podcast Peter Attia 2026-01-26 topics

#381 ‒ Alzheimer's disease in women: how hormonal transitions impact the female brain, the role of HRT, genetics, and lifestyle on risk, and emerging diagnostics and therapies | Lisa Mosconi, Ph.D.

Audio

Show notes

Lisa Mosconi is a world-renowned neuroscientist and the director of the Women’s Brain Initiative at Weill Cornell Medicine, where she studies how sex differences and hormonal transitions influence brain aging and Alzheimer’s disease risk. In this episode, Lisa explores why Alzheimer’s disease disproportionately affects women and why longer lifespan alone does not explain their nearly twofold risk compared to men. She explains why Alzheimer’s disease may be best understood as a midlife disease for women, beginning decades before symptoms appear, and how menopause represents a fundamental brain event that reshapes brain energy use, structure, and immune signaling. The conversation also examines what advanced brain imaging reveals about preclinical Alzheimer’s disease, estrogen receptors in the brain, and why genetic risks such as APOE4 appear to affect women differently from men. Finally, Lisa discusses the nuanced evidence around menopause hormone therapy, the legacy of the WHI, her new CARE Initiative to cut women’s Alzheimer’s risk in half by 2050, and practical, evidence-based strategies to support brain health through midlife—including lifestyle, sleep, metabolism, mood, and emerging therapies such as GLP-1 agonists and SERMs (selective estrogen receptor modulators).

Subscribe on: APPLE PODCASTS | SPOTIFY | RSS | OVERCAST

We discuss:

Timestamps : There are two sets of timestamps associated with the topic list below. The first is audio (A), and the second is video (V). If you are listening to this podcast with the audio player on this page or in your favorite podcast player, please refer to the audio timestamps. If you are watching the video version on this page or YouTube, please refer to the video timestamps.

How Lisa’s personal family history and scientific background led her to focus on the intersection of women’s health, brain aging, and Alzheimer’s disease (AD) [A: 2:45, V: 0:11];
The long preclinical phase of AD and the emotional burden carried by patients before dementia becomes severe [A: 7:15, V: 4:58];
How AD compares to other common forms of dementia: prevalence, pathology, symptoms, diagnostic challenges, and more [A: 10:45, V: 8:40];
Why AD disproportionately affects women: how AD is not simply a disease of old age or longevity but a midlife disease in which women develop pathology earlier [A: 16:15, V: 14:36];
Menopause as a leading explanation for women’s increased Alzheimer’s risk, and how advanced braining imaging can detect early changes in the brain [A: 26:15, V: 25:05];
How a new method for imaging estrogen receptors in the brain is changing how we think about the menopause transition [A: 35:45, V: 35:38];
What estrogen receptor imaging can and cannot tell us about hormone therapy’s potential impact on brain health [A: 48:45, V: 49:40];
Lisa’s studies on the relationship between levels of systemic estrogen and density of estrogen receptors in the brain [A: 58:00, V: 59:55];
Why blood estrogen levels poorly reflect brain estrogen signaling, and how tightly regulated brain hormone dynamics complicate our understanding of menstrual-cycle and lifestyle effects [A: 1:02:15, V: 1:04:49];
The CARE Initiative: Lisa’s research program looking to slash AD rates in women [A: 1:07:45, V: 1:10:49];
The dramatic difference in AD risk between men and women associated with APOE4 [A: 1:10:45, V: 1:13:58];
What the evidence suggests about menopausal hormone therapy (MHT) and AD risk, and why timing, formulation, and uterine status appear to matter [A: 1:12:00, V: 1:15:13];
How the CARE initiative plans to study MHT and AD risk, within the practical constraints of a three-year research window [A: 1:17:30, V: 1:20:57];
How to think about starting hormone therapy during perimenopause: balancing symptom relief, hormonal variability, and individualized care [A: 1:21:00, V: 1:24:55];
Investigating selective estrogen receptor modulators (SERMs) as a targeted approach to brain health during and after menopause [A: 1:25:00, V: 1:29:10];
Why estrogen became wrongly associated with cancer risk and what the evidence actually shows [A: 1:29:30, V: 1:33:58];
Why better biomarkers are central to advancing women’s Alzheimer’s research [A: 1:38:30, V: 1:44:09];
Modifiable risk factors for dementia, the limitations of risk models, and questionable conclusions drawn from observational data [A: 1:44:15, V: 1:50:20];
GLP-1 agonists and brain health: exploring potential neuroprotective effects of GLP-1 agonists beyond metabolic benefits [A: 1:49:00, V: 1:55:48];
The importance of lifestyle factors in reducing risk of dementia: practical strategies for women to support brain health [A: 1:53:45, V: 2:01:21];
Why long-term, consistent lifestyle habits are essential for building cognitive resilience and protecting brain health over decades [A: 2:01:15, V: 2:09:58]; and
More.

Show Notes

Notes from intro :
Lisa Mosconi is a neuroscientist, neuroimager, and the director of the Women’s Brain Initiative at Weill Cornell Medicine
Where she leads research on sex differences, especially how menopause and hormonal transitions shape brain aging and Alzheimer’s risk
She is a professor of neuroscience and a pioneer in brain imaging approaches that map Alzheimer’s disease decades before symptoms appear

In this episode, we talk about

Why Alzheimer’s disproportionately affects women, and why women’s increased lifespan over men does not fully explain that 2x difference
The idea that Alzheimer’s is actually a midlife disease for women Beginning long before symptoms
How menopause is fundamentally a brain event and what happens to brain energy, structure, and immune signaling during that transition
What advanced imaging reveals about preclinical Alzheimer’s disease
Lisa’s work in imaging estrogen brain receptors
APOE4, specifically other genetic risks and why they impact women seemingly more than men
The nuanced evidence around menopause hormone therapy: risks, benefits, timing, formulations, and why the WHI caused decades of confusion
Lisa’s new initiative, called the CARE Initiative : a global effort to cut women’s Alzheimer’s risk in half by 2050
Some practical evidence-based strategies for supporting brain health throughout midlife transitions including: Lifestyle Sleep Metabolism Mood, The evolving role of medications including GLP-1 agonists and SERMs
Beginning long before symptoms
Lifestyle
Sleep
Metabolism
Mood,
The evolving role of medications including GLP-1 agonists and SERMs

How Lisa’s personal family history and scientific background led her to focus on the intersection of women’s health, brain aging, and Alzheimer’s disease (AD) [A: 2:45, V: 0:11]

This is a wonderful podcast because it combines 2 topics that we have spent a lot of time on in this podcast and in Peter’s clinical practice, but it is probably the first time we’ve brought them into an intersection here
1 – All things that pertain to women’s health In particular the transition through pre, peri, and postmenopause
2 – Brain health There isn’t a single person listening to this podcast who doesn’t appreciate both the role of the dementing diseases and how they truncate lifespan, but perhaps much more importantly, how they truncate healthspan
The reason Peter wanted to talk with Lisa today was because she sits at the intersection of these two
Her work is asking the questions as they pertain specifically to women and brain health
In particular the transition through pre, peri, and postmenopause
There isn’t a single person listening to this podcast who doesn’t appreciate both the role of the dementing diseases and how they truncate lifespan, but perhaps much more importantly, how they truncate healthspan

Tell me how you came to find this as your focus

It’s quite personal for Lisa
She was born and raised in Florence, Italy It’s really pretty; she never appreciated how pretty Florence is until she moved
In Italy, many families live together Her parents live in Florence and her grandparents were in Florence
Both of her parents are nuclear physicists
She comes from an interesting family where half of the family has a PhD (usually in physics) and the other half is in the army Very disciplined scientists
She grew up in this environment where everything was about physics and biology and studying and learning, and she decided to apply that knowledge to medicine
Lisa has a PhD in neuroscience and nuclear medicine, which is a branch of radiology
She does a lot of brain scans
Around the time she started studying neuroscience (specifically memory and language), her grandmother (who lived with her and her parents) started showing signs of cognitive decline
Her grandmother was the rock of the family She was this really strong, extremely intelligent woman who went through World War II and she raised the family
Her grandfather was a prisoner of war, being in the army for a long time
Nothing broke her spirit until she started losing her memory, until she started losing the ability to communicate, until she started losing the ability of taking care of the family, where she could not remember how to cook
It’s really pretty; she never appreciated how pretty Florence is until she moved
Her parents live in Florence and her grandparents were in Florence
Very disciplined scientists
She was this really strong, extremely intelligent woman who went through World War II and she raised the family

Lisa shares, “ That really broke my grandmother and broke us and led to a diagnosis of Alzheimer’s disease over time .”

What was even scarier was that her grandmother’s 3 sisters also developed Alzheimer’s disease and passed away from it Her grandmother’s only brother was spared, even though they all lived to the same age (late 80s)
Her grandmother’s only brother was spared, even though they all lived to the same age (late 80s)

Peter asked, “ How long did she suffer with the disease? When did it start? ”

At least a decade
It was very subtle
Very often Alzheimer’s disease starts in a gradual way
At first, there’s some mild cognitive impairment, which she was able to almost masquerade She had strategies to find the answer, keep going about the day without really telling us that she was having a hard time
But then it became quite evident, and, in the end, it was very severe, because she was healthy otherwise Her body was healthy, but her mind was not
She had strategies to find the answer, keep going about the day without really telling us that she was having a hard time
Her body was healthy, but her mind was not

All 3 sisters succumbed to this in their late 80s, having onset in their late 70s this is a very typical trajectory

The long preclinical phase of AD and the emotional burden carried by patients before dementia becomes severe [A: 7:15, V: 4:58]

Given that Lisa had such a personal experience, one of the things people often ask Peter is at what point do patients become aware of what’s happening such that it creates enormous distress for them versus when is the cognitive impairment so severe that they are no longer suffering, and it’s only those of us around them who are suffering, but we could potentially take some solace in the fact that they are no longer suffering?

