Ep 96: The Menopause-Alzheimer's Connection: Why Timing Matters for Women's Brain Health with Dr. Rachel Buckley (part 2)

Dr. Rachel Buckley discusses the critical link between menopause and Alzheimer's risk in women with BrainStorm host Meryl Comer. Dr. Buckley explains that early menopause can be associated with faster cognitive decline and higher tau levels in the brain. She emphasizes the importance of timing for hormone replacement therapy and how estrogen plays a vital role in brain health through receptors that regulate communication between brain regions and mood. Dr. Buckley advocates for proactive conversations with doctors starting at age 40, midlife cognitive checkups around age 55, and better sex-specific reporting in clinical trials, noting that recent Alzheimer's treatments showed dramatically different results in men (42% benefit) versus women (12% benefit). As leader of a Welcome LEAP research team, she's working to cut women's lifetime Alzheimer's risk in half within three years, representing a new wave of prevention-focused research that coincides with the critical menopause transition period. This is a must listen episode!

Transcript

Rachel Buckley (00:00):

Even if women didn't go through menopause, I think we're starting to get to that point of having midlife cognitive checkups. This is because of the huge successes that we've started to see in our anti amyloid therapies, and there will be others. We are starting to gain an incredible amount of momentum in the Alzheimer's disease field for both prevention and intervention. And one of the biggest areas I think that is hot right now and is only going to get hotter is prevention. We are starting to go earlier and earlier and earlier.

Introduction (00:35):

Welcome to Brainstorm by us against Alzheimer's, a patient-centered nonprofit organization. Your host, Meryl Comer, is a co-founder 24 year caregiver and Emmy award-winning journalist and the author of the New York Times bestseller, slow Dancing With a Stranger.

Meryl Comer (00:52):

This is Brainstorm and I, Meryl Comer. Our guest is Dr. Rachel Buckley, associate professor of neurology at Mass General Hospital and Harvard Medical School. She leads one of 16 research teams on a $50 million Welcome Leap Care grad at aims to cut in half the lifetime risk of Alzheimer's for women. I asked her whether a woman who enters menopause early is at higher risk for getting dementia.

Rachel Buckley (01:20):

There has been actually quite a lot of research into age at menopause, both in terms of the spontaneous menopause, what used to be called natural menopause. We like to refer to it as spontaneous now, or a surgical menopause. So either of those profiles, if it happens earlier in life, so be earlier than the age of 40, it is actually associated with increased risk. We have seen in earlier studies that earlier age of menopause, particularly before the age of 40, is associated with faster rates of memory decline over time in later life. And our own work has shown that if you have earlier age at menopause, you have higher levels of tau in the brain, particularly if those women already have higher levels of amyloid. Just that kind of association I was mentioning before. The issue interestingly though, is there may also be added components associated with surgical intervention of menopause, and it might be due to the rationale behind having a surgical intervention. We're not entirely certain, but there does seem to be also not just the age at which menopause is happening, but potentially whether or not there's been a surgical intervention or not a bilateral ectomy, the removal of the ovaries in particular.

Meryl Comer (02:34):

Rachel, we've talked about the potential benefit of hormone replacement therapy when started near perimenopause. What happens if hormone therapy is initiated after the age of 65? Is that a positive or negative

Rachel Buckley (02:48):

If women are initiating hormone therapy use much later in life? Our own work has started to show a lot of mirroring of the Women's Health Initiative findings, suggesting that women who do delay initiating hormone therapy until much later in life. In our particular study, we didn't actually see it in necessarily 65 year olds. It was women who were initiating, say, five to 10 years after menopause. And menopause was around 50, so be more like 60 year olds. But we were seeing that delayed initiation was associated with higher levels of tau, and we know that in the Women's Health Initiative, those women who were initiating at 65 or over were having at least, you know, nearly two times greater risk of progressing to dementia. So what this has initiated in the field is a theory of the timing hypothesis. So there's two elements to this timing hypothesis.

Rachel Buckley (03:41):

One is how delayed your window might be in when you initiate your hormone therapy use. The more delayed you are, the higher risk it might be that this reintroduction of estrogen into your body may actually increase risk rather than give you protection. But the other piece of this timing is simply also the amount of reproductive, the endocrinological fluctuations that are occurring in your body. If you have a more extended amount of estrogen flowing through your body throughout life, the idea is that there may be more protection that way. So if you have, say a later menses, so a later first period in your life and an earlier menopause, that amount of exposure to estrogen endogenously naturally throughout your life in your body does maybe increase your risk as well. So it's not just about when you're initiating hormone therapy, but there is something potentially about how long you're able to expose your body to estrogen throughout life.

