“In the next three minutes, 3 people will develop Alzheimer’s. Two of them will be women.”

As neuroscientist Dr. Lisa Mosconi says in her New York Times article, “The Menopause-Alzheimer’s Connection” while women account for two-thirds of Alzheimer’s cases, little is being done to understand why simply being a woman significantly increases your risk of developing the disease.

Dr. Mosconi is Associate Director of the Weill Cornell Alzheimer’s Prevention Clinic, where she and her colleagues are working to understand this critical – and critically overlooked – piece of women’s healthcare.

 

Menopause and increased risk of Alzheimer’s disease

Team genneve came across this story because Dr. Mosconi and others have linked Alzheimer’s disease with menopause. They postulate that as estrogen levels subside in a woman’s body as she ages, so do its neurological protections.

As Dr. Mosconi puts it: “In straight talk: menopause causes metabolic changes in the brain that seem to increase the risk of Alzheimer’s disease.”

“In straight talk: menopause causes metabolic changes in the brain
that seem to increase the risk of Alzheimer’s disease.”

Fortunately, as Dr. Mosconi has helped identify the problem, she has also helped point to some powerful solutions. Exercise and nutrition, she says, can play a significant role in preventing cognitive decline.

In Part 1 of her podcast with genneve CEO Jill Angelo, Dr. Mosconi explains the mechanism behind menopause and Alzheimer’s risk. Continue on for Part 2, where she discusses how women can protect their brains as they age.

Learn more about Dr. Mosconi, the Alzheimer’s Prevention Clinic, and how you might participate in their research. If you want to start nourishing your brain against age-related decline (“eating for retirement,” as Dr. Mosconi puts it), get your hands on a copy of her fascinating and very readable book, Brain Food: the Surprising Science of Eating for Cognitive Power.

For further reading on nutrition and your health: read up on good gut flora and, now that you’re going to eat so much better, how to give up sugar.

Jill: Well, Lisa, it’s a pleasure to have you with us today. We’re going to talk today about menopause and any correlation it might have to brain health and Alzheimer’s in particular. This topic hits really personal to me, because Alzheimer’s is quite prevalent in my family and I’ve seen its impacts. So, this is a personal conversation for me today and I just deeply appreciate the work that you’re doing. So, welcome!

Dr. Lisa:  Thank you. Thank you so much and thank you for having me.

What is neuroscience, and how did you get started studying Alzheimer’s?

Jill: First and foremost, you’re an expert in brain science. Help us understand what that means and how did you get started in this field?

Dr. Lisa:  So brain science is really the study of what happens in the brain. And for me, I was particularly interested in the medical applications of that. So, my background is in neuroscience and nuclear medicine, which is code for brain imaging. So, my work is really focused on detection of whatever goes on inside the brain from a structural, functional and chemical perspective, all of them.

And how I started …. My parents are nuclear physicists, both of them. They introduced me to nuclear medicine very early on, because my mother was teaching nuclear physics to medical doctors and to physicists that then transitioned to medicine. So, I started very early on, and pretty much when I started my PhD, my grandmother started showing signs of cognitive decline and cognitive impairment.

Within a matter of years, she just transitioned to full-blown dementia. So, almost by chance, I had started working on Alzheimer’s due to my PhD; I was actually working on the prevention of Alzheimer’s and early detection of Alzheimer’s. And just around the same time, my grandma was pretty much a textbook case of what happens to somebody with dementia and it was terrible, it was terrible to witness not just on her, but on my family as well. And that was really, you know… she had Alzheimer’s, so dementia, probably it was mixed dementia with a strong vascular component. Her sister had exactly the same, and then her younger sister developed it too.

So, like you were saying about your family, you really want to protect your parents at that point. You want to make sure that, in my case, my mother would not have to go through that and that I wouldn’t have to go through that and that my daughter wouldn’t have to go through that. So, prevention has been the main focus of my research ever since I started, and I moved to New York 15 years ago, at this point, to really have the opportunity to do more and better research. Because Italy is Italy – you are lucky if you have any money at all for research. That’s why I moved here and I never left.

So, I started at NYU School of Medicine and now I am working at Weill Cornell Medical Center. And I’m actually the Associate Director of the Alzheimer’s Prevention Clinic at Weill Cornell. And this is the first Alzheimer’s prevention clinic in the country.

How many people worldwide have Alzheimer’s disease?

Jill: Wow, wow! Speaking of Alzheimer’s for a moment, how many Americans or even people worldwide does it affect?