Do you have a sense of that from your experience?

Now that we’re getting better at diagnosing Alzheimer’s disease, not just using clinical tools but using biological markers like brain imaging and biological fluids in blood, we can tell when a person is at risk for Alzheimer’s or is showing red flags for Alzheimer’s fairly early on
And then it’s possible to correlate that with what the patient is telling you
Because the the cognitive tests that we’ve been basing the Alzheimer’s diagnosis on for decades are quite late They’re not sensitive to the earliest possible manifestations of the disease, which are usually subjective
They’re not sensitive to the earliest possible manifestations of the disease, which are usually subjective

What we’re learning now is that there’s a phase that is a preclinical phase where the disease is underway

You can see the proteins and the lesions either in the brain or in biological fluids
But, objectively, there is no impairment, there is no deficit at that point on cognitive testing

Many patients will tell you that they don’t feel the same. There’s this idea that they are aware that something is changing, that their performance is not the same

It’s very hard to say if it is just aging or something more severe

⇒ It looks like the preclinical phase of Alzheimer’s disease can last decades

Where the disease is underway, it starts with negative changes in the brain that very slowly but surely eventually exceed the brain’s ability to compensate
But it takes a long time

“ The brain is an extremely resilient organ. ”‒ Lisa Mosconi

Unfortunately, many patients are in this gray area, if you will, where they know that something is amiss, but when they come for a neurological evaluation, everything is fine When they go to see a neuropsychologist, they test with the normative value by age and education
So it’s really hard to provide counsel and to offer a treatment plan if we are not able to diagnose the fact that they are in fact on the path towards Alzheimer’s disease
When they go to see a neuropsychologist, they test with the normative value by age and education

That could last decades ‒ it could last a really, really long time until the deficits are such that there is an objective diagnosis

⇒ Usually patients do experience discomfort and depression and anxiety for years until dementia is severe enough that they start forgetting who they are, or they start forgetting that they have a family perhaps, or they start forgetting why they are where they are

Unfortunately, it’s a heartbreaking disorder

How AD compares to other common forms of dementia: prevalence, pathology, symptoms, diagnostic challenges, and more [A: 10:45, V: 8:40]

How much of what you just described through the lens of Alzheimer’s disease specifically is comparable in other forms of dementia, such as Lewy body dementia or frontotemporal dementia or vascular dementia?

Alzheimer’s disease is the most common form of dementia, but it is far from the only cause of dementia

Do you want to put it in the context of these other diseases, both in terms of maybe some of the prevalence of these but also any of the subtle differences in what you just said as far as onset and presentation?

Dementia is an umbrella term that includes different disorders that are typically categorized in terms of pathology, in terms of clinical symptoms and sometimes age of onset Pathology is the kind of lesion that every disorder expresses most abundantly
Now most people are familiar with Alzheimer’s disease and they usually think that Alzheimer’s and dementia may be the same thing ‒ it’s a common misconception
Pathology is the kind of lesion that every disorder expresses most abundantly

⇒ Alzheimer’s is the most common form of dementia, accounting for about 70% of all dementia cases

There are other types of dementia.
Now we hear more and more about frontotemporal dementia , because Bruce Willis unfortunately has been diagnosed with that
In that case, the presentation is a little bit different

⇒ When we do brain scans, actually, we can tell whether a patient has frontotemporal dementia or Alzheimer’s disease based on the pattern of changes in the brain

Frontotemporal dementia tends to occur a little bit earlier in life and predominantly is associated with aphasia , which is disturbed language production

Whereas Alzheimer’s is more about memory function, it’s more about forgetting things

However, at the end of the day, the different types of dementia are quite severe, there is a lot of overlap in terms of symptoms that may occur

The pathology, the pathophysiology is different, but the symptoms at the end tend to overlap; so it’s quite difficult to do a good differential diagnosis

Lewy body dementia is another form of dementia that is due to mutation in the alpha-synuclein protein
It’s a little bit different from Alzheimer’s, where the main problem is an amyloid beta A fibrillar amyloid beta production in lesions that aggregate into plaques, and also neurofibrillary tangles inside neurons
A fibrillar amyloid beta production in lesions that aggregate into plaques, and also neurofibrillary tangles inside neurons

Each one of these dementia has a slightly different biological substrate

Vascular dementia is also very common and tends to overlap with the other types of dementia
In fact, very often we talk about mixed dementia

⇒ It’s quite rare for a patient to only have Alzheimer’s, for instance, and not some vascular damage; it’s rare for a patient to have only Alzheimer’s disease and not also some features of Lewy body dementia

For many, many years, the diagnosis was purely clinical

Diagnosis came late: you needed to have very clear-cut symptoms in order to be diagnosed as Alzheimer’s or Lewy body or frontotemporal dementia

“ Now that we have access to biological markers, we’re getting better and better, and the diagnosis has been done earlier and earlier. ”‒ Lisa Mosconi

So that is hopefully leading to better therapeutic routes for each type of dementia and development of pharmaceuticals that are able to
Right now we’re trying to reverse the damage that, at least in Alzheimer’s, makes results Optimistically, we might say we’re trying to halt progress [of disease] We’re trying to move back in time
We’re trying to catch people when they’re still relatively healthy and the potential for delaying the onset of the symptoms Hopefully preventing the accumulation of the lesions in the brain is feasible
Optimistically, we might say we’re trying to halt progress [of disease]
We’re trying to move back in time
Hopefully preventing the accumulation of the lesions in the brain is feasible

Lisa adds, “ We’re trying to work with people who are fairly young, and that is very new in the field of Alzheimer’s. ”

When she moved to New York, she was already looking at what could be done for Alzheimer’s prevention (that was 20 years ago)
She was working at NYU (New York University) at the school of medicine with her mentor Dr. Mony de Leon He was a pioneer in the field of Alzheimer’s prevention His team was one of the very few teams in the world to work with individuals who were younger than 65
He was a pioneer in the field of Alzheimer’s prevention
His team was one of the very few teams in the world to work with individuals who were younger than 65

Peter remarks, “ The point you make about the overlap is really interesting. ”

It means that if you look at the prevalence of each type, it will not total 100%

You said 70% of dementia will have an Alzheimer’s component. What are the approximate numbers of frontotemporal, Lewy body, and vascular in terms of just aggregate presence?

It’s difficult to really come up with specific numbers, especially for vascular dementia, because it’s always intermixed
Lewy body is usually around maybe 10, 20%
Frontotemporal, pretty much the same
Lisa doesn’t know that we can really say

Why AD disproportionately affects women: how AD is not simply a disease of old age or longevity but a midlife disease in which women develop pathology earlier [A: 16:15, V: 14:36]

We know that Alzheimer’s disease occurs disproportionately in women by about 2 to 1

Do any of the other forms of dementia disproportionately occur in women?

No, and that’s actually something that was very interesting to Lisa when she started looking at the association between female sex and Alzheimer’s disease
She would ask the question: Is it just my family or is there a bigger lesson that we need to learn?

“ We’ve known since the 1990s that after aging, after getting older itself, being a woman is the strongest risk factor for developing Alzheimer’s. ”‒ Lisa Mosconi

But when she asked, can we do something about it, the answer was mostly: well, the point is longevity; it’s just aging
The idea is that women live longer than men, and Alzheimer’s is a disease of old age
So at the end of the day, unfortunately, more women than men have Alzheimer’s disease
But there are 2 things that contradict in part this statement, and clearly aging is important

Peter agrees, “ The first one, by the way, is just a simple actuarial analysis. I did this myself 10 years ago back of the envelope because that was the first guess. ”

The first time he thought about that question was in 2015, and the obvious answer was women, on average, live 2.5-3 years longer, and that must account for it
But if you actually go through even something as rudimentary as the CDC mortality tables and slice them by 5-year increments, you can’t explain the increased prevalence by a factor of 2 to 1 on that delta in age

Lisa’s explanation for why this was not the case

One thing that came to mind obviously was that the difference in the longevity gap was not 10 years It wasn’t that wide It was just a few years
For instance, in England, the gap is about 2 years
It wasn’t that wide
It was just a few years

“ But Alzheimer’s disease and dementia, the whole category is the number one cause of death for women and not for men .”‒ Lisa Mosconi

The other point is that if it was just aging, then women would have a higher prevalence of other age-related disorders and neurodegenerative disorders relative to men, only they do not
Peter points out that cancer and cardiovascular disease are also age-related

Differences within the dementias

For vascular dementia, it’s 50-50 [women and men are affected equally]
Parkinson’s disease with dementias is more prevalent in men
Frontotemporal dementia seems to be more prevalent in men
Lewy body dementia is about 50-50

Women living longer doesn’t seem to be a good way or good reason to dismiss an important question

Is it safe to say the scientific community today has stopped with that sort of excuse and we’ve now fully accepted the fact that there is something biologically different about women that is leading to this enormous mismatch?

Lisa wishes we could say theory were past it; we’re not

It’s still a subject of very active debate in her field

We’re still debating that age is the reason that it’s happening
We’re still thinking that survival and longevity is something that may be driving the higher prevalence
The argument for this is that it’s not a bad argument
They say prevalence is something that you look at cross-sectionally

When does the incidence come on?

The question is: If prevalence is higher, but incidence is not, then it could be aging?
So the question is: Do women develop Alzheimer’s at higher rates than men?

Peter explains what that means

Incidence is the number of cases that occur over a given period of time
So you might say the incidence of this cancer is this many cases per 100,000 people per year
Prevalence is the cross-sectional cumulative number of people at any point in time that have the given condition

To Lisa’s point, if the incidence is identical at every section in time, but the prevalence keeps getting larger as time goes on, then you might have to ask the question, are fewer women dying of the disease and therefore accumulating cases?

