Is There a Link Between Menopause and Alzheimer's?
A neuroscientist talks about her research into the question
(This article previously appeared on the Neurotrack page of Medium. It is an abridged version.)
It started with an artichoke. Or rather, it started with my inability to recall the word artichoke, even though I was holding one in my hand. “What did you get for dinner?” my partner Will asked from the other room, and I said, “Salmon and…” My brain went blank. Or rather it went from blank to asparagus, even though I knew that asparagus, while in the correct spiky vegetable ballpark, was wrong.
“Yes?” said Will.
I started to panic. Words are my stock-in-trade. They are how I make my living. If I couldn’t come up with a simple word for the vegetable right there in my own hand, who was I? I carried the mystery object into the room where Will was working. “What is this?” I said. “I can’t remember how to say it.”
He looked alarmed. “You mean… an artichoke?” He smiled. Was this some sort of a joke?
"The brain is in charge of the rest of the body, but pretty much everybody assumes that the rest of the body doesn't have much of an impact on the brain. And that turns out not to be true."
My relief was palpable. “Oh my god, yes! Thank you!” And yet I was still disturbed. What just happened? I’d been having what I thought were all the normal issues with word recall, keys and glasses locating, and wait-why-did-I-just-go-into-this-room moments over the last few years, after I turned 50, but this felt different. More disturbing. More urgent.
I immediately Googled “memory loss menopause,” and 13.8 million hits appeared on my screen. Was memory loss an inevitable byproduct of menopause? And if so, why? I started digging. And that’s when I stumbled upon a recent Op-Ed in the New York Times by neuroscientist Dr. Lisa Mosconi, who is studying the link between menopause and Alzheimer’s.
Mosconi is an associate professor of neuroscience in neurology and radiology at Weill Cornell Medical College in New York, where she also serves as director of the Women’s Brain Initiative and associate director of the Alzheimer’s Prevention Clinic.
The question she asked herself, in her research, was a deceptively simple one: Why do twice as many women get Alzheimer’s as men? The statistics with regard to women’s longevity versus men’s cannot explain away this enormous discrepancy. Could menopause?
So on a warm spring day, just after the artichoke incident, I biked from my home in Brooklyn to Mosconi’s office at Weill Cornell. (Exercise, we now know, is one of the key risk reducers for Alzheimer’s when done in conjunction with healthy eating, getting enough sleep, and stress reduction.)
Herewith is a slightly condensed transcript of my conversation with Mosconi, which I’m keeping long not only because nearly everything she said was both fascinating and news to me, but also because I’m assuming if you are a menopausal woman reading this right now (or someone who loves us), you might have lots of questions and/or unnamable artichokes in your life, too.
Deborah Copaken: So. Let’s start at the beginning. How did you get interested in this specific topic? Alzheimer’s in general, but also Alzheimer’s in women, specifically?
Dr. Lisa Mosconi: When I was in college, my grandmother started showing cognitive and behavioral changes, and within a couple of years she was not just herself anymore. She was diagnosed with dementia. It was a very slow and painful process. Everything went backwards. She was up all night and asleep all day. My mom turned into the primary caregiver, and that was devastating for her. Not just emotionally but also really physically.
And she was also trying to hold onto a job. And those were the years when my mom was going through menopause as well. So it really was shocking to witness what was happening to my grandmother and at the same time what was happening to my mom. My grandmother had three siblings; two girls — you know two sisters — and one brother. The two sisters got the same exact thing years later. Her brother did not.
Oh my goodness.
So that was quite shocking, and I was like 'Oh dear, what if it runs in families?' I knew nothing about Alzheimer’s. I was nineteen. And so I started doing a lot of research on that. My parents are nuclear physicists. And their students were babysitting me when I was little, but we stayed in touch, and as soon as I mentioned wanting to look at the brain and Alzheimer’s, they said, 'Volunteer with us. We’ll train you.'
You were nineteen, and you were researching in nuclear medicine already?
A year later, yes, I was twenty.
Okay, so you were still in university, but studying nuclear medicine on the side. As one does. So how old is your mother right now?
How’s she doing?
She’s fabulous. She goes to yoga three times a week, she can do headstands, she eats super healthily, she is incredibly intellectually active.
I’ve seen studies that show that instead of just doing brain games such as Sudoku or crossword puzzles, there’s evidence that just staying at your job in your sixties and seventies is good intellectual training if you want to try to avoid cognitive decline. What do you say to that?