Dr. Lisa:  Currently, it’s 46 million Alzheimer’s patients worldwide. And what is even more terrifying, in some ways, is that the number of cases is estimated to increase to 130 million by the year 2050. It’s really an epidemic. We are facing an epidemic, and I think we are not prepared.

So, you’re studying the things that cause Alzheimer’s?

Jill: And your work – would you say it’s all around looking at causation or things that cause that; that are going to contribute to that incredible growth in Alzheimer’s?

Dr. Lisa:  Yes. Our work is definitely focused on identifying all possible risk factors for Alzheimer’s. All the factors that will make you develop Alzheimer’s. Even if you don’t have a genetic mutation that is causative of Alzheimer’s. And this is really important, because when I started about 15 years ago, most people would think about Alzheimer’s as either an inevitable consequence of getting older, or as a consequence of bad genes in your DNA, or both. And it turns out neither one of these alternatives is really true, in that getting older is not a linear path to dementia, and genes are not your destiny.

In fact, one percent of the population develops Alzheimer’s because of genetic mutations; 1 percent, no more than that. For 99% of us, of course, your genetics play a role on some level: they can put you at risk, they can give you a higher risk, a lower risk, but they are not the entire story. And your lifestyle and your environment play a huge role that was always underestimated until very recently.

“getting older is not a linear path to dementia,
and genes are not your destiny”

So, what we have learned is that 1 in every 3 Alzheimer’s cases could be prevented by addressing lifestyle and medical factors, like factors for cardiovascular risk, but also lifestyle, in terms of exercise, intellectual stimulation, and perhaps, most of all, diet.

Is cognitive decline preventable?

Jill:  Do you think we’ll ever get to the point where Alzheimer’s is, like, 99% preventable?

Dr. Lisa:  Well, I think that’s optimistic, but I think we can probably shoot for 30% to 50%, depending on who’s looking at it. The most conservative estimate is 30%. The most optimistic estimate, at this point, is 50% preventable. And look, it’s great, right? 75 million people, that would be fantastic, I think.

What about Alzheimer’s and menopause?

Jill:  It sounds like there are so many corollary factors and I think we are going to need another podcast just on all of that, but today let’s talk a little bit about the relationship between Alzheimer’s and menopause. You recently published a piece titled “Alzheimer’s and Women’s Health, an Urgent Call.” To me, that seems alarming. Can you explain a little bit about your findings and what you’ve learned?

Dr. Lisa:  Yes, gladly and thank you for the question. As scientists, we have long known that female sex is a major risk factor for Alzheimer’s. The number one risk factor is aging, but the number two, so the second most important risk factor, is actually being a woman. And for many, many years nobody looked into why. This is alarming, because of every 3 Alzheimer’s patients, 2 are women, everywhere in the world, regardless of geography, regardless of cultural background, regardless of a variety of factors. Alzheimer’s affects more women than men.

And people can say, “oh, that’s because women live longer” and they just say, “well, it’s because you guys live longer,” but that is just so not the case. Women outnumber men 2 to 1 in the Alzheimer’s population and this is already accounting for the increased longevity relative to men. You can look at that in any age group; like, if you look at people who are 60 to 70 or 65 to 75, 75 to 85, any age range has exactly the same ratio. Out of every three patients with Alzheimer’s, two are women, one is a man.

Also, if you control for that statistically like we do, with survival analysis, accounting for mortality rates, etc. – it’s exactly the same story. So, it’s not just that we live longer. There is something about just being a woman that puts us at a higher risk for Alzheimer’s as compared to men. And that is really important because it doesn’t happen for other neurological diseases, it’s only for Alzheimer’s. If you look at vascular dementia, it’s not the same rate. If you look at Parkinson’s disease, actually more men suffer than women. So, there’s really a strong connection between female sex and Alzheimer’s, and we just did not know what it was.

What we thought was, well, for a really long time, people thought of Alzheimer’s as something that just turns on when we are older. And all my work has always been about early detection. How early on can I catch signs of future Alzheimer’s? Because we are using brain imaging techniques, we can really track development of Alzheimer’s in brain from when people are in their 30s and 40s and 50s. And what we have found – and what other people have found – is that Alzheimer’s is not a disease of old age. It starts in mid-life with changes in the brain when you don’t have cognitive symptoms, you have no clinical symptoms, you have no cognitive decline whatsoever, but it’s already inside your head. And then it takes 20 years before the brain basically gives up and has no more reserve to withstand it, and then people develop symptoms. So there is a twenty years’ gap between the onset of changes in the brain and the onset of clinical symptoms.

And sure enough, what happens only to women and not to men, when they turn 45, 50? They go through menopause.