Meryl Comer (04:37):

Rachel, I've read that estrogen loss is tied to depression, anxiety, mood swings, insomnia, and cardiovascular risk. What is estrogen's role in those brain regions that regulate emotion and the symptoms just mentioned?

Rachel Buckley (04:53):

This is incredible work by Dr. Jill Goldstein and others at MGH, and there is a lot of really interesting work suggesting that there might be an influence of estrogen on the brain circuitry, how the brain actually communicates with other areas of the brain. We can look at these sorts of communications and circuitry with neuroimaging. And what has been suggested is that how different brain regions talk to one another, how they turn off and on, how quickly they do it, how elastically they do. It all seems to be tied to some extent with how much estrogen you might have, not only in your body, but also how it's fluctuating. There is also some really interesting literature with how your mood fluctuates just throughout a period cycle, menis cycle of how your circuitry can change both structurally and functionally. And what I mean by functionally is in an FMRI scan, we can see the different brain regions correlating and talking to one another, and these can change.

Rachel Buckley (05:52):

They become more correlated and less correlated based on how much estrogen you have in your brain. The more estrogen you have, the more tighter these relationships and the better the communication. And the opposite is true when your estrogen is low, and there is really potent evidence suggesting that these declines in estrogen at a very large level through menopause, seem to be very much exacerbating risk for depression and anxiety and other sort of mood and behavioral related conditions. And so one suggestion is that there's estrogen receptors in the brain. So it's interesting when we think about menopause, we're often thinking about our ovaries. We're often thinking about, you know, our wounds and how everything is changing down there, but actually there's a lot going on in the brain as well. We know that our brains are replete with estrogen receptors, and what a receptor is, is it's basically key and a lock situation, and you have estrogen keys circulating in your brain and you have the estrogen receptor locks and the estrogen keys will come in and they'll just click into that lock and they'll unlock it and do all sorts of amazing things. But as estrogen recedes, those locks are left empty and then over time they just sort of die. They go away. What's the point of them anymore? This is all still theory. There's still a lot we don't know, but the suggestion is that as these locks go away, they're not helping us to communicate in the brain as much.

Meryl Comer (07:11):

Rachel, you've mentioned surgical interventions where women are often told that since they're not having more children, their ovaries aren't necessary. Is that thesis changing?

Rachel Buckley (07:23):

You know, it's interesting. I actually have family related information about that too now. I've witnessed it myself, the implications of a hysterectomy and ectomy and what that means for later life. And I have my own sort of anecdotal evidence of doctors just saying, well, you're not going to need it anyway, so we should just get rid of it because it's probably better for you in the long run. But I think it would've been far better had we thought more deeply about what are the long-term ramifications of removing all the equipment downstairs, as my parents would like to say. And I think yes, medical world is shifting in terms of its decision making around who should undergo surgical intervention and under what situations and what the ramifications of that should be. I certainly can say from the research that we see, surgical history does have an impact on increased risk for later life illnesses. So I suppose right now the pros and cons need to be weighed up by both the patient and the medical practitioner, which is what is the immediate threat of having this particular organ in the body and what is the threat over time if it is removed? And it's that weighing up of those options to decide what would be the other components that need to be taken care of. But certainly I think it was much more common in previous generations and now maybe much more assessed and carefully made that decision.

Meryl Comer (08:47):

Rachel, listening to you, it occurs to me that most women don't know the questions to ask their doctors. So help us out. What questions should we be asking for? The answers that we need to know,

Rachel Buckley (08:59):

This is my own personal feelings when I go to the doctor, I'll be transparent, I'm 40 now and I start to think myself about menopause and menopause symptoms and when I should be starting to be alert to these and what I should be thinking about for potential interventions. And my first questions are always to my PCP, my primary care practitioner, and that I often will say, what should I be looking out for? In particular, I was quite interested in what could reduce vasomotor symptoms. My mother went through horrific hot flushes and I just thought to myself, gosh, and then that was one of the reasons she went on hormone therapy and I'm so glad she did because it was, it was a real nightmare. And I think that the biggest ameliorator of those sorts of symptoms are still is hormone therapy for brain health. It's exactly the same.