It’s been very difficult to get a good estimate of incidence because the diagnosis of Alzheimer’s disease has changed over time, and we’re catching more people now even earlier than we did in the past

⇒ There are more and more studies showing that the incidence is also higher among women, especially in countries with low to middle socioeconomic status

Peter explains another way to think about this mathematically

Incidence is very complicated because the diagnosis is so complicated, it might be easier to look at mortality and tally up the mortality differences
You would reverse-test this hypothesis : If you think incidence is too high, you should see men dying at a much higher rate at a comparable stage of disease to women In other words, the women should be outliving the men with Alzheimer’s disease if they’re all getting it at the same rate (which Peter doesn’t think is the case) but that would be a way to test that hypothesis in the negative
If you think incidence is too high, you should see men dying at a much higher rate at a comparable stage of disease to women
In other words, the women should be outliving the men with Alzheimer’s disease if they’re all getting it at the same rate (which Peter doesn’t think is the case) but that would be a way to test that hypothesis in the negative

⇒ Lisa points out that in some countries, Alzheimer’s disease is actually the #1 cause of death for women over 65

In some European countries and some parts of the US (the data is just coming out)

Many scientists are puzzled that longevity has been the only explanation for the disparity

We’re not looking at risk in ways that they think are doing more justice to the question that we could do before, especially by looking at biological markers
And this is a lot of Lisa’s research: when we do brain imaging or we look at other biofluids in midlife and we compare men and women

Comparing men and women

Let’s say that we have a population of men and women who are like 45 to 65, and all these participants, all these people have a family history of Alzheimer’s or perhaps the [APOE4](https://en.wikipedia.org/wiki/Apolipoprotein_E#Polymorphisms:~:text=neutral%22%20APOE%20genotype.-,%CE%B54,-(rs7412%2DC%2C%20rs429358) genotype

So they are technically at higher risk for Alzheimer’s than the average person, than people who do not have these risk factors

If you look at the brain scans of men and women, the women tend to show more red flags for Alzheimer’s disease in midlife as compared to men at the same age ‒ this is quite consistent

Lisa’s work and the work of many other scientists have shown this

She has also seen that the progression of lesions in the brain tend to be faster in women

So then when you compare men and women who have the same symptoms and the same level of dementia severity

The women’s brains actually harbor more pathology

What seems to happen is that women start developing the lesions of Alzheimer’s (the pathology in the brain) earlier on than men starting in midlife, and we live longer with it
But we’re able to compensate more in that the tests that we use to diagnose Alzheimer’s are heavily reliant on things like verbal memory, which women have a little bit of an advantage in And so, it’s more difficult to diagnose Alzheimer’s in women early because they have a higher cognitive reserve in the metric you’re using to test
In a way, women are masking the fact that there is Alzheimer’s in their brains, but not necessarily overperforming They’re starting at a higher level of cognitive reserve
And so, it’s more difficult to diagnose Alzheimer’s in women early because they have a higher cognitive reserve in the metric you’re using to test
They’re starting at a higher level of cognitive reserve

Lisa’s findings suggest that women live with Alzheimer’s longer, and that may lead to a higher number of Alzheimer’s patients among women down the line

“ That really changed the whole question about women’s brain health and Alzheimer’s risk, because what we and others have shown is that Alzheimer’s is not a disease of old age .”‒ Lisa Mosconi

Alzheimer’s a disease of midlife with symptoms that start in old age

Alzheimer’s starts in midlife with negative changes in the brain and that later on lead to the symptoms and the clinical diagnosis of dementia

That changes the question, because if Alzheimer’s is not a disease of old age, but it’s a disease of midlife, women have a higher risk of Alzheimer’s disease, a higher long-term risk of Alzheimer’s disease as compared to men starting in midlife

Lisa makes the point, “ Then the question that we should be asking is: What happens to women and not to men in midlife that could then potentially explain the higher risk of Alzheimer’s down the line? ”

Peter thinks that’s such a profound statement
It reminds him of a statement he’s made many times on the podcast, where a guest said, “ Osteoporosis is a childhood disease. It just doesn’t manifest in childhood. ” But you reach your genetic ceiling of your bone density, in the case of a woman, by the time she’s 18 or 19 years old So if a woman isn’t able to create enough deformation in her bones and all of the things that lead to strong bones by the time she’s 18, 19, her risk has already started, even though that disease won’t manifest until she’s 60 [ episode #322 with Belinda Beck]
Peter thinks Lisa’s example is frankly even more terrifying, but it’s well-stated
But you reach your genetic ceiling of your bone density, in the case of a woman, by the time she’s 18 or 19 years old
So if a woman isn’t able to create enough deformation in her bones and all of the things that lead to strong bones by the time she’s 18, 19, her risk has already started, even though that disease won’t manifest until she’s 60
[ episode #322 with Belinda Beck]

Menopause as a leading explanation for women’s increased Alzheimer’s risk, and how advanced braining imaging can detect early changes in the brain [A: 26:15, V: 25:05]

Let’s talk a little bit about some of the theories for this

Peter and Lisa are in pretty strong agreement that age alone cannot explain this even if it partially contributes to it
There must be some tail effective age (let’s accept that)
The first idea that would pop into anybody’s head if they’re thinking about this for than two minutes is a fundamental difference between men and women is that men have a very gradual loss of androgens throughout their life, but they’re never shocked with androgen deprivation
Whereas women have a sudden and shocking loss of androgens at about the time you’re talking about: in the middle of their life, they will lose their sex hormones

The question is, does that play a role? Where does that idea fit into this and what other ideas fit into it that could explain this?

This is a subject of very active debate in Lisa’s field, to the point that people almost feel like they have to take sides
It’s an interesting time to be doing this work
A good way to answer is by doing brain imaging (which is what Lisa has been doing)
Back in 2017, she published the first study showing the brains of women before and after menopause Everything we had up until that point was done after menopause, looking at menopause more like an outcome Whereas this was looking at what happens during the transition to menopause, which is the most neurologically active phase, if you will
In this study, there were 3 groups of women: Premenopausal with a regular menstrual cycle Perimenopausal with a regular menstrual cycle Post menopausal up to age 65 (no menstrual cycle for over a year)
There was no hormone replacement therapy
They had age-matched men, because premenopausal women tend to be younger than the postmenopausal ones
What we found was before menopause, at the premenopausal stage, with regular menstrual cycles, there were barely no differences between women’s brains and men’s brains
They used MRI to look at brain volume and the presence of lesions in the brain
Everything we had up until that point was done after menopause, looking at menopause more like an outcome
Whereas this was looking at what happens during the transition to menopause, which is the most neurologically active phase, if you will
Premenopausal with a regular menstrual cycle
Perimenopausal with a regular menstrual cycle
Post menopausal up to age 65 (no menstrual cycle for over a year)

Technical aspects and utility of different types of brain scans

Peter wants to be very technical because he thinks this really matters

The way he explains different types of brain scans to patients

When you look at a test like an MRI , you are doing it for anatomical resolution
Again, you can choose how you do that You can T1 versus T2 This FLAIR versus that You can highlight white matter versus gray matter You can highlight the vascular system But you’re looking for anatomic resolution
Conversely, if you do something like an FDG-PET scan , you’re not looking at anatomic information, you’re looking at functional information In the case of FDG-PET, you want to understand how metabolically active the cells are
CT scans tend to be much more anatomic
You can T1 versus T2
This FLAIR versus that
You can highlight white matter versus gray matter
You can highlight the vascular system
But you’re looking for anatomic resolution
In the case of FDG-PET, you want to understand how metabolically active the cells are

Would you agree with that way to think about them? How do you think of the suite of different radiographic studies that can be used?

Yes: what’s most important is what you’re measuring
You can use different tools to measure different things

The really good definition is whether you’re looking for structure, information for function or information for biochemical, or pathological information

With MRI scans , what you can do is look at the anatomy of the brain, to look at volumetrics You want to make sure that some parts of your brain are really nice and dense with neurons Whereas if we find signs of atrophy, that could be a risk factor for future dementia
You want to make sure that some parts of your brain are really nice and dense with neurons
Whereas if we find signs of atrophy, that could be a risk factor for future dementia

Lisa adds, “ There’s one part of the brain that we always look at is the medial temporal lobe , which is a combination of structures that are quite primitive, if you will, and that they’re highly involved in memory function and also emotional regulation .”

There’s one structure in particular, the hippocampus , which is considered a biomarker for Alzheimer’s risk You really want the hippocampus to be as big as possible ‒ you want the volume to be really nice and large
You really want the hippocampus to be as big as possible ‒ you want the volume to be really nice and large

⇒ When we find reductions in volume and thinning of the structure of the hippocampus and the parahippocampal gyrus (which is right below), that is a risk factor for Alzheimer’s

It doesn’t mean you have Alzheimer’s
It means that that is a red flag for a potential Alzheimer’s risk down the line
A T1 MRI : we usually use it for volumetrics also to make sure that there are no brain tumors, that there are no obvious vascular damage, stroke It’s a good first baseline
We also usually do T2 and FLAIR scans that give you additional information on other parameters that are important If you have gliosis in your brain, which is a bit nonspecific, but it is a sign of white matter integrity damage, it’s like little punctuations in the brain that tend to emerge with aging, but could also be a sign of inflammation, of vascular insults It’s good to monitor that
We can look at the vascular system in the brain using MRI with some modifications Lisa has it in all her biomarker panels
We can do DTI (diffusion tensor imaging) where you can see the structural connectivity of your brain, all the different fibers that connect to different neurons, and you can extract a lot of information from those images
Then we also use a modified version of an MRI to look at blood flow with ASL (arterial spin labeling) , which is completely noninvasive and is also really quick It is helpful to look at whether the brain receives enough blood flow at any given time
We use spectroscopy, a 31P (phosphorus-31) magnetic resonance spectroscopy to look at A TP production in the brain So far, it’s the only technique, except there’s one potential with PET that’s still being established But this technique can give you a good read on the ratio of phosphocreatine to ATP production, which we find to also be a potential biomarker for brain stress almost, when the brain is in a state of energetic damage or crisis that could signify that the neurons are under metabolic stress.
It’s a good first baseline
If you have gliosis in your brain, which is a bit nonspecific, but it is a sign of white matter integrity damage, it’s like little punctuations in the brain that tend to emerge with aging, but could also be a sign of inflammation, of vascular insults
It’s good to monitor that
Lisa has it in all her biomarker panels
It is helpful to look at whether the brain receives enough blood flow at any given time
So far, it’s the only technique, except there’s one potential with PET that’s still being established
But this technique can give you a good read on the ratio of phosphocreatine to ATP production, which we find to also be a potential biomarker for brain stress almost, when the brain is in a state of energetic damage or crisis that could signify that the neurons are under metabolic stress.

