Ep 95: Women, Menopause, and Alzheimer's Risk: Breakthrough Research on Brain Health with Dr. Rachel Buckley (part 1)

Dr. Rachel Buckley of Mass General Hospital and Harvard Medical School discusses groundbreaking research revealing stark sex differences in Alzheimer's disease with BrainStorm host Meryl Comer. Her studies found that while men and women show similar levels of amyloid protein, women consistently display significantly higher levels of tau. This discovery has sparked a $50 million Welcome Leap Care grant aimed at cutting Alzheimer's lifetime risk among women by half.

The episode clarifies widespread confusion about hormone replacement therapy, explaining that the problematic Women's Health Initiative study used outdated hormone formulations on women over 65—far past the optimal window for intervention. Dr. Buckley emphasizes that current evidence supports HRT use within certain parameters and stresses the importance of women advocating for themselves when experiencing perimenopause symptoms like brain fog and sleep disturbances. The research highlights menopause as a critical period that may influence Alzheimer's risk decades later.

Transcript

Rachel Buckley (00:01):

I guess the thing that really sparked my interest and really catalyzed me into going deeper and deeper into this is we never saw very convincing differences in men and women in their levels of amyloid pet, but we saw incredibly striking differences in tau. Women across the board showed higher levels of tau than men across many different regions of the brain, including those that are particularly affected in Alzheimer's disease.

Introduction (00:30):

Welcome to BrainStorm by UsAgainstAlzheimer's, a patient center 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 (00:47):

This is BrainStorm and I’m Meryl Comer. There is now a growing research consensus that Alzheimer's disease has its genesis in midlife with symptoms that start an old age. That's what's driving a $50 million welcome Leap Care grant that aims to cut the lifetime risk of Alzheimer's among women by half. That means reducing the risk for 330 million women worldwide. On the Elite Global team is our guest, Dr. Rachel Buckley, associate professor of neurology at Mass General Hospital and Harvard Medical School. Welcome, Rachel. Thrilled to have you.

Rachel Buckley (01:24):

Thank you so much, Meryl. It's such a pleasure to be here.

Meryl Comer (01:27):

Share with us why the Welcome Leap Care grant is focused on women midlife around menopause and why that is potentially such a groundbreaking step forward.

Rachel Buckley (01:37):

Yeah, it's such a great question. As you know, we've known for a long time that women are at greater risk of dementia. This has been a statistic that's been around for many, many years and over the last I'd say five to 10 years, it's become an even bigger and more demanding question of why. What is it that might be driving this increased risk in women? And there still remains so many questions left unanswered and where sort of the welcome trust, the Care Leap Foundation has come in is to try to really get to the root of what might be driving this elevated risk in women in particular. Obviously there are also risks in men. The point being right now that we understand that both sexes do present with dementia and have higher risk, but what is it about each sex that really sort of drives their level of risk of Alzheimer's disease?

Rachel Buckley (02:27):

What the care leap is set up to do is to try to understand, particularly the endocrinological state, the phases that are happening in a woman's life, particularly around menopause, but it doesn't have to be. There are a lot of endocrinological changes that are happening both through puberty all the way throughout life. What we'll be doing is in this particular leap, what they call thrust, which is this sort of huge step forward in research, is to try to understand these sort of fluctuations in hormones throughout life and how these are having an impact both on the brain and the body to impact later life risk for Alzheimer's disease.

Meryl Comer (03:08):

Rachel, your current research focuses on optimizing women's brain health with a specific focus on the role of menopause. How does that relate to your earlier studies that looked at the extent to which sex differences exist?

Rachel Buckley (03:22):

To what extent are women vulnerable or in fact resilient, and how do men and women differ in their level of risk and the types of things that really knock them on the path towards a neurodegenerative disease? One of the things that had not yet been answered in the field at the time when I started to get interested was, are there differences in pathology in the brain between men and women? So there'd been a lot of interest and really just sort of deep diving into the dementia, the actual cognitive symptoms and the diagnosis, the outward diagnosis. But no one had really looked at sort of pet images before. We have one of the largest collections of amyloid and tau PET imaging. There's many in the us. One of those is ours here at the Harvard Aging Brain Study, and we simply just looked at men and women and how they differed on amyloid PET scans and tau PET scans.