Rachel Buckley (09:44):

What you would do for your body is exactly the same you would do for your brain. I have brought up with my PCP already is based on your understanding of the evidence. What are the things that I should be doing proactively now? Are there things that would be helpful to me and my health to help me get through the menopause transition as easily as possible? It was interesting because the advice that I received was, look, there is no easy way possible. Unfortunately, women will go through their own beautiful concoction of menopause in their own customized way. It was kind of a beautiful way to put it, but the other thing that was said to me was exactly the same as anything that we would think about with heart health and brain health in order to give yourself the maximal and optimized experience as possible as you age as a woman.

Rachel Buckley (10:29):

I think one of the big things, at least when thinking about going to the doctor and knowing what to ask questions, I think should always be raised. When you are starting to sort of get to that 40 to 50 range, you should be bringing these things up. If the doctor is not bringing it up with you, you should be bringing it up with them. What should I be thinking about? Are there any symptoms I should be paying attention to? Are there things that I should be thinking about proactively about menopause? If these things are constantly brought up every year at your annual physical or any other time, then it also keeps that in the forefront of their mind as well. I think it's a dialogue that has to happen.

Meryl Comer (11:05):

So Rachel, if menopause marks the turning point in a woman's cognitive aging, can you envision a time when we're going to have midlife brain health checks and targeted dementia prevention strategies that are part of menopause management

Rachel Buckley (11:21):

Even if women didn't go through menopause? I think we're starting to get to that point of having midlife cognitive checkups. This is because of the huge successes that we've started to see in our anti-amyloid therapies and there will be others. We are starting to gain an incredible amount of momentum in the Alzheimer's disease field for both prevention and intervention. And one of the biggest areas I think that is hot right now and is only going to get hotter is prevention. We are starting to go earlier and earlier and earlier and Dr. Resa Sperling and Dr. Paul Zer are just two ambassadors of that idea. And the clinical trials that they run are some of the earliest in disease you can think of and where we're starting to go. If we're going early in disease, we know that Alzheimer's disease is protracted. It goes for about 20 years from the point of that first really seeing evidence of amyloid in the brain all the way to a diagnosis of dementia.

Rachel Buckley (12:17):

If we think of a diagnosis of dementia generally happening in the mid seventies, we take that back 20 years, we're starting to think about 55 and 55 is just around the time of menopause or right after. So no matter what, I think we're starting to get to this point where we either will have a blood test for all over time or we will have a blood test in combination with some other types of metrics that will be used. And, and I don't know when this is going to happen, but I know it will happen. It is starting to get to that point. We're starting to really know a lot about Alzheimer's disease and I think that as we start to marry our knowledge of menopause with our increasing knowledge of prevention in Alzheimer's disease, the two are naturally going to become hand in hand. Rachel,

Meryl Comer (13:06):

Help us imagine how we approach Alzheimer's prevention for women. What would you change from the clinics to the culture?

Rachel Buckley (13:14):

What I would want to see changed at the moment is how we are handling the reporting of sex segregated results in clinical trials. And I know that this is a very high level comment to make, but I'm going to break it down for a second. So the kinumab findings that came out, they were so exciting because they were the first real robust evidence that we could move the needle in our prevention and our slowing of disease over time. And yes, I know it's incremental and there are still many things that we can learn and and more that we can do to prevent, but we started it, which was so exciting, but buried in the supplementary findings of that paper were the sex desegregated results. And what I mean by sex desegregated is they split the results by men and women. The overall finding was about a 32% benefit on this particular drug in terms of memory and cognitive function.

Rachel Buckley (14:09):

But when you split it into men and women, you found that in fact, men showed a 42% benefit and women only showed 12 that was buried in the supplemental. It wasn't a top line result, it wasn't made a major point to know about. And I understand why they weren't powered to do this. So statistically, they weren't set up to actually run the analysis. The study design wasn't set up in that way. So I understand they didn't want to necessarily report something that may in fact be artifactual. But what I would like to see more and more over the next while is when clinical trials are either being designed straight away or are being reported once the findings are released, that we should be really putting out more and more about how women and men are differing in their responses to treatment. This has been true for many, many different conditions and many different drugs where women and men in fact turn out to respond very differently to drugs. And this can have huge implications for outcomes, health outcomes down the line. So I think that's something I really wanna see changed.

Meryl Comer (15:15):

Is there another area of research where we're not doing justice to diversity in women?