This is all MRI, so we can do everything in less than an hour

Peter asks, “ You will get all that information on multiple sequences of one scan? ”

Well, it’s different scans
You run the patient through different sequences, but under one table time The patient is brought out of the scanner for just a minute to switch the coil for the spectroscopy scan, and then they go right back in
The patient is brought out of the scanner for just a minute to switch the coil for the spectroscopy scan, and then they go right back in

Peter asks, “ How many coils do you need for that scan? ”

At least 36; you switch from the hydrogen to the phosphorus, but that’s just something the technician does
This is something you would have a really hard time doing outside of the brain because of motion
One advantage of the brain is you lock that head in place and it’s a short distance under the magnet
Those are really good images.

Specialized PET scans

We also do positron emission tomography or PET scans
We use FDG that looks at metabolic activity in the brain
And we also use another tracer, it’s called C-11 PiB, Pittsburgh Compound B , which shows Alzheimer’s plaques in the brain That is we would colloquially refer to as an “amyloid PET” It’s just the tracer is then carbonated as a C-11, which means that you can do the FDG and the C-11 PiB right away, back to back (you don’t have to wait and bring the patient back the next day)
Another advantage is the PiB has a clearer signal than the fluorinated tracers, which is helpful The signal-to-noise ratio tends to be a little bit higher, so you get a clearer read, which is helpful for people who are younger because we’re not using it diagnostically, we’re using it for research. You need to have a cyclotron right there, you need to have a chemist that can make it for you and then just run upstairs and you inject because it decays really quickly, so you need to have this big nuclear medicine capability on site If you don’t, or if you prefer to use a fluorinated tracer that you can buy commercial, then it’s perfectly fine
That is we would colloquially refer to as an “amyloid PET”
It’s just the tracer is then carbonated as a C-11, which means that you can do the FDG and the C-11 PiB right away, back to back (you don’t have to wait and bring the patient back the next day)
The signal-to-noise ratio tends to be a little bit higher, so you get a clearer read, which is helpful for people who are younger because we’re not using it diagnostically, we’re using it for research.
You need to have a cyclotron right there, you need to have a chemist that can make it for you and then just run upstairs and you inject because it decays really quickly, so you need to have this big nuclear medicine capability on site
If you don’t, or if you prefer to use a fluorinated tracer that you can buy commercial, then it’s perfectly fine

How a new method for imaging estrogen receptors in the brain is changing how we think about the menopause transition [A: 35:45, V: 35:38]

Lisa is really excited about the new ability to do brain estrogen imaging

This is the first time that people have been trying to measure estrogen hormones in the brain for a really, really long time
It’s very hard to do it for a number of reasons
Back in 2019, Lisa went to her radiochemistry department and said, “ We think that menopause is very important for Alzheimer’s risk for women. And we assume that it’s the decline in estrogen levels that drive the increased cellular aging and biomarker risk of Alzheimer’s in women, but that needs to be proven because all the information we have is from rats, so we need to see what happens in women. And we also need the tool to measure what hormone therapy is doing in the brain .”
And they said to her, “ Well, that sounds really, really great, but we don’t have it .”
Lisa wanted to measure both estrogen and estrogen receptor density in women

What she can measure today is estrogen receptor density

What we do is that we have estradiol (the hormone) and we label estradiol with the fluorinating molecule (it’s just attached to the estradiol)
Then there’s an injection: the estradiol goes in the body but accumulates in the brain
And the way it works is that this little molecule mimics estradiol itself and looks for the target

Lisa’s analogy to understand hormone action

The way the hormones work is that the hormone is like a key that needs to open a lock
And the lock is the receptor
And every type of hormone has a specific receptor So estrogen has estrogen receptors, progesterone has progesterone receptors
So estrogen has estrogen receptors, progesterone has progesterone receptors

How estrogen receptors can be measured in the brain

The way that this tracer works is called a fluorinating fluoroestradiol, and it goes up in the brain and it looks for the estrogen receptors
It binds to the receptors, and it works by kind of jamming the lock So the receptor is almost frozen in time for the period of time that the estrogen is there
And then the F-18 molecule starts shooting out gamma rays, and we can take a picture of that from the outside
Then we use filter back projection and other techniques to get an image of the brain
And we can use that with kinetic modeling to get a measure of estrogen receptor density in every part of the brain
We can finally do that
And just in 2024, she published the first proof-of-concept study showing that we can get a signal Especially in the pituitary gland where the signal is specific, and it’s not confounded by metabolites or by blood-brain barrier
So the receptor is almost frozen in time for the period of time that the estrogen is there
Especially in the pituitary gland where the signal is specific, and it’s not confounded by metabolites or by blood-brain barrier

Peter’s reaction

This is not counterintuitive ‒ we would expect to see a high density of estrogen receptors in the pituitary gland independent of the disease we’re talking about just because we want to see the feedback

He asks, “ I guess we’d expect to see it in the hypothalamus even more? ”

Because we would want to get feedback for FSH and LH, is that your thinking?

Yes
The blood-brain barrier is a big issue

But the pituitary is slightly, because the hypothalamus is outside, right?

The hypothalamus is inside the blood-brain barrier
The pituitary is half and half, so the back is protected by the blood-brain barrier, the anterior part is not
The tracer goes in really easily, which is helpful to us

For now, we’re able to measure estrogen receptor density in the pituitary

How is estrogen getting across the blood-brain barrier outside of that access to half of the pituitary?

There are transporters

What is the time course?

If you injected me in the arm through my IV, how long until it traverses, and does it only traverse in the free component?
Does the estrogen have to be unbound or does it bind to albumin or something else?
It does bind, yes
That’s why we need kinetic modeling

The timing is relatively fast: if we inject now, we can see uptake within minutes

And then what we do is that we keep seeing the tracer accumulating up in the brain
So we do a time activity curve, a tracer uptake in the brain relative to the tracer kinetics in blood, and we need both to gather a good sense of how much is actually sticking to the receptors and for how long and how much is just pushed back into the circulation

The whole scanning time is 90 minutes, but the peak of uptake is within 30 to 35; so between 30 and 50 minutes is when you get the most signal

And then you start to saturate

Also, there’s a component of blood flow that you need to disentangle

There’s a whole mathematical model that we’re using, it’s called the Logan plot Lisa doesn’t know if listeners want to know this (Peter does)
Lisa doesn’t know if listeners want to know this (Peter does)

Lisa explains, “ We have spent so much time trying to find a good reference region for the modeling, because if you have a reference region that you know to be free or almost free of estrogen receptors… ”

It’s your negative control ‒ you can subtract it out That’s exactly the problem that took a long time to figure out
Lisa had to talk to preclinical scientists, to cell biologists, to pathologists, to people who really specialize in the estrogen receptors
And she’s been working with Dr. Roberta Diaz Brinton , who’s a legend in her field She’s been doing this for 40 years She knows everything about estrogen receptors
And working with her and looking at all the postpartum studies, we found that there’s a very specific part of the cerebellar cortex , it’s this part of the brain that people say is mostly involved in movement control, but it has a number of different functionalities
That’s exactly the problem that took a long time to figure out
She’s been doing this for 40 years
She knows everything about estrogen receptors

⇒ There are estrogen receptors deep in the white matter of the cerebellum

But if you look at the cerebellum from the side, if you look at the inferior-most part of the gray matter of the cerebellum , like the thinnest layer possible towards the posterior-inferior part, that seems to be consistently void of estrogen receptors Whatever receptors are found there tend to be β receptors
Whatever receptors are found there tend to be β receptors

⇒ There are 3 types of estrogen receptors ( α , β , and GPER ), and this tracer that Lisa uses is more specifically looking for estrogen receptor α

Why Lisa is using 17α-estradiol (not 17β-estradiol)

A tracer for 17β-estradiol has not been developed yet Even though it’s the biologically active estradiol – but not in tumors
In tumors, 17α-estradiol is active, and these tracers were developed for oncology [breast cancer]
It’s hard to make ligands for PET ‒ it takes years and years
Lisa is working with what was developed off-the-shelf We repurposed a tracer that is commonly used now in oncology to see if we could apply it to the brain This is win-win situation because we don’t have to reinvent the wheel
Even though it’s the biologically active estradiol – but not in tumors
We repurposed a tracer that is commonly used now in oncology to see if we could apply it to the brain
This is win-win situation because we don’t have to reinvent the wheel

So by using this reference region [that she mentioned earlier], the other thing that needs to happen is that the signal needs to be the same

Let’s say if you’re looking at women who are premenopausal, perimenopausal, postmenopausal, the signal in that reference region needs to be invariant, which we demonstrated
Therefore, we were able to do kinetic modeling using the cerebellum, that specific part of the cerebellar cortex as the reference

Lisa shares her novel findings, “ And by doing that, we show the estrogen receptor density in the pituitary gland starts increasing during the perimenopausal window, but is actually higher after menopause, which goes completely against whatever knowledge we had from preclinical studies .”