Rachel Buckley (04:14):

And as you know, amyloid and tau are the sort of hallmark pathologies of Alzheimer's disease. And I guess the thing that really sparked my interest and really catalyzed me into going deeper and deeper into this is we never saw very convincing differences in men and women in their levels of amyloid pet, but we saw incredibly striking differences in tau. Women across the board showed higher levels of tau than men across many different regions of the brain, including those that are particularly affected in Alzheimer's disease. And since that paper came out in the, I think it was 2019, there have been countless studies independent of ours that have been able to replicate that finding.

Meryl Comer (04:55):

So Rachel, what do we know today about how women's brains age differently than men and what don't we know yet?

Rachel Buckley (05:03):

Unfortunately, what we know is less than what we don't know right now. I can tell you what we know. We know that women tend to show much higher levels of tau particularly than men. And this is true I think in the cases in particular where both sexes already have a level of risk for Alzheimer's disease. So that might be that they are an E four carrier. For instance, we know that APO E four, the APO E four gene increases your risk genetically for Alzheimer's disease later in life. So that is one of those conditions. If women carry the E four allele, they tend to show much higher levels of tau than men who carry the E four allele. We know that also, this is true if they have higher levels of amyloid, if women have higher levels of amyloid, they're going to tend to show higher levels of tau as well.

Rachel Buckley (05:50):

The other thing we know too, and that we've started to see more and more in the literature is that women for a given level of tau, let's say we make the amount of pathology similar in the brain for both men and women. Women actually show faster rates of decline in their memory and their thinking over time as well. This is a particularly potent finding because we actually know across the board that women tend to outperform men on many different tasks. Most of that memory tasks, particularly if they're verbal women outperform men. They're much better at these tasks. So at the baseline you'll normally see women are much better performing, but there tends to be this loss, this loss of this better performance over time, perhaps sort of resulting in this higher level of prevalence of dementia later on in life. The other things that we know as well is that men and women tend to differ in their level of risk throughout life.

Rachel Buckley (06:44):

So we know that men are much more likely to have higher cardiovascular burden and different cardiovascular profiles tend to have great heart disease, more heart attacks, ischemic heart attacks and things like that, which can have a very different sort of outcome or a different result in how they will either manifest dementia or be diagnosed with dementia later in life. The other thing that has been of great interest are the potential drivers of these differences, and two of the biggest areas that people have been focused on that have been trying to do some more so digging is to understand the hormonal consequences of both estrogen or estrogens and progesterone, particularly in women and testosterone in men.

Meryl Comer (07:28):

Rachel, the fear that hormone replacement therapy would increase cancer risks in women turned off a generation, and now research suggests that estrogen, particularly estradiol may be in fact protective.

Rachel Buckley (07:41):

Once women go through this transition of menopause, they start to decline in these levels of hormones. And there's something here that we're really starting to see is that this sort of menopause transition might actually be a quite critical event in a woman's life that may have sort of negative impacts on Alzheimer's disease later in life. But for men, there's also some suggestion that there could be some influence of protection or risk related to hormones in the body. Testosterone is seen as quite protective over life. And then a final piece that people are starting to get to know a little bit of, but there is vast areas we don't, is the X chromosome. What does the X chromosome confer in terms of risk and protection against Alzheimer's disease? There are some hints that there are some genes on the X chromosome that when are expressed in women in particular because we have two Xs, which means we can have a little bit of extra built-in redundancy that that might actually be protective against things like memory decline might be protective against some of the pathologies we see in Alzheimer's disease. A lot of the findings we have right now are still early days, so there are many, many things that we don’t know.

Meryl Comer (08:54):

Rachel, let's stay with hormone replacement therapy because there's been tremendous confusion in this space. What does the evidence actually confirm and what do we think is still missing?

Rachel Buckley (09:05):

A few decades back in the late nineties, early two thousands, there was a women's health initiative that was initiated, which was tens of thousands of women who were basically put on a randomized control trial. It's one of the strongest study designs you can think of to try to address a very simple question, does the initiation of hormone therapy confer protection against a range of different health outcomes in later life? These things worth things like heart disease, osteoporosis, and other related older age conditions. One thing they didn't really think about at the time was dementia, but it was also a part of the secondary outcomes that they were interested in. What they did was they primarily initiated hormone therapy use in women who were over the age of 65, and the reason for that was to look at these later life conditions and how could the introduction of hormone therapy use immediately have very beneficial outcomes, not sort of worrying about around the time of menopause.