There is an association between Alzheimer’s risk and education, and also occupational attainment: having a job that you’re good at. So there’s an association between being good at your job — having a job that brings out the best in you in some ways, whether intellectually or in other forms — and lower risk of dementia down the line.
There are some studies showing that postponing retirement has also been associated with a lower risk of dementia in later years. And I think it all comes down to cognitive reserve.
Yes, cognitive reserve. You brain is built of neurons and connections between neurons. And these connections need to be strengthened, because otherwise they will die. There’s a process called pruning, where if you don’t use your dendrites, the connection between neurons, they will atrophy, they will actually withdraw. So it’s really kind of a 'use it or lose it' situation in the brain.
Right. Which brings me to my next question, a personal one: I know that writing is good for my brain, but at fifty-three years old, having been a writer my entire life and now going through perimenopause, I find...
Would you want to get your brain scanned?
Yes, let’s do it, that would be fun!
That would be wonderful.
Because what I have noticed, as a writer who obviously needs words to create what I do, I sometimes cannot remember … the other day I could not remember the word … and here I am forgetting it again! It was, oh my God, see, here I go again. It’s not asparagus, but it’s the thing that looks like this, and it’s got the little pointy things...
Artichoke! Yes. See, I knew it started with an A, and it looks like the top of the asparagus, so that came to mind, but I couldn’t think of the word for artichoke. And it was driving me crazy. I had it in my hands, even, and I couldn’t remember what it was called. And if you hadn’t just said it right now, I would have had to look up vegetables on my phone, I mean literally look up green vegetables pointy leaves and find it on Google. But this happens all the time to me now and I’m thinking that, oh no...
Word finding. Exactly. And I don’t have any history of Alzheimer’s, but I have noticed just in 'brain abilities,' let’s call it, I’m losing it. And as a writer, that’s scary.
Well, for sure.
So when I read your op-ed, even though I work in this field, I did not know that women are twice as likely to get Alzheimer’s as men.
At the same time, I also know that women’s health is poorly studied. I will give you an example from my own life. So when I had my uterus out, a hysterectomy, I was asked, what do you want: a partial, full or a supracervical? And I was like, I don’t know.
They’re asking you?
They’re asking me! And they said 'Well, it is believed that the cervix plays a role in sexual pleasure.' And I was like, seriously, are you kidding me? This was back in 2012. So they took out the uterus, kept the cervix. Five years later, the cervix becomes diseased, has to come out, and when I went to see the surgeon who was going to remove it, she said, 'Why didn’t you get this out when you got the hysterectomy?' I said, 'I was told that it plays a role in sexual pleasure.' She goes, 'No, no, that was debunked last year.' I was like, 'Why don’t we know these basic things about female health?' She goes, 'Welcome to my world.'
I agree. We know even less about women’s brains. I mean, if we can’t even get the cervix right...
We finally just got a 3D model of the clitoris two years ago! Two years ago! So now I know these things about my reproductive organs I should have known years ago. What I’m concerned about now is the brain, women’s brains in particular. So what does your research show? What have you found about menopause, perimenopause and women’s brains?
Well for one, we have known for a good ten years that taking out the ovaries or the uterus increases risk of dementia in women.
This is true.
This is news to me right now.
[At this point, I have to turn off the tape recorder, catch my breath, and curse. Loudly.]
Let’s start again, shall we?
It’s true. There’s a strong association between early menopause and an increased risk of Alzheimer’s in women. And an oophorectomy, which is the surgical removal of the ovaries, increases the risk up to seventy percent.
Yeah. If it’s done bilaterally, meaning you have both the ovaries taken out. But then there were other studies showing the risk is also increased when the uterus is removed, regardless of whether the ovaries are still in place.
The reason being, when you remove the uterus, blood flow to the ovaries is also compromised, you’re disrupting the system. In some ways, the ovaries may or may not be impacted by that. So there is an increased risk of Alzheimer’s also with a hysterectomy. And that’s why many people have been looking into estrogen, and the connection between estrogen and Alzheimer’s.
There was that disastrous clinical trial called the Women’s Health Initiative. For many years, women were given estrogen as soon as they entered menopause, with the idea that lack of estrogen is what causes a lot of the problems during menopause, from increased bone frailty, increased risk of heart disease, increased risk of diabetes and increased risk of dementia. The association was quite well established, so it makes sense to think, well, can I just give you the estrogen back? Right?