What you would expect to happen in the pituitary as estrogen levels decline

As estrogen levels decline, you would almost expect the pituitary, in a greater and greater appetite for estrogen, to upregulate expression of receptors to say, “ I want more, I want more, I want more. ”
And we know that it’s screaming for estradiol because it’s secreting more and more FSH and LH

So is that effectively what you think is happening?

Lisa thinks that’s what’s happening, but that does not happen in rodents

All the models that we have for menopause are based on preclinical work and animal models

And what happens in rats is that most studies utilize an ovariectomy: it’s a surgical removal of the ovaries of the female rat So you induce menopause surgically
What the studies have found is that there is an initial overexpression on the estrogen receptors, but then there’s a sudden crash, so the window of opportunity is very narrow
So you induce menopause surgically

[Lisa wrote about this widow of opportunity in her 2025 review , illustrated in the figure below]

Figure 1. Progression of AD and the timing of preventative interventions . Image credit: The Journal of Clinical Endocrinology & Metabolism 2025

And when you translate into human years, there’s an inverted U shape, but it’s more like a little like Gaussian curve It’s so narrow that within no more than 5 years after the final menstrual period, the idea that the estrogen receptors have declined to have the density that they used to have prior
It’s so narrow that within no more than 5 years after the final menstrual period, the idea that the estrogen receptors have declined to have the density that they used to have prior

Is that the prediction you would’ve had in women?

Yes, but we didn’t find that at all

We found that up to age 65, estrogen receptor density was still nice and high

This is off topic, but Peter asks, “ Would this not potentially suggest that a woman in her 60s who went through menopause 10 to 15 years sooner, who was not treated with menopausal hormone therapy [MHR] , would still be a candidate [for MHR] given that she clearly has upregulated her estrogen receptors in her CNS and therefore, at least physiologically, suggests an appetite for estrogen? ”

Yes
We’ll come back to that in detail
Peter adds, “ We just keep banging on all the greatest hits of the mantras of modern medicine ” Which says even if someone has finally come around to say maybe menopausal hormone therapy is not the worst thing you can do to a woman (Peter’s being facetious), you better give it to her the day she enters menopause God forbid we take all of these women who are out there who are in their 60s, who were deprived of hormones 10 years ago, and give them hormones ‒ their window is closed, the door is shut
That was Lisa’s concern
Which says even if someone has finally come around to say maybe menopausal hormone therapy is not the worst thing you can do to a woman (Peter’s being facetious), you better give it to her the day she enters menopause
God forbid we take all of these women who are out there who are in their 60s, who were deprived of hormones 10 years ago, and give them hormones ‒ their window is closed, the door is shut

When Lisa was writing the protocol for this study she deliberately designed it to include women ages 35-65 ‒ she wanted to map the whole window of opportunity

And it paid off
All of the women in the study are naive to hormone therapy No one was taking hormones of any type No oral contraceptives either
No one was taking hormones of any type
No oral contraceptives either

Peter asks, “ How long had they been off oral contraceptives? ”

In the first study, most of them had never used birth control (a really naive population)
But at least 3 years
There was the exclusionary criteria
And for the postmenopausal women, they were all never users of hormone therapy

Lisa adds, “ Now that we have hundreds of women in the study, we can be more flexible and account for different things statistically or try to stratify between past users of hormone therapy, never users, current users. We also have users now, which is very interesting .”

What estrogen receptor imaging can and cannot tell us about hormone therapy’s potential impact on brain health [A: 48:45, V: 49:40]

What are you seeing in women who use hormone therapy?

It’s not published yet, so Lisa is not sure that she’s allowed to talk about it
Anecdotally or descriptively, we do see that the windows shift, the curve is shifted
So we now have women who are older than 65, and we’re starting to see where the estrogen receptors are starting to come down in terms of density
But in the hormone therapy users (for now) it seems like the curve does not stop at that age It looks like maybe there is preservation of density
It looks like maybe there is preservation of density

And then the question is, is it a good thing or not?

Because we don’t know if the estrogen receptors are functional
We don’t know if the transcriptional pathways are still working the way they’re supposed to do Are we stimulating receptors that are not functioning?
Are we stimulating receptors that are not functioning?

Steroids work by driving transcription factors

When estrogen or testosterone binds to the receptor, what it’s really doing, what matters is what it’s doing inside the cell
It has to go into the cell, it has to go to the nucleus, it has to bind to the DNA, and it has to say, “ Hey, start making RNA that’s going to make protein that’s going to do those things. ” And it’s that process of transcription and translation that matters
And it’s that process of transcription and translation that matters

Peter’s takeaway from what Lisa is saying

Don’t get too excited, Peter
All we’re able to check with this assay is does the hormone bind to the receptor?
The assay can’t measure whether the mechanism of that is translated all the way through to protein?
Lisa agrees

Lisa explains: the idea is there’s a supply and demand system around estrogen

[The upregulation of estrogen receptors] is like the brain is calling for hormones and the ovaries are delivering the hormones

As long as the feedback loop is stable, we know that usually the estrogen receptors are doing what they’re supposed to do

Which is more blood flow to the brain, more energy production in the brain, a stronger immune system, more neuroplasticity, more synaptic growth

But we also know that with age and with disease, the estrogen receptors, as many other receptors, may start to malfunction

They may also go through conformational changes
That means that the output may not be as good

Peter responds, “ Say more about that. I mean, if I’m going to be honest with you, that’s a terrifying thought. ”

What can we point to in the periphery to help us understand that (where it’s easier to study this question)?

Lisa was thinking about oxidative stress

One functionality of estrogen

When estrogen attaches itself to estrogen receptors in the mitochondria The mitochondria are the energy factory of every cell in the body, including neurons What the mitochondria do is that they transform energy into ATP or they take the byproduct of glucose metabolism
And there’s a structure called the electron transport chain , that produces oxidative stress and free radicals at the same time that they’re making ATP
The mitochondria are the energy factory of every cell in the body, including neurons
What the mitochondria do is that they transform energy into ATP or they take the byproduct of glucose metabolism

Usually the balance favors ATP, but if the estrogen receptors change conformation, that may lead to a less-favorable balance where more oxidative stress has been produced relative to the amount of ATP that is being made

So yes, there’s still energy that’s being produced, but there’s more oxidative stress, and this is an issue in the brain

Couldn’t there be other explanations for why we see the inefficiency of the electron transport chain there [in women’s brains]?

Peter is thinking of something even more basic
Couldn’t we do a similar experiment of 35, 45, 65-year-old women and look at the periphery, and look at mRNA expression of something very straightforward in response to estradiol administration?
So you take hormone-naive women, inject all three of them with estradiol and measure for equal amounts of estradiol, how much mRNA gets produced for something that we would predict?

Lisa replies, “ That’s a clinical trial. ”

Peter agrees, but according to this hypothesis, we would expect to see declining mRNA, which would suggest at least possibly that something
And of course, to make it a really cool study, you’d still want to do the labeling study to assume you’re getting at least equal amounts of binding
You would normalize ‒ you would basically say, “ Look, I’m going to take the strength of the binding signal and I’m going to normalize it to the mRNA that comes out .”

Lisa points out, “ Yeah, you could if you had the money and if funding agents… There are so many interesting questions that have not been asked. ”

Peter thinks this is a jugular question

“ This question implies, can we throw more estrogen at the problem? ”‒ Peter Attia

Lisa doesn’t know about the periphery, but for the brain, studies have shown that timing is really important

So if you have neuronal tissues that are healthy and you introduce estrogen, estrogen is supportive of the neurons

But if the neurons are diseased, if there’s ischemic damage, there’s amyloid pathology surrounding the tissues or tangles inside the neurons, then estrogen makes it worse

What’s the evidence for that?

Studies Dr. Brinton did many years ago looking at how estrogen impacted mitochondrial function
This is specifically mitochondria, but there seems to be evidence for that in clinical studies as well Like the Women’s Health Initiative (WHI) which Peter has very elegantly unpacked [episodes #253 , #42 , & #348 ]
Like the Women’s Health Initiative (WHI) which Peter has very elegantly unpacked [episodes #253 , #42 , & #348 ]

“ There’s clearly an age-related benefit-to-risk ratio when it comes to hormone therapy and brain health .”‒ Lisa Mosconi

And many people have argued that the women in the Women’s Health Initiative, the memory study component (they looked specifically at dementia incidence.) ‒ those women were potentially too old to start taking hormone therapy at that age And granted, different formulations, higher doses of hormones, it’s not what we do clinically today
Nonetheless, it confirmed this kind of timing hypothesis , especially for those whose MRI scans showed evidence of an existing, not a pathology necessarily, but for instance, vascular lesions (white matter hyperintensities)
And granted, different formulations, higher doses of hormones, it’s not what we do clinically today

In subanalysis, the idea is that women who already harbor damage in their brains may not be responsive to hormone therapy the same way that women with healthier brains would be ‒ this is completely to be demonstrated

Do you think we have a sense of the difference between the two variations on that theme?

One variation is once disease has set in, estrogen is unlikely to reverse it, but that’s different from estrogen will exacerbate it?

Yes
It’s different

Second, is the current formulation of topical estradiol safer than the estrogen used in the WHI?