Rachel Buckley (15:21):

A lot of our studies right now really look at non-Hispanic white women and that's great, wonderful. And they often tend to be highly educated. And so we know quite a lot about women in these groups, but we don't really know a lot about women who come from other walks of life. And we really need to do a lot better at understanding the earlier life implications of that as well as any biological implications. One of the big things that we do know, at least in pregnancy outcomes, is that women who are from minority or underrepresented communities tend to have much poorer pregnancy outcomes. We don't have as much data on the Alzheimer's disease outcomes. And so we really need to do a lot more to understand society at a broader level, not just in these much more cleaned data sets of older white, well-educated women. So one thing that we do notice is that as people get older and they start to show memory decline, or even if they don't, if you lose a spouse, for instance, your world sort of starts to decrease a lot and you really lose a lot of independence.

Rachel Buckley (16:25):

And one of the things that is often said in in amongst all of the heart health related matters is also trying as best as possible to keep your networks. So as many friends as you can keep or make or go out and do things with is really, really vital. Isolation, loneliness. These are very, very key indicators of poor health outcomes actually including dementia as well as poor mood and other behavioral issues. So I think all of the heart health things you should, as we normally would do, but that added element of trying to maintain social networks and social engagement in some way is a really vital, vital thing.

Meryl Comer (17:04):

Rachel dollars for research are challenging these days. Speak to the opportunity presented by private philanthropy like the welcome Leap Care grant and the timeline of three years to get to gold.

Rachel Buckley (17:18):

It's amazing. What they've done is they've taken something and they've turned it into a real deliverable contract, much more like industry than you would say a traditional sort of grant. Think of darpa, but it's a health related it's, it's like a Harper, if that makes sense. It's a very different design. The other thing that's really fascinating about it is it's a collaborative, so it's between LEAP and the different sites that have been awarded grants. So we're all in this together. Anything that I find in my particular project will be passed on to the rest of the welcome league constituents. And we will work on projects for deliverables every single year and every time there's any issue or hold up or any new information that changes the course of the next few years means that the contract will be changed and things will be set up in a new way. So it's an incredibly new flexible, quick design, which I think is valuable for both innovation, but also knowing where the dead weight is, where we are not going to get much bang for our buck and we can move on and move to the next thing. So I, I'm really excited about it. The other thing I would like to say about the philanthropic investment is the time is perfect right now. I think there's always been a huge interest and a huge support for medical health research, not just in the United States, but across the world.

Meryl Comer (18:39):

Can you speak to how the private philanthropic center is trying to fill the serious funding gaps that are a direct result of current administration cuts in research?

Rachel Buckley (18:50):

We know that there can only be much better outcomes for public health and chronic disease if we publicly invest in health. Now, when this recedes, there is a huge gap and people don't just go, oh, well I guess that's something we'll worry about in the future. There is a massive change and a massive drive by lots of different foundations and philanthropic groups who immediately realize we need to fill this gap. So I think one thing that has been very heartening in this changing environment over the last while is to see how much support there really is and to know that people have got our back, even if they don't necessarily have money to throw at it, they have the power and the energy to ask for it, and they're really wanting to help no matter where they're coming from. And I've really noticed that myself in my own work. But the Welcome LEAP was just a beautifully designed program to really say, we've got three really incredible questions we want to answer. You are going to do it. We're giving you three years. And I'm really excited to see what happens.

Meryl Comer (19:57):

Rachel, for someone who began her research career analyzing secondary data, how has technology accelerated your work?

Rachel Buckley (20:05):

Massively. And we're really starting to see the benefits and the complications involving machine learning and artificial intelligence. I think one thing that's been really incredible about technology is how the interoperability of data sets has become much more of a a feasibility. So what I mean by that is we're starting to be able to work across multiple data sets on a single platform that is cloud-based. Anyone can access it from anywhere in the world and you can do whatever you want with it, publish your findings, and then it's already harmonized. It's already there to go. There are still some limitations, some hurdles we need to jump over in order to be able to really see a nirvana in this space, but we're really starting to get there. But the other piece of this is how are we using data science and data analytics in a different way to what we would've traditionally? So I used to be a very simple statistical. I was very focused on the basics of statistics. Nowadays, the things that you can do with data, the things you can do with visualizations, the things you can do with communicating your science, it's a totally different ball game. And honestly, it's really accelerating our findings as well as how we disseminate them and report them out, which is really exciting. Well,

Meryl Comer (21:19):

You've been given three years for the Welcome LEAP Grant.

Rachel Buckley (21:23):

Can't wait to show you what we find

Meryl Comer (21:26):

Our guest, Dr. Rachel Buckley, associate professor of neurology at Mass General Hospital and Harvard Medical School. That's it for this edition. I'm Meryl Comer. Thank you for brainstorming with us.

Closing (21:40):

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