And so many providers did that. It was actually kind of the norm for women with the diagnosis of menopause, which is at least twelve consecutive months without your period, to be put on estrogen and left on estrogen for life. And that was done for so many years before the NIH [National Institutes of Health] started a clinical trial to test the efficacy of these formulations.
So, the Women’s Health Initiative started in 1993, and it was huge. There were like more than fifty thousand women involved in the trials. The trials went on for many, many years and then all of a sudden there were halted because early findings showed an increased risk of pretty much everything: an increased risk of blood clots, an increased risk of stroke, an increased risk of cardiovascular disease. So, it was basically a disaster.
Ugh. Let’s go back to women and Alzheimer’s and your family. So, you have your grandmother and your two great aunts, all of whom get Alzheimer’s. But your great uncle, their brother, doesn’t. Why?
Yes. I wanted to know why this is happening. And everybody was like, it doesn’t matter if you’re a man or a woman, it’s exactly the same. I was like, no it’s not. You can see the patients! They walk in the door, and sometimes there are women who are clearly having a problem, but they do not ‘test’ impaired.
A doctor wouldn’t be able to give them a diagnosis of dementia or mild cognitive impairment because their cognitive performance is still good even though they’re clearly dysfunctional in every other aspect of their lives. But they don’t score impaired. This came out a few years ago, that the tests we were using to diagnose Alzheimer’s were not sensitive enough for women at the early stages. Because women score better than men on cognitive tests and always have.
The cognitive score declines a bit with menopause, and then after menopause, but even women with a diagnosis of early Alzheimer’s may score better than men with the same diagnosis of Alzheimer’s.
So, the doctor can see plaques on the brain, they know these women have Alzheimer’s, but they’re testing well on cognitive exams.
They’re testing fine! We couldn’t see the plaques in the brain until ten years ago, we didn’t have the technology. So, now that we had the technology to find the plaques, we actually understand that we probably misdiagnosed women forever. And that could be one of the reasons why some treatments don’t work that well in women.
There’s also this whole thing, because we catch them too late, that the typical Alzheimer’s drugs work better in men than in women. And one possibility is that men and women with the same symptoms do not have the same brains. The men’s brains are still here, but the women’s brains are down here…
[She holds her right hand up high, representing men’s brains, her left hand down low, representing women’s brains.]
…and that’s why the drug just can’t bring them back up. So there’s an entire field that’s been severely gender-biased, and the bias is just now being revealed. It literally has been only two years that now everybody is talking about it, finally.
Yes it is, but it took me twenty years to get grants to actually look into this discrepancy.
It took you twenty years to get grants to look into this?
It took many years to convince the medical community that Alzheimer’s differs by gender.
I’m reading a book right now, I forget the name cause I probably have Alzheimer’s too, but I’m reading a book right now about women and data bias. [Note: Invisible Women: Data Bias in a World Designed for Men by Caroline Criado Perez.] The author has this part where she talks about how they studied Viagra.
Yes! Female Viagra, which was tested in twenty-three men and only two women!!!
Yeah, but they studied Viagra, and they found that with women, it completely eliminated period cramps for four hours at a time with no side effects. And the doctor that discovered this went back to the NIH, twice, and said, 'We need further studies on this. This is the holy grail for women,' and they said, 'Well, dysmenorrhea [painful menustration, often with abdominal cramps] is not a real issue.' So we now know everything we need to know about penises and how they get hard, and how Viagra can make them harder, but nothing about how Viagra could be helping the other fifty percent of the population, enormously.
Yes, there are so many things that were just completely disregarded.
Even this desk. This desk is not built for me, and it’s not built for you either. I was at the New York Public Library before I came here, and I was sitting there going, this table, this is made for a six-foot tall man. I can’t type here. It’s too high. I was with my boyfriend, who is six-feet tall, and I was like, you are comfortable at this table, I am not: discuss.
Yes, absolutely, we need pillows! And then the solution for a woman is to sit on a pile of pillows and make it work. We get this all the time, you know, just make it work.
And the same is in medicine. What we found, when we finally got an opportunity to look into that, is that women’s brains age differently than men’s brains.
That seems really important and unknown. What? Women’s brains age differently than men’s brains. How so?
For example…wait, I also want to underline that it’s not that we age worse, but differently. That’s important because...