Peter points out that in the WHI, we were dealing with oral conjugated equine estrogen Which is known to actually slightly increase coagulation Which would be an enormous concern for exacerbating the vasculopathy that would accompany this disease
Therefore, whereas we don’t see any evidence of an increase in vasculopathy with topical estradiol , we don’t see any increase in ASCVD risk, so therefore we might assume that topical estradiol is much safer (much is a strong word) than oral estradiol
Potentially
And also the progestin
Peter’s belief still remains that if there is some clinically meaningful uptick in the incidence, though not mortality, of breast cancer, the progestin is the most likely culprit
Which is known to actually slightly increase coagulation
Which would be an enormous concern for exacerbating the vasculopathy that would accompany this disease

Lisa explains, “ MPA ( the kind of progestin that was used in the Women’s Health Initiative) has later on been shown to potentially increase the risk of vascular damage, and that’s the reason we don’t use it. ”

Menopause hormone therapy used in the WHI was MPA coupled with conjugated equine estrogen (CEE) taken orally Those are getting a bad rap They still serve a purpose
Lisa would like to see more research done on the very specific types of hormone therapy because there are so many different options that one can work with
What she would really like to see is what these therapies do in the brain, because everything Peter said makes perfect sense, but it’s not been seen We can do it. We have the tools now.
Those are getting a bad rap
They still serve a purpose
We can do it. We have the tools now.

Lisa’s studies on the relationship between levels of systemic estrogen and density of estrogen receptors in the brain [A: 58:00, V: 59:55]

In your study , obviously, you have to be clean and as neat as possible, so you have to normalize everybody to the same point

What did you inject?

Just the ligand
We work with the menopause clinic at Weill Cornell Medicine (or the OB-GYN department) and we have women who are now going on hormone therapy for menopause

⇒ The vast majority is transdermal estradiol with or without micronized progesterone (that’s the standard of care today)

The women we recruit for this study need to be similar in terms of what kind of therapy they’re taking

Lisa would like to see oral estrogen, CEEs , and the other formulations and see if we get a differential signal or not

Peter thinks that would be interesting, but the most important question would probably be answered through the lens of the formulation of the day (transdermal estradiol) and oral micronized progesterone
Peter has taken the conversation far off the path into these details, but this is incredibly fascinating

We’ve established through this discussion that something is happening in the brain of a woman [during the menopause transition]

One final question on that topic. Did you have age-matched male controls?

For the estrogen ligand study ‒ no, we were doing only women

So we don’t know if in a man’s brain, the estrogen ligands remain constant or Peter would predict it will go up slightly as he ages because his estradiol is going down with testosterone?

Yeah

The idea is that the brain compensates for changes in estradiol levels and other hormone levels by increasing the density of the estrogen receptors

Usually, the brain really loves stability
The human brain is built for stability, so when hormones are fluctuating throughout the menstrual cycle, the concentration overall is still predictable So the brain needs to make very little effort to maintain a certain number of receptors
This is another thing that is very interesting: the receptors are not just there, the brain needs to make them It’s an active process
And when estradiol levels increase, then the brain needs to make fewer receptors, so we see this decrease in estrogen receptor density
But when estradiol levels come down, then there is this compensatory adjustment where the brain will overexpress or make more of these receptors in order to just grab every little bit of estradiol that is in the circulation
So the brain needs to make very little effort to maintain a certain number of receptors
It’s an active process

The question is, when does this mechanism crash?

Eventually, estradiol levels will be permanently low and the brain is going to have to give up, because making receptors is a very metabolically-expensive process
So eventually, there will be a state or a stage where estradiol is low and the estrogen receptors are low or gone, but when does that happen?

Peter asks, “ It’s after 65, it seems like? ”

In Lisa’s studies, it seems to be after 65
What she’s trying to do now is to get more people to also use ligand
And we’re also working to make new ligands that could look at the receptors better, that can give us better signal in other parts of the brain Like we want to look at the hippocampus, the amygdala, the frontal cortex, the cingulate cortex With higher specificity and better signal-to-noise ratio
Like we want to look at the hippocampus, the amygdala, the frontal cortex, the cingulate cortex
With higher specificity and better signal-to-noise ratio

How quantitative is your assay?

It’s fully quantitative

How much radiation does it expose the patient to?

Very little, 6 millicuries (that’s <1 millisieverts)

Why blood estrogen levels poorly reflect brain estrogen signaling, and how tightly regulated brain hormone dynamics complicate our understanding of menstrual-cycle and lifestyle effects [A: 1:02:15, V: 1:04:49]

A study Peter thinks would be cool

He would love to take a group of 35-year-old women and scan every one of them the day they get their period and then every five days for 30 days Just out of pure curiosity Very expensive
Oh yes, Lisa agrees
Peter thinks that is your natural experiment of exactly what you just described That is going to be the absolute-highest, absolute-lowest level of estrogen and progesterone in the brain in a 30-day window [to see any changes in estrogen receptor density in the brain]
And the fact that it’s quantitative means you can now really develop a sense of: How quickly can this compensation occur and what’s the highest high and the lowest low?
Lisa agrees
She would then compare that to the estrogen levels in the blood
Just out of pure curiosity
Very expensive
That is going to be the absolute-highest, absolute-lowest level of estrogen and progesterone in the brain in a 30-day window
[to see any changes in estrogen receptor density in the brain]

Lisa emphasizes, “ I think it’s so important to clarify: the estrogen levels in the circulation have nothing to do (or very little to do) with estrogen levels in the brain. ”

Say more about that

That’s the problem that we’re having clinically We can measure estrogen in blood, but that will tell you nothing about whether or not you’re having hot flashes or forgetfulness or any of the neurological symptoms of menopause Because we don’t know the receptor density
And also, the brain levels of estradiol are very highly regulated All the hormones in the brain are sheltered from changes in the circulation
We can measure estrogen in blood, but that will tell you nothing about whether or not you’re having hot flashes or forgetfulness or any of the neurological symptoms of menopause
Because we don’t know the receptor density
All the hormones in the brain are sheltered from changes in the circulation

Are these transporters active?

They’re active, yes
The brain calls for hormones

Let’s talk more about that. Peter thought this was a passive diffusion

No, not necessarily
There are periods of time where it could be and times where it’s not Which is why you can’t just push stuff inside the brain It’s so hard to get a tracer that goes in because the brain doesn’t want a lot of molecules (a lot of things just can’t come through)
Which is why you can’t just push stuff inside the brain
It’s so hard to get a tracer that goes in because the brain doesn’t want a lot of molecules (a lot of things just can’t come through)

“ It’s so difficult to come up with this brain scan. ”‒ Lisa Mosconi

Peter asks, “ So you’re telling me that if we did my thought experiment of every 5 days or every day (it’s just a thought experiment), every single day you draw a woman’s blood throughout her cycle, and you’re going to see estradiol go from next to nothing to 200 and back down? ”

You see that in blood
In the brain, we don’t know

And so you’re saying in the brain it could be uncorrelated?

It certainly would not be… partially correlated

There has to be a response, but it can’t be as dramatic

What do you think is driving it?

This is now becoming a very complicated thought experiment If you did this on a woman every single day for a year, and she had say, 12 normal cycles throughout a year But one of those months she had the flu, and one of those months she was sleep-deprived, because whatever was happening One of those months, she was under a lot of emotional stress One of those months she was eating well, one of those months she was eating garbage food
If you did this on a woman every single day for a year, and she had say, 12 normal cycles throughout a year
But one of those months she had the flu, and one of those months she was sleep-deprived, because whatever was happening
One of those months, she was under a lot of emotional stress
One of those months she was eating well, one of those months she was eating garbage food

You see where Peter is going with this?

You will need a control for every single one of those months
Use identical twins One of her sisters is perfectly doing the same thing every time
But also she kind of serves as her own control in a way, right? There must be a month that she is okay (in January)
One of her sisters is perfectly doing the same thing every time
There must be a month that she is okay (in January)

What Peter wants to understand is, “ How much do the externalities of her life (which obviously impact her peripheral physiology and must impact her central physiology)… How much do you think, if you had to predict, how much would you guess those are the drivers of the brain’s demand for estrogen? ”

Lisa hopes they are not the drivers

Hopefully, hormonal production and hormonal demand is queued mainly by hormonal needs for the brain ‒ because if that weren’t the case, we would have a lot of trouble thinking straight

Lisa thinks that’s one of the reasons that the brain really very tightly regulates entry of nutrients or chemicals from the circulation
Because if the levels of receptor activity were to fluctuate too quickly or too frequently, that could lead easily to cognitive impairment, or to mental confusion, or to an inability to just function

But at the same time, it is important ‒ your lifestyle has an impact

Lisa doesn’t know that the impact would be visible on a month by month basis This is hopefully not
But over time, the poor lifestyle, sleep deprivation, high stress levels, that in theory would negatively impact the brain itself making perhaps the receptors are not as functional as they used to be Or estrogen uptake is not as tightly regulated or carefully planned as it used to be And then there could be glitches that are more long-term.
This is hopefully not
Or estrogen uptake is not as tightly regulated or carefully planned as it used to be
And then there could be glitches that are more long-term.

