change that women can start using to hopefully reduce their risks 20 years from now. I think that it's part of my passion and my ethical [inaudible 00:23:12] to really think that this is something important to do now.

Glen Stevens, DO, PhD:

Excellent. Any new research in the field going on that you want to share with us?

Jessica Caldwell, PhD:

Yes. There are a few things that are going on right now that are very exciting. One of them I alluded to a bit before, but hormone replacement therapy is a very hot topic, and there have been active investigations, some just starting by Dr. Roberta Brinton, who's at Arizona, and these studies are so exciting to me because the question is, who should take hormone replacement and can we build a better hormone replacement? I think that this is the approach that will be needed if we really, truly want to take advantage of some of these body systems that we know about, but have risks as well as benefits and if we can really use that precision medicine, personalized medicine approach to target treatments toward the right people.

Glen Stevens, DO, PhD:

Jessica, do you have any closing remarks that you'd like to share with our audience today before we end?

Jessica Caldwell, PhD:

I think it's important to just know that there's hope when it comes to Alzheimer's disease. There are things that women and everyone can do to start reducing risks, and that women in particular might be hesitant or nervous to bring these topics up with their doctors and just having that conversation, if you have an opportunity, it can be really powerful for patients and really life changing.

Glen Stevens, DO, PhD:

Well, Jessica, it sounds like you're doing some really great work out there. If you open up a post-menopause study, then I'll be right out there to join it with you, but would really like to thank you for joining us today. Thanks a lot.

Jessica Caldwell, PhD:

Thanks for having me.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.