Because there’s a judgment associated with better and worse, got it.
There’s a judgment, yes. We just age differently, that’s all. And basically what we found — and this is a lot of my own research — is that Alzheimer’s is not a disease of old age.
We tend to associate it with the elderly, because that’s when the clinical symptoms become manifest. But in reality, Alzheimer’s begins with negative changes in the brains at least a decade prior. Most often than not, in middle age. Middle age is considered to be forty-to-sixty years old.
So then the question that we asked was okay, we know that Alzheimer’s affects more women than men, and we know that Alzheimer’s starts in midlife. What happens to women and not to men, in mid-life, that could potentially trigger an Alzheimer’s predisposition and that could potentially initiate Alzheimer’s?
And I was thinking, thinking, thinking, and I said: menopause? It’s the one defining event in a woman’s life that happens to every single woman and does not happen to men. Could that impact the brain?
And my background is in nuclear medicine, which is a branch of radiology, then I work in neurology. Nobody talks about hormones. Nobody talks about menopause as something that could potentially impact your brain, because nobody has done the studies.
So we were like, hmm... we have the population, which is quite unique, because usually people who do brain scans, like I do, look at patients who are sixty and older, whereas I wanted to look at risk factors for Alzheimer’s, so I’ve always been working with people who are younger. Forty to sixty. Because before forty, you shouldn’t have hormonal changes, unless you have a hysterectomy.
But we looked at women without hysterectomy or (ovariectomy) who were forty-to-sixty years old, and we divided them into pre-menopause/regular cycle, perimenopause, when you start skipping your cycle and you start having hot flashes, night sweats…
Yup. That’s where I am. Fun!
…insomnia, some depression, some word-finding issues, cognitive slippage. And then we have men, exactly the same age. And we did brain scans in all of them, and then we looked at the data.
And what we found is that if you are a man, forty-to-sixty years old, your brain is broadly fine. You have high brain activity, you have no Alzheimer’s plaques, and if you do it’s just a few, and your brain is not shrinking. On average, you’re fine. But if you’re a woman, it makes a huge difference whether you’re pre, peri or postmenopausal. If you’re a premenopausal woman you’re broadly the same as a man’s brain, for the same age.
If you’re perimenopausal, we find a dip in brain energy levels, which is really brain glucose metabolism, the way the brain burns glucose to make energy. In some cases, it’s up to twenty percent worse for women, and that gets even worse once they transition to menopause. The scan literally goes from bright red and yellow to green.
What does that mean? What does the red and the yellow mean?
That your brain activity is nice and bright, and then it drops. In some women by as high as fifty percent.
And green is bad?
Well, darker is worse, yes. You want your brain scans... I’ll show you.
Yes, I’d love to see.
[She opens a file on her computer.]
At the same time, we found that the women who show these energy drops, they start accumulating Alzheimer’s plaques. We have at this point hundreds of patients, and we also follow them over time, and we really show the change as women go from pre-menopause to peri-menopause to post menopause. Not all of them. There are some women who are fine, and some women whose brains are much worse.
Because, when women tell you I’m having hot flashes, I’m having night sweats, I can’t sleep at night, I can’t think straight, I have brain fogs, I get confused, I can’t multitask — so many women tell me I used to be so good in multitasking, and now I just can’t quite do it as well — those symptoms don’t start in your ovaries. They start in your brain! And it’s something that’s been completely overlooked. These are neurological symptoms of hormonal changes.
And we’re associating hormones only with what’s going on in the uterus, right?
Yes. We’re just thinking it’s about not having kids anymore. But that’s not the point. The point is that my brain, in middle age, is changing, and how do I make it better?
Yes. How do you make it better?
Well, it depends.
So there are two separate components, and this is really what I’m trying to clarify. All women experience hormonal changes. For some women, they’re not a big deal. For some women, they range in severity, from mild to severe, and they need to be addressed. For some women, they are so severe, that they can actually trigger Alzheimer’s.
Yeah. If you have a predisposition for Alzheimer’s disease.
Genetic predisposition to it, right? Or just any sort of predisposition?
Any sort, because we have patients here who do not have any known genetic predisposition for Alzheimer’s, but they start accumulating Alzheimer’s plaques, and we know that Alzheimer’s is genetic in one percent of the population.