Peter’s takeaway, “ It basically says we are only at ankle-deep water at this point, in terms of our understanding of this process. ”

Yeah, it’s really just the beginning
And this is a reason that Lisa launched CARE , which is her new program of research

The CARE Initiative: Lisa’s research program looking to slash AD rates in women [A: 1:07:45, V: 1:10:49]

Lisa just launched a $50 million program of research sponsored by Wellcome Leap, which is an independent subsidiary of the Wellcome Trust It’s called CARE, Cutting Alzheimer’s Risk through Endocrinology It’s 50 million unrestricted funds, which is amazing for this specific question
It’s called CARE, Cutting Alzheimer’s Risk through Endocrinology
It’s 50 million unrestricted funds, which is amazing for this specific question

⇒ CARE is effectively the largest research program on women’s brain health, menopause, and Alzheimer’s disease ever attempted

What we’re doing with CARE is, it’s like the movie, Oppenheimer Where Dr. Oppenheimer was in charge of designing the research program And then basically inviting other scientists from all over the world to work with him on a sprint: just 3 years It’s a high risk, high reward research initiative, which for them, ended up with the atomic bomb
Where Dr. Oppenheimer was in charge of designing the research program
And then basically inviting other scientists from all over the world to work with him on a sprint: just 3 years
It’s a high risk, high reward research initiative, which for them, ended up with the atomic bomb

With CARE, it will hopefully end with a means to half the risk of Alzheimer’s disease for women by the year 2050 ‒ that is the target

“ We estimate that if everything goes according to planning, we hit all our marks, then we should be able to reduce the risk of Alzheimer’s for an estimated 330 million women globally. ”‒ Lisa Mosconi

And given current global conversion rates to Alzheimer’s, we could potentially prevent 55 million new Alzheimer’s patients among women in the next, hopefully 25 years

There are 3 different components to CARE

1 – We want to understand how neuroendocrine aging and specifically hormones really speak to Alzheimer’s risk for women

Because all the predictive models that we have so far are sex aggregated
We look at risk factors that work for men and women, but they can do genderless
The fact of sex has been removed statistically, but there are things [that can help women]

⇒ The vast majority of models, we talk about this now that Alzheimer’s risk is multifactorial but potentially preventable in about 45% of cases

The 45% comes from studies that have looked at all sorts of risk factors in cohorts that combine men and women
And more often than not, the predictive models adjust for sex as a covariate

So, you want to statistically remove the effects of sex and see whether diet is associated with Alzheimer’s

Peter asks, “ We can’t get the raw data and reinsert? ”

Yes, this is what we’re doing with CARE

“ Whatever we know about Alzheimer’s risk so far is genderless. ”‒ Lisa Mosconi

Whatever we know about Alzheimer’s risk so far is genderless It works for men and women Which is still, it’s a wonderful study
It works for men and women
Which is still, it’s a wonderful study

The dramatic difference in AD risk between men and women associated with APOE4 [A: 1:10:45, V: 1:13:58]

For example, should the risk of APOE3/APOE4 genotype be more nuanced?

One copy of the APOE4 allele increases your risk of Alzheimer’s disease by about 2x

Should that be more nuanced? Should we say in a man, it increases the risk by “X” and in a woman it increases it by “Y”?

In women, carrying 1 copy of APOE4 increases the risk of Alzheimer’s disease 6-fold This is something Peter did not know He usually talks about it without differentiating between sex ‒ clearly that’s a mistake
This is something Peter did not know
He usually talks about it without differentiating between sex ‒ clearly that’s a mistake

If we’re talking about comparing people who are heterogeneous, APOE3/APOE4 versus 2 copies (APOE3/APOE3), what’s the relative risk increase for women specifically?

⇒ Women with one copy of the APOE4 allele have a 4-fold increase in the potential risk as compared to non-carriers; but women who have 2 copies of the APOE4 allele , the risk is between 12-15x higher relative to non-carriers

It’s a big jump in risk going from men to women

What the evidence suggests about menopausal hormone therapy (MHT) and AD risk, and why timing, formulation, and uterine status appear to matter [A: 1:12:00, V: 1:15:13]

Let’s now talk a little bit about the role that hormone replacement therapy or menopausal hormone therapy can play in women with or without an APOE4 allele .

Let’s also talk about it in the context of initiation of therapy at an appropriate time, just to start. So, what do we know about this?

This is a tortured part of our field of research because unfortunately, there’s only one clinical trial that’s ever looked at hormone therapy and Alzheimer’s incidence in women, the Women’s Health Initiative Memory study
In that specific study, the risk of dementia was increased for women who were taking the combined estrogen-progesterone therapy As mentioned earlier, it’s oral conjugated equine estrogen and MPA
And the risk was also 50% higher for women who were taking only oral estrogens following a hysterectomy
However, that risk increase was not significant
That’s the only clinical trial we have looking at the incidence of Alzheimer’s disease relative to hormone therapy use
And all the women were post-menopausal and by a long shot
As mentioned earlier, it’s oral conjugated equine estrogen and MPA

Lisa adds, “ Unfortunately, we don’t have clinical trials where hormone therapy is given in midlife for relief of menopausal symptoms, which is the appropriate indication where we also measure the incidence of dementia because those trials are just not feasible .”

It would be a 20-year, 30-year trial, and it’s just not possible to do it that way
In that case, observation of research offers more information about whether there is a differential beneficial effect relative to initiation timing And we do know that observation of research is subject to bias, so this is just more descriptive than definitive
It is interesting that meta-analysis do show the timing of initiation matters and also the type of formulation A meta-analysis is a statistical integration of all available data
Women who do not have a uterus who have received a hysterectomy (surgical removal of the uterus with or without the ovaries) are typically treated with estrogen-only therapy They don’t have to but can also have a progesterone, but generally practice is let’s just go with estrogen
And we do know that observation of research is subject to bias, so this is just more descriptive than definitive
A meta-analysis is a statistical integration of all available data
They don’t have to but can also have a progesterone, but generally practice is let’s just go with estrogen

⇒ Whereas women with a uterus need a progesterone, whether a synthetic progestin or micronized (what people say bioidentical progesterone) [in addition to estrogen]

Now if you look at these 2 factors when you start: Which is within 10 years or the final menstrual period or over 10 years, so the final menstrual period And whether you have a uterus or not
Which is within 10 years or the final menstrual period or over 10 years, so the final menstrual period
And whether you have a uterus or not

The observation of research so far shows a 32% reduced risk of Alzheimer’s with dementia for women with a hysterectomy who have undergone hysterectomy and they’re taking estrogen-only therapy

This is significant, very consistent risk reduction across all the studies available, almost all the studies
We have now one study for Northern Europe that does not show that protective effect This is when hormone therapy is initiated within 10 years, so the final menstrual period
This is when hormone therapy is initiated within 10 years, so the final menstrual period

For women with a uterus starting hormone therapy within 10 years, there’s a 23% risk reduction, which is however a trend level

[Lisa’s meta-analysis from 2023
A 2025 publication in Nature Reviews Neurology states, “T he risk of AD was 32% lower among women who started HRT within 5 years of menopause than in those who received a placebo or no treatment. Conversely, initiation of HRT at ≥65 years of age was linked to a 38% increase in AD risk .”]

⇒ Some studies show an increased risk, most studies show a reduction in risk

So, we need to better understand what’s happening there

Lisa cautions, “ When we look at starting hormone therapy more than 10 years after the final menstrual period, there is no obvious benefit for estrogen-only therapy for women with a hysterectomy. And there is an increased risk for women with a uterus who were taking estrogen and progesterone of any type. ”

We do not yet have enough studies

We can’t yet separate progestins from micronized progesterone. We cannot yet look at each specific type of hormone therapy because the data is just not there. We need to do more research.

Lisa adds, “ This is a fairly old-fashioned way to look at this question. ”

What Lisa thinks would make more sense to study

It would be better to start hormone therapy today and look at biological markers of Alzheimer’s as the therapy is progressing
In fact, what would be ideal is to start hormone therapy today, look at the estrogen receptors, use brain estrogen imaging to monitor whether the therapy is doing what it’s supposed to be doing
And also look at biological markers of Alzheimer’s to make sure, or at least to test whether they’re either not showing up or they’re being delayed in their progression or evolution relative to a placebo group
Which is what we’re trying to do now with CARE

How the CARE initiative plans to study MHT and AD risk, within the practical constraints of a three-year research window [A: 1:17:30, V: 1:20:57]

Does this mean that one of the initiatives in CARE is actually a prospective randomized trial that will administer MHT at the appropriate time during perimenopause? And then we prospectively follow the various markers.

Peter has a whole soapbox on why we have to start this in perimenopause Don’t wait until menopause [to start menopause hormone therapy]
Don’t wait until menopause [to start menopause hormone therapy]
Lisa replies, “ Half is yes. ”
We have only 3 years [of funding]
Running a clinical trial in 3 years is just not feasible from start to finish

Lisa shares, “ What we’re going to do in the 3 years, our goal is to provide evidence at convincing scale that hormone therapy has or doesn’t have (but we’re hoping it might have) a beneficial effect on biological markers of Alzheimer’s by working with women who spontaneously decide to start hormone therapy. ”

So you don’t have to enroll and randomize, you follow women who do go on hormone therapy and women who do not

And that’s what you can do in 3 years

How will you match them for health consciousness?

Peter thinks there’s an inherent bias that slips into women who opt into hormone replacement therapy because the barrier to entry is high Most women who want hormone replacement therapy are going to face an uphill battle with their doctor who, no disrespect, but their doctor’s ignorant, busy, just believes it’s bad And so, the women who ultimately end up on hormone replacement therapy had to jump through a few hoops They’re also probably a little bit more health conscious on average Whereas the woman who doesn’t go on hormone replacement therapy, it’s less of an active decision (probably more of a passive decision)
Peter can come up with some [other] examples: maybe you have women with a very strong family history or personal history of breast cancer that might be equally health conscious, but decide to opt out for reasons that have to do with that
So, that might be one way to match them
But otherwise, you have to be very careful with this type of analysis because the healthy user bias runs deep
Yes, Lisa agrees: it’s one of the concerns with observational research
Most women who want hormone replacement therapy are going to face an uphill battle with their doctor who, no disrespect, but their doctor’s ignorant, busy, just believes it’s bad
And so, the women who ultimately end up on hormone replacement therapy had to jump through a few hoops
They’re also probably a little bit more health conscious on average
Whereas the woman who doesn’t go on hormone replacement therapy, it’s less of an active decision (probably more of a passive decision)

Lisa points out, “ The other concern is that women with the most symptoms are also more likely to start hormone therapy .”