“Out of every three patients with Alzheimer’s,
two are women, one is a man.”

Jill:  When you said, ok, that is the unique thing that women go through and men don’t, you said, “hmm, let’s look at this, let’s look at it … deep”?

Dr. Lisa:  Yes. And I was amazed that so little had been done. I mean, it’s such an obvious conclusion to reach, right? And there was so little done to really look into that.

One reason that we thought we should really investigate that is that estrogen is not just involved in fertility. Estrogen plays a huge role in the brain, all the time, throughout our lives – from the minute you’re born to the very last minute of your life, estrogen plays a huge role.

And in particular, it is neuroprotective. So, it literally shields your brain from harm.

So, as you go through menopause, there’s a decline in estrogen levels, and yes, that affects your fertility and your ability to have kids, but at the same time, it gives all sorts of neurological symptoms that are just not thought of as neurological.

So when women suffer from hot flashes, those are not in your ovaries; those start in your brain, right? When you go through menopause and you develop insomnia, depression, confusion, night sweats, memory loss for some women – not loss, but memory decline, memory impairment – that’s not because of your ovaries, that’s because of your brain. There’s something going on in your brain that is not making it function as well as it used to.

And that’s because estrogen plays such a huge role as a neuroprotective agent and also as a stimulant. It literally stimulates certain parts of your brain to be active and to be metabolically engaged.

So, as the estrogen goes down, as women, we lose protection, and that leaves us more vulnerable to brain aging and dementia.

Jill:  So, the first question that pops up in my mind is: so what about men? Do they never have that kind of protection? What’s protecting their brain?

Dr. Lisa:  Testosterone. Men have more of a balance between estrogen, testosterone, progesterone – they are not as dependent on estrogen as we are. And also, men go through andropause, when they’re, like, 70. So, whatever changes they experience are milder and later on in time. Also, their estrogen levels don’t go down. They start low and just remain whatever… whatever level…

We knew from animal studies that the menopause transition has an impact in brain physiology. Now, these are studies in mice. And as a neuroscientist who works with people, I can tell you, whatever happens in mice, does not necessarily happen in people. So, we started with those studies because they’re fantastic, and they were mostly carried out by a wonderful friend of mine, Dr. Roberta Diaz Brinton at the University of Arizona. She is incredible, and she’s such a powerhouse in so many ways, she’s just a fantastic person; such a strong advocate for women’s health.

She actually came up to me when I was giving a talk at some conference, and she said to me, “what do you think about menopause in Alzheimer’s risk”? And I was like, “eh, nothing?” She goes, “well, you should, because we have shown this, this, this and that…” And it was such incredible new research, that I was immediately interested, and I said to her… well, what they’re showing is that in female mice… so mice don’t go through menopause naturally, as we do. You have to induce it. And once you induce menopause, their brains, kind of shut down. You can tell, there is a very sudden reduction in brain activity that is related to a suppression of mitochondria function. Mitochondria are little parts, little organelles inside our cells that are responsible for production of energy. So if the mitochondria, kind of, slow down, our ability to produce energy also slows down. This is everywhere in the body and the brain.

So, they showed that menopause really triggers a kind of bio-energetic crisis in the brain of mice. And she said to me, “I would love to see what happens in women.” And so, we did it. We ran one of the very first studies with women. Actually, I think, probably the first one with women prior to menopause.

We studied healthy women without Alzheimer’s, without any cognitive impairment, and they were all 40 to 60 years old. Some were pre-menopausal, meaning they had no symptoms whatsoever, they were doing fantastic. Some were perimenopausal – so they were starting to show signs of menopause. And some were post-menopausal. We also had a group of men of the same age and educational level, so we matched them, they would be, like, our controls.

And we measured a lot of things. We measured… in everybody, we looked at clinical measurements, cognitive performance, lab tests – all sorts of lab tests – cholesterol, homocysteine, vitamin B12s, etc.

But most importantly, we did brain imaging on all of them. So we looked at their brain structure – if their brains showed any sign of atrophy, which is, like, a proxy for neuronal loss. We looked at brain glucose metabolism, which is an indicator of how active their brains are. And also, we looked at Alzheimer’s pathology. We can do brain scans and take a picture of whatever’s in the brain. If you show any Alzheimer’s plaques in your brain, we will see them on the scans and we can quantify how much you have of that pathology.

And we also measured mitochondrial activity. So we had a lot of information, and no matter how you slice it, post-menopausal and perimenopausal women showed on average 45% lower mitochondrial activity than pre-menopausal women. And they showed reduced brain activity by 30%. And the post-menopausal women also showed a lot more amyloid than the pre-menopausal women and men of the same exact age.