Then about thirty percent has some genetic risk factor that doesn’t cause Alzheimer’s, but they increase your risk, like having a family history or having some specific genes. But the rest of the population has none of this, and they still get Alzheimer’s.
So, the question is why?
One day we’ll find out what causes Alzheimer’s in people. Right now we don’t know, but we do have markers of risk.
So, if I know that you’re at risk, then I’d want you to take action. And then it depends, are you having the symptoms of menopause but not the increase of Alzheimer’s risks? Then we address menopause only. But if you also have a risk for Alzheimer’s then we really need to address that now. Because that’s when your brain is triggering these changes.
Estrogen is a really strong neuroprotective hormone. It’s strongly associated with immune system, it’s a neuroplastic hormone, so if you lose it, your brain starts aging faster.
And is that the same as testosterone in men?
So, what do they have in their bodies that’s equivalent to estrogen that’s keeping their brains plastic?
Men’s brains are more testosterone-driven, but the thing is they also have a little bit of estrogen. The thing is that testosterone can be converted into estrogen at any time.
I did not know that.
Yes, and the other thing is that in men, they go through andropause, which is the male equivalent of menopause, but it’s a slow gradual process that takes a long time. There are men who become first time fathers when they are seventy-five.
Saul Bellow. He became a father at eighty-four.
Then there’s Mick Jagger.
Right, exactly. I’d probably have Mick Jagger’s baby if I still had a uterus.
[She laughs] There are plenty of examples. They’re given a chance, they can still have babies, whereas women can’t.
So, for them their brains are not as nearly affected by that. It’s almost the same as aging. What I think happens is that for men, chronological aging and hormonal aging kinda go hand by hand, slow and steady. Whereas for women, chronological aging is the same as men, but endocrine aging is just: boom!
Yes, endocrine aging, so hormonal aging...
Endocrine aging, meaning you fall off the cliff, basically.
Yes. And we know that in the rest of the body, when you lose your sex hormones — your estrogen and progesterone, FSH, all these hormones — the rest of your body starts aging faster. Your arteries get harder faster, your bones become more fragile faster, pretty much anything that can age, ages a bit faster than before.
All women know that intuitively that when you’re past forty-five, if you go on a diet, it will take forever to lose the weight because your metabolism changes too.
Yes! I’ve eaten the same as I’ve always have, and I’ve put on like a pound a year since my mid-forties. It’s all sitting here, right in my mid-section, and I don’t do anything different. And I used to be thin and now I’m...
No, you are still thin, but your body changes.
And the shape of it changes, where the fat goes, everything. And I see the number on the scale climb, and I’m like what, why? I’m being nice to you, body! I feed you good food, I exercise.
Yeah, it’s the same for every woman, and it is a consequence of estrogen depletion.
Every woman knows that as you reach menopause, your hair goes dry, your skin goes dry, that’s aging. Nobody ever thought that the same thing would happen in the brain. Now why are we not thinking that? Because, in neurology, we are trained to think that the brain is completely separated from the rest of the body.
The brain is in charge of the rest of the body, but pretty much everybody assumes that the rest of the body doesn’t have much of an impact on the brain. And that turns out not to be true. In every possible discipline. I think people who discovered the microbiome really helped change this view of the brain.
You mean bacteria in the gut?
The bacteria in the gut, yes. They have shown that the microbiome has a huge impact on the health of the brain. So, if your bad bacteria outnumber your good bacteria, that has an impact on the brain. And everyone said that’s impossible, but it’s not.
There are products of these bacteria that can travel up the vagus nerve and affect the permeability of the brain, they can get inside your brain, they can change your production of GABA, which is a soothing, calming neurotransmitter.
So, if GABA is not being produced, you get stressed out and anxious, which is what the bad bacteria do to you. They kinda hijack your brain and then you get all stressed out and you keep doing all the negative things that will put even more bad bacteria into your body.
So, they’ve shown very clearly that your gut health has a strong effect on the health of your brain, but we know that. We know your heart, if your heart is not healthy, your brain is not healthy, because the oxygen can’t get in, the nutrients can’t get in, your iron can’t get in, you get anemia, you feel crappy.
And the same for your ovaries; there’s a feedback loop between the ovaries and the brain, it’s called the HPG axis: a highway that we have inside the body, it connects the brain to the pituitary gland to the ovaries and the thyroid. So hormones can travel back and forth. And that’s how your ovaries are communicating with your brain. And that changes your brain in a big way.