And there seems to be an association between more hot flashes like the severity and frequency of hot flashes, especially at night, and amyloid beta levels in plasma and white matter hyperintensities in the brain
So there’s few things that we need to ascertain
Lisa thinks the way to do it is #1 with education
And a lot of her colleagues, and Peter and his colleagues are doing a fantastic job of making sure that women understand that hormone therapy is on the table
And then they can come to us, the research sites where they also have access to the gynecology department, to the menopause clinics Where our clinicians are open to the notion that if you do have the symptoms or menopause and if you’re willing, interested in starting hormone therapy, that is perfectly doable By working with us, certainly there shouldn’t be much of a barrier to access hormone therapy if indicated We do follow professional guidelines
Where our clinicians are open to the notion that if you do have the symptoms or menopause and if you’re willing, interested in starting hormone therapy, that is perfectly doable
By working with us, certainly there shouldn’t be much of a barrier to access hormone therapy if indicated
We do follow professional guidelines

How to think about starting hormone therapy during perimenopause: balancing symptom relief, hormonal variability, and individualized care [A: 1:21:00, V: 1:24:55]

Is there any woman who is in that perimenopausal transition who you think needs to be cautious of hormone replacement therapy as far as her brain health is concerned?

The concern about starting hormone therapy before menopause is that hormone levels are fluctuating
Using birth control, for instance, by blocking ovulation, we make sure that once you do go on birth control, you receive a standard dose of hormones that have been tested And that can be clearly monitored You know exactly what dose you’re given at any given time
Whereas with hormone therapy for menopause, depending on what you’re doing, you can’t really do a blood draw every day or every moment
And that can be clearly monitored
You know exactly what dose you’re given at any given time

So the concern is once your level of estradiol are low enough, then we should be fine; but if they’re spiking and you put more hormones in the systems, you may amplify the spike

Peter’s view on when to start menopause hormone therapy (MHT)

Start MHT once women are symptomatic
We’re not doing this based on blood, but women can be symptomatic for a year, 6 months, or 3 years
There’s just so much variability in this system
But there’s evidence that as soon as they’re symptomatic, both from an estrogen and progesterone standpoint, although the estrogen tends to be the symptoms that dominate
The benefits accrue immediately with respect to vasomotor symptoms, bone health, cognitive performance in the short term, sexual health and sexual function
And that waiting until a woman [her menstrual cycle] has completely stopped, her FSH is 40, and her estradiol is unmeasurable You could spend 5 years getting to that point from the moment you started having symptoms And again, there’s evidence that you’ve actually taken steps backwards with respect to health
Now, what’s the trade-off? The trade-off is you’re going to have loops, meaning you’re going to have ovulations that force their way through the system And you’re going to have all sorts of estradiol spikes
You could spend 5 years getting to that point from the moment you started having symptoms
And again, there’s evidence that you’ve actually taken steps backwards with respect to health
The trade-off is you’re going to have loops, meaning you’re going to have ovulations that force their way through the system
And you’re going to have all sorts of estradiol spikes

Peter adds, “ I can tell you that clinically, most women are far less bothered by this than the reverse .”

“ At the end, it’s really about feeling better .”‒ Lisa Mosconi

To Lisa’s point, Peter agrees that this requires nuance

This is not a set it and forget it policy
Peter had Rachel Rubin on the podcast [ episode #348 ] ‒ this is where doctors like Rachel matter because they understand how to titrate the system They understand that even though normally you might put somebody on 200 mg of micronized progesterone when they’re fully in menopause, you might only need 50 mg today And you might need 100 mg next year So, it’s not an on-off switch
It’s more like a precision medicine-type approach
Lisa thinks it would be so good to have more research happening in parallel
She has noticed that there are many clinicians who are now open to working with their patients to address the needs of the patients, and kind of base what they’re doing on their own experience and their relationship with the patient
Lisa knows a lot of them, she’s friends with many of them
They understand that even though normally you might put somebody on 200 mg of micronized progesterone when they’re fully in menopause, you might only need 50 mg today
And you might need 100 mg next year
So, it’s not an on-off switch

What Lisa thinks would be lovely to have is data that really works in parallel so you have maybe not clinical trials yet, but at least some information that can help guide the diagnostic process

Peter points out, “ And the challenge is there’s not a natural owner to doing that study. It’s not as simple as, here’s the latest version of a GLP-1 agonist. And we’re going to go out and we’re going to test whether it’s more or less efficacious for weight loss or type 2 diabetes, where there’s an obvious sponsor for that research. Here, we’re talking about drugs that are cheap and not protectable. ”

Investigating selective estrogen receptor modulators (SERMs) as a targeted approach to brain health during and after menopause [A: 1:25:00, V: 1:29:10]

Lisa thinks one thing that is probably interesting is the selective estrogen receptor modulators (SERMs)
SERMs are very interesting compounds because there are different types of estrogen receptors, at least 3 types that we know of: the estrogen receptor α , β , and GPER
And estrogen receptors are distributed differently in different parts of the body For instance, within the brain, we have some structures like the pituitary gland and the hypothalamus that contain similar amounts of estrogen receptor α and β, but are predominantly α because they’re more reproductive tissues The α receptor is more abundant or more expressed in reproductive tissues, whereas the β receptor, for instance, is more expressed in the cognitive parts of the brain
For instance, within the brain, we have some structures like the pituitary gland and the hypothalamus that contain similar amounts of estrogen receptor α and β, but are predominantly α because they’re more reproductive tissues
The α receptor is more abundant or more expressed in reproductive tissues, whereas the β receptor, for instance, is more expressed in the cognitive parts of the brain

What some scientists and clinicians have been trying to do is to develop compounds that selectively attach themselves to the β version of the estrogen receptors

For instance, Dr. Robby Brinton developed one of the first NeuroSERMs It’s a neurological selective estrogen receptor modulator that comes from plants, She looked at all different phytoestrogens and compounded them together into a formulation that’s been shown to bind with very high affinity to estrogen receptor β specifically
She tested that very thoroughly in animals, and she did a phase I clinical trial
We’re now doing a phase IIb in women
But what she found is that this specific substance leaves your reproductive organs alone, but goes up into the brain and binds to the estrogen receptor β with high affinity Therefore stimulating cognition in terms of memory, for instance, or executive function And also supports mitochondrial activity because she’s done a lot of work on mitochondria and seems to improve neurogenesis as well (that’s preclinically)
It’s a neurological selective estrogen receptor modulator that comes from plants,
She looked at all different phytoestrogens and compounded them together into a formulation that’s been shown to bind with very high affinity to estrogen receptor β specifically
Therefore stimulating cognition in terms of memory, for instance, or executive function
And also supports mitochondrial activity because she’s done a lot of work on mitochondria and seems to improve neurogenesis as well (that’s preclinically)

The goal of this research

We’re looking at whether that formulation can improve brain energy levels in women and hopefully memory performance
And also we are hoping to reduce the risk of developing Alzheimer’s plaques
And we are working with women who are very early postmenopausal

Is this pre-IND or is this in phase I yet?

PhytoSERM is phase II , but the FDA considers this a supplement

Because it comes from plants
It is GRAS-approved by the FDA

Peter asks, “ So, the purpose of these studies is to be able to make claims. It’s not regulatory. ”

They have done all the regulatory phase

We are now doing a clinical trial very specifically to test whether it supports cognitive function and brain energy levels in women at risk for Alzheimer’s

And Robby’s also looking at hot flashes and vasomotor symptoms in a separate clinical trial

The reason Peter brought it up is he thinks it is a fairly unexplored avenue for support of brain function and also for relief of menopausal symptoms in women

It makes sense to go for the source of the symptoms that they have flashes, the night sweats, insomnia, mood symptoms, cognitive symptoms ‒ they start in the brain
So, it would be wonderful to have a molecule that’s never been associated with an increased risk of cancers to any reproductive organs; and just goes into the brain, it does what it’s supposed to be doing in the brain
But then we miss the activity in sexual organs, we miss the bones. I mean, there’s still so many benefits
Maybe not the bones, Lisa thinks there are β estrogen receptors in the bones

Peter asks, “ But you’re not going to get it with a SERM. ”

Not with this specific SERM, no
But there may be other SERMs that are developed in the future

Why estrogen became wrongly associated with cancer risk and what the evidence actually shows [A: 1:29:30, V: 1:33:58]

Peter points out, “ But we have the perfect one, it’s called estradiol. Why are we afraid of this? ”

He thinks this is the problem: we have to stop giving the fear-mongering people an excuse Which is there is no evidence that estrogen causes breast cancer: this is a complete fallacy.
The Women’s Health Initiative data by itself makes it very clear Not a single additional woman died of breast cancer as a result of taking even the conjugated equine estrogen If there was any increase in incidence, but not mortality of breast cancer, it was due to the MPA
How many women take MPA today? None It’s been discontinued
Today women are all taking bioidentical , micronized progesterone
Which is there is no evidence that estrogen causes breast cancer: this is a complete fallacy.
Not a single additional woman died of breast cancer as a result of taking even the conjugated equine estrogen
If there was any increase in incidence, but not mortality of breast cancer, it was due to the MPA
None
It’s been discontinued

Peter emphasizes, “ I want to be very careful that I never let someone have that out of saying, ‘But estrogen causes cancer.’ It doesn’t. ”

Lisa agrees that estrogen does not cause cancer That word cause has been misleading women for a really long time
Because the idea is that you have no risk of cancer, you have no cancers already; and somehow you take this estrogen molecule, and boom, you get cancer That’s not what’s happening
That word cause has been misleading women for a really long time
That’s not what’s happening

Peter points out, “ And again, the analogy that we should have women understand is the analogy between testosterone and prostate cancer. ”

This is a very good analogy, because it has been unequivocally demonstrated that testosterone, either endogenously or given exogenously, does not drive prostate cancer [This was the subject of episode #310 ]
Does that mean that when we have a man for whom we’re treating him for prostate cancer, if he’s not a surgical candidate, that we don’t do androgen deprivation therapy ? No, of course not We do androgen deprivation therapy But once a man has surgical therapy for his prostate cancer, guess what? We resume testosterone replacement therapy He had prostate cancer, we’re giving him testosterone; but guess