Rachel Buckley (10:05):

So most of the women in this trial were over 65 and they were also taking one of the most prescribed hormone therapies out there at the time. And at the time it was a conjugated equine estrogen, which is important to know actually, because nowadays we would never prescribe CEE and it was actually not a very good hormone therapy formulation. So this trial started and within a few years it had to halt. It had to halt early because they actually found increased risk across the board, not just cancer, which they knew might increase over time, but there was also increased heart risks. But there are some interesting caveats to that study that people I think have not really taken to heart over time. One really important point is those women were much, much older when they were taking hormone therapy or when they initiated, and so what we learned from that particular trial is that we probably shouldn't delay the onset of initiation of hormone therapy. The other piece is that the hormone therapy that was used is very different to the compounds that are used now or the formulations that are used now.

Meryl Comer (11:13):

Rachel, if I recall correctly, that study came out of the Women's health Initiative whose research is foundational to our understanding of how diseases from heart disease to cancer, osteoporosis to dementia affect women differently.

Rachel Buckley (11:28):

The unfortunate thing about the Women's Health Initiative is that it was the one of the largest RCTs in the world that was ever conducted. And because it was such a failure, there has been a lot of resistance by funding bodies and pharma companies to run such a big trial ever again. The trials that have happened since have been somewhat inconclusive. Some of the trials have suggested yes, there might be increased risk. Some of them have found no increased risk at all, and others have found potential protection. But one thing is very clear from not only these trials but observational studies as well. What we know and what is now very widely published in national and international guidelines from menopause societies is that hormone therapy use is okay to take and can be recommended within certain parameters. Generally, they recommend around 10 years, but again, it really depends on the patient's sort of profile and other sort of comorbidities associated with their health.

Rachel Buckley (12:29):

But it is really important to understand that yes, hormone therapy has been associated with increased risk for a range of different outcomes, but a lot of these studies that have come out are associated with different sort of nuances that need to be taken into account when thinking about what does hormone therapy mean for later life risk? We don't really know what the sort of comorbidities of a woman's sort of health profile really matter when thinking about the recommendation for taking hormone therapy. And then the other piece that is very unclear because we need very longitudinal studies is exactly what the impact of hormone therapy use might be on later life dementia risks. So there's still a lot of things we don't know and we're still trying to piece together.

Meryl Comer (13:13):

Rachel, I am of the generation where OBGYNs were protective and proactive in taking women off hormone replacement therapy despite those of us willing to take the risk. Let's update the research and look at perimenopause. Many women report brain fog, memory lapses and anxiety. It's often dismissed by their doctors. What advice do you give to women experiencing these changes?

Rachel Buckley (13:40):

I actually wonder about this myself, and this is not just because it's of interest to me professionally, but also I think all women really grapple with these questions on a day-to-day basis, and it becomes a very personal issue very quickly. One thing I would want to put out there, and it's something I've noticed personally as well, not just professionally, but women don't tend to talk about their menopause symptoms as much openly. And I think that sometimes we can often negate our own experiences because we just don't feel comfortable. We don't know if they're unnatural, you know, or whether these things are unusual and we should persist with speaking and following up and self-advocating or our symptoms. One really big piece that I've been really thinking about more and more over the past years is how we really need to make this a more open conversation at a national level, but also at a sort of in your backyard having a grill with friends situation where you're just talking with people about menopause and your experiences and what is normal and what should be followed up further.

Rachel Buckley (14:43):

The other piece to this that I always recommend to people, because I would like to be very transparent and say I'm not a clinician, I'm only a PhD, but one thing I, I always tell panels or even my friends, self-advocacy is very important. We know this from the research, particularly for women's health. Women are often set aside for many different things. There have been some really incredibly unbelievable situations in medical research and medical health history where women have been discounted for real problematic symptoms simply because they don't fit the profile, they don't seem to fit the norm, and therefore we just ignore it as a female hysteria or something similar. And I think one thing that I've learned from many of the studies I've been reading and other sort of perspectives is that self-advocacy is incredibly important. If it's something that you aren't really worried about, it's something you've really noticed changing, it's absolutely worth continuing and seeking second opinions and finding specialists who are able to help you or able to at least dig deeper and find an answer rather than immediately dismissing

Meryl Comer (15:49):

Rachel, our generation is egging your generation on to do Exactly that is the timing of when women enter menopause an issue.