Should women be taking hormone replacement therapy (HRT)?

Jill:  Those are big gaps. When you think about that disparity and that difference and the impact, and the vulnerability that we have in our brains to Alzheimer’s, it begs the question, should I be taking hormones? Or, you know, what can I be doing as a woman – and so many women are conflicted about hormone replacement therapy. What’s your point of view on that? Did you have any conclusions around that at this point?

Dr. Lisa:  I’ve done research on that, because in 10 years I’ll be perimenopausal, and I want to be prepared. So I looked into that, because that was exactly my question for Dr. Brinton when she contacted me and said, “well, so what do we do?” And my understanding from the media, I guess, was that HRT or estrogen replacement therapy or hormonal therapy increased the risk of breast cancer. And pretty much that’s what everybody thinks. And she got so frustrated, she was like, “aah, another one!” And she said to me, “just figure it out. Just read and then we’ll talk about it.”

Jill:  And I’m sorry to interrupt you, but you will hear a lot of OB/GYNs or MDs, really, they’re supportive of hormone replacement therapy in the right way, you know, provided. And so, I can see where her frustration came from.

Dr. Lisa:  Yes, I think it was misinformation. Actually, I was talking to the chairman of my department, who’s really supportive of our work and really wants to promote what we’re doing. And he was saying to me, “look, many years ago in 2002 and 2004, there were very big clinical trials that were interrupted almost overnight – the Women’s Health Initiative trials – because they did report that women who were taking the combination therapy – estrogen and progestin – they showed an increased rate of breast cancer and increased incidence of breast cancer. Whereas women who were only taking estrogen, did not. Actually, they showed reduced incidence of breast cancer, but that was enough for the media to basically sound the alarm.

If I understood correctly, a lot of people actually sued the pharmaceutical companies or there was some kind of… upheaval. So, they just interrupted the trials. And I would say those trials were not perfectly designed, because they looked at women who were fairly old. They were 50 to 79, so they were already post-menopausal. Actually, they were not old, I’m sorry, 50 is not old – a terrible thing to say!

Jill:  It’s not old anymore, it’s a lot younger than it used to be!

Dr. Lisa:  Absolutely, but I meant, you know, endocrinology… well, from an endocrine perspective, 50 is not young. So, they were just post-menopausal. And there is evidence from follow-up studies … also what they showed was an increased risk of cardiovascular events for both groups. So, regardless of whether you were on estrogen-only or estrogen and progestin, they really showed the increased risk of cardiovascular events, and that was also a big concern.

But there’s evidence that if you start therapy prior to menopause, the risk of cardiovascular disease is actually reduced. And even if you start HRT after menopause, but not later than nine years’ post-menopause, there seems to be still benefit.

So, I think what we need is more research, at this point. I think the risk of cancer is scary for everybody. But I think there’s a lot of thought that needs to go into that. If you have a uterus, then estrogen alone is problematic. If you had a hysterectomy, then you can tolerate it without necessarily developing cancer. But it’s also really important, I think, to do genetic testing. And see if you have any genetic risk-factors for ovarian cancer or breast cancer. And that’s something we need to know prior to starting any therapy.

Obviously, if it runs in your family, then you know that you are sensitive to estrogen replacement therapy, you know that. If you carry the Angelina Jolie gene, for instance, then that’s a big red flag; so the BRCA gene, if you are positive for that then, I would say, you should not take estrogens.

But for people who don’t test positive for the genetic markers, then I think we need more research and we need to understand when to initiate therapy or what kind of therapy or what kind of dosage, what’s the source of the estrogens, right? Many formulations are from horses. Is that the best way? Could we take phytoestrogens, for instance, from plants? Would that be more gentle on the body? You know, I think there are so many questions that we’re just not asking, and it’s a pity, because everybody goes through menopause, everybody. It’s insane that there is no relief.

Jill:  Whether you experience the symptoms or not, every woman or any person with a uterus goes through menopause.

Dr. Lisa:  Yes, absolutely. But also I would say, 80% of women do have symptoms; there’s only about 20% who just breeze through it, like my mom. But 80% is a lot. I think there are 850 million women in the world who are entering menopause or just entered menopause. And we have no ways to help them.

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Shannon Perry

Shannon is a celebrated author and global educator. Whether she’s interviewing a physician or producing a podcast, her appetite for research, facts, and truth culminates in credible health education and programming that women can rely on. An avid runner, cyclist, and climber, Shannon knows a thing or two about thriving in midlife and lives in Seattle with her cat, dog and boyfriend.

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