By Maddy Zee | July 6th, 2020

As research into Alzheimers disease progresses and awareness grows, one fact remains consistent: women are disproportionately affected by the disease. Several theories exist, but a recent study suggests that the link between Alzheimers and menopause, a part of aging for most women, could be the answer.

Being Patient spoke with Dr. Richard Isaacson, a neurologist and director of Weill Cornell Universitys Alzheimers Prevention Clinic, about his involvement in the study on menopause and the role of the link between Alzheimers and menopause in future research.

Being Patient: What is it about our hormones thats related to the brain? What do we know about the connection between estrogen and the brain?

Dr. Richard Isaacson: Well, well take one little step back. If you were to ask me this question ten years ago, I would have said I have no idea. Five years ago, we started the Alzheimers prevention clinic at Weill Cornell and New York Presbyterian back in 2013. It took a couple years to kind of get my feet wet and understand not just how people are doing, but how sex differences go in pre-clinical normal patients who are at risk for Alzheimers.

It started becoming much more clear like you said that its not just because women live longer. Two out of every three brains affected by Alzheimers is a womans brain, and we used to say we dont know why. Honestly, I dont believe that thats the case anymore. Im pretty confident that we have significant clues that can not just understand the risk factors, but also how we can maybe intervene to reduce risk. All that being said, there are, I believe, several reasons and its not just hormones.

I think hormones are very important and well talk about that. Im a physician, Im a neurologist, Im a practicing clinician in the Alzheimers prevention clinic, so we get a lot of questions: should I be on hormones? What should I take? Should I take a pill? Should I take a cream? When should I start? Im not menopausal yet, Im just starting to have pre-menopausal symptoms, Im done with menopause, should I start now?

These are very common questions, and while I cant say we have the perfect road map or instruction manual of answers, there are multiple reasons why a woman could be on a different trajectory than a man. Hormones we will definitely talk about, but its more than that.

During the pre-menopause transition there are bio-energetic shifts, and what that means is that the brains energy pathways change. When that shift happens in certain women they will be on a different fast forwarding road to Alzheimers disease, and our goal as a clinician, my goal in the clinic, is to get them off of that road using evidence-based and safe interventions. Is hormone replacement one of those interventions? Im fairly sure it is, but its not a one-size fits all answer. When to start, what to start, theres just so many questions here and I think I understand it much more now than five years ago.

Being Patient: Estrogen traditionally begins dropping in a womens mid-thirties. Is it true that different women have different degrees of an estrogen drop? And is there evidence that sharper drops of estrogen, like falling off a cliff, are worse for the brain?

Dr. Richard Isaacson: Sure, so the falling off the cliff analogy is a good one and the thing that immediately makes me think of what would make a women fall of the cliff in terms of a precipitous and immediate drop in estrogen levels, the number one thing I can think of is surgical menopause, which basically means a hysterectomy where they take out the ovaries.

Now, in the past 20 years ago and earlier when women got hysterectomies, and theres a variety of reasons why women have to get hysterectomies, but when you take the uterus out and you take the ovaries out with it and prior to that the ovaries were working and there were some degree of regularity of ups and downs of estrogen which is normal throughout the cycle, when you take that out its like falling off a cliff. I dont know that we have the perfect answers and the perfect evidence, but both the study that we just published and also other studies basically suggest that when you fall off of that cliff, that could be a problem in certain women, in many women, but not all women. And thats a complicated thing.

Does the womans genetics play a role? I think yes. The other thing thats really important is, did that woman go on hormonal replacement therapy immediately? Okay, thats important. What was that hormonal replacement therapy? What was the dose? Was there progesterone? Was there just estrogen? What type of estrogen was it? Was it a pill? A patch? A cream? How long did they continue the estrogen replacement for?

If I had to say a yes or no and you boxed me into a corner, is estrogen protective on the brain? Sure, I would lean towards yes. I shake the eight ball, and all signs are pointing to yes. But its just not that simple, you know, a woman just cant just say that I heard this in this video, Dr. blah blah blah prescribed me estrogen, I want to prevent Alzheimers. Its, unfortunately, a little more complicated than that. What this study showed is that we kind of understand more now about how hormone replacement therapy, how the pre-menopause transition, how a hysterectomy for example, all these three things might not just affect Alzheimers risk but really how they affect brain pathology.

So in the brain we can look at characteristics from the size of the brain if theres shrinkage in parts of the brain that basically cause or are associated with Alzheimers, the hippocampus the memory center of the brain we look at the grey matter and the white matter, we look at the size of the brain or atrophy, we look at something called glucose metabolism. If we see hypo-metabolism, well thats a clue that there could be a problem especially if those are hypo-metabolic reduced energy consumption, and really reduced energy metabolism is a better term in parts of the brain related to Alzheimers.

And finally is there amyloid in the brain, amyloid is the pathologic protein that builds up in the brain of people with Alzheimers. Is it the cause of Alzheimers? I dont really think so. Is it related to Alzheimers? Absolutely, its a biomarker that accumulates in the brains of people with Alzheimers.

In that study we really showed that women who are in the pre-menopause transition and during menopause and also women that do hormone replacement therapy and other things, we understand now the relationship between those characteristics and brain pathology related to Alzheimers. So long story short, it takes a long time to figure this out and I think this study is important because its a little bit more clear now.

Being Patient: Do we just think that we are losing our memory, or are we actually losing our memory because were reaching menopause?

Dr. Richard Isaacson: Im going to give a collective apology on behalf of most physicians out there because when I was in med school almost twenty years ago we never learned that menopause causes cognitive changes, like that was not even on the radar, like zero. And then we kind of learned that there were some cognitive aberrations but its fine, its just due to, I dont know, hormones or whatever, lack of sleep, its not real.

And the problem is that I said its not real. Well absolutely thats not correct. These are real symptoms, these are absolutely real, but how Im going to characterize it is different from what you just said. These are absolutely real, tangible cognitive changes. You used the term memory, memory is a loaded term.

When Im talking the word memory, I know its memory because I do the tests. The problem with cognitive function, is that if your attention is less than it used to be, if your processing speed is lower than it used to be, if your ability to learn new information is less than it used to be, the person may say that theyre having a memory problem, but not necessarily. We test all these different factors, you know theres downstream and upstream right?

If someone cant consolidate information and get it into the memory banks, Papez circuit, long-term, short-term, if you cant consolidate the memory that may be an attention thing or a processing speed thing, thats not memory. So what I would say here is its essential to characterize the exact cognitive change related to the perimenopause transition before jumping on memory and saying, Oh, I have Alzheimers, I think.

All that being said, theres certainly some memory dysfunction, because a lot of the time its not memory. In the women that have a memory problem during the perimenopause transition, who have multiple family members with Alzheimers that have an ApoE4 variant one or two, thats when I start getting a little worried.

Thats when I say, How is your exercise? What is your cholesterol? I need to know everything about you. Not just how many days a week you are exercising, what are you doing? What is your average heart rate during your exercise? Oh, youre on an elliptical but youre texting, no thats not intense exercise enough. Oh youre not doing strength training, what do you mean, you need to build muscle, because if you dont build muscle youre not going to increase your metabolism.

I get really serious with women who truly have an objective memory problem, we do like multiple different cognitive tests in our cognitive battery 45-55 minutes, if its a memory problem, Im legitimately concerned and and I will predict that there is a bio-energetic change in the brain that we can really detect. So, I completely buy it. I think its totally real, but we just have to be careful how we characterize it.

When a woman is having these symptoms I also really dive deep into sleep. Sleep disturbances through the perimenopause transition are like absolutely so essential at characterizing in our clinic, we have over fifty people wearing this risk biosensor and we just published on this in the journal of Prevention of Alzheimers Disease where we can use biosensor information and put it in an algorithm to predict how the brain is functioning.

Its actually pretty cool stuff but we can track sleep, and not just total sleep, its how long does it take to fall asleep, deep sleep, how much REM sleep there is, we look at cardiovascular measures like something called heart rate variability, is a woman ruminating about their symptoms, are they having repetitive negative thinking which fast forwards amyloid and tau deposition which fast forwards shrinkage of the memory center of the brain.

So in women during the perimenopause transition, its not just about the hormones, its about everything thats downstream from the sleeping disturbed by the hormones, so Im ruminating about it, is this a serotonin problem, is it an estrogen problem, we need to talk about pharmacological and non-pharmacological approaches, sleep hygiene, could we take a supplement, are you exercising, are you having caffeine before bed? Theres so many different things we need to address for a precision approach.

Edited for clarity

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Dr. Richard Isaacson: The Link Between Alzheimer's and Menopause - Being Patient

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