Rachel Buckley (15:58):

The timing is actually a really tricky thing. Perimenopause is actually a very, very difficult thing to discuss in terms of when it actually starts. You know what would be great is if you just got a ping on your phone and it says, oh, it looks like you are starting menopause now. Would you like any more information about that? But it actually is a very insidious, very slowly encroaching set of symptoms that can be protracted for many years. Some women can go through perimenopause for about 10 years, and menopause itself can be protracted as well. And I'm sure that many women who are listening to this may have experienced that themselves. It sort of comes up to you over time, and it's not till maybe later that you start to think, oh, maybe this is something to do with menopause, or it might even be adopted.

Rachel Buckley (16:46):

It might say to you, you know, that sounds a little bit like you might be going through menopause and it might not even be apparent to you at the time. So I think that the timing is actually very difficult to ascertain, at least at an individual level. In studies, we have specific guidelines of when we actually stage what we consider to be the different stages of menopause, and these are associated with levels of hormones and types of symptoms that women may be experiencing and putting them all together. They're something what we call the straw 10 guidelines, and these are sort of research-based frameworks for trying to group women in particular categories so that we can study them based on what we think these menopause levels are. But I think the one thing I wanted to state is that these guidelines are long-term guidelines, so you have to measure people over a period of time. You can't just take someone's blood one time and get them to fill out one survey and that's it.

Meryl Comer (17:39):

So Rachel, what are the changes in symptoms like sleep pattern and hot flashes and how do they contribute to brain fog?

Rachel Buckley (17:47):

One of the biggest I, I think, changes in symptomatology that women tend to notice throughout this sort of perimenopause phase. One is the change in sleep and the other is the vasomotor symptoms. Now, not all women actually experience vasomotor symptoms. These are sort of the hot flushes that we hear about or that we have experienced ourselves. Not all women go through them, but unfortunately, usually the vasomotor symptoms occur at night. And so you have this horrible sort of dual system of horse sleep associated or maybe even prompted by the vasomotor symptoms and some of what is suggested in the literature, although again, research is somewhat patchy in this area, but what they suggest is that potentially this poor sleep, the vasomotor symptoms and other things may be contributing to what we call brain fog, which is this change in cognition or this haziness that women refer to this inability to sort of hold onto things so well maybe not be able to recall things as easily, maybe not be able to remember somebody's name.

Rachel Buckley (18:44):

Now, this brain fog symptom that has been sort of talked about a little bit certainly is much more known sort of in the community lay term speak when we're referring to it. Brain fog research, however, is much less progressed than you might want it to be. What we do know and what I have seen, not speaking from a lot of knowledge in this particular area, there's a dearth of research really, but also it's not necessarily my area of knowledge, but what I do know is that there isn't a necessarily a clear relationship between brain fog experienced during menopause and risk for Alzheimer's disease later in life. Now, that's not to say there is nothing there, but there needs to be more research done to understand what are the cognitive fluctuations that are happening during menopause and how might that, if at all, have any impact on your likelihood to show changes in your memory later in life.

Meryl Comer (19:36):

Our guest is Dr. Rachel Buckley, associate professor of neurology at Mass General Hospital and Harvard Medical School. In part two of our conversation, we delve into the correlation found between the age of menopause onset cardiac issues and the faster rates of memory decline over time in later life.

Rachel Buckley (19:58):

We have seen in earlier studies that earlier agent menopause, particularly before the age of 40, is associated with fast rates of memory decline over time in in later life. And our own work has shown that if you have earlier agent menopause, you have higher levels of tau in the brain, particularly if those women already have higher levels of amyloid.

Meryl Comer (20:20):

That's it for this edition. I'm Meryl Comer. Thank you for brainstorming with us.

Closing  (20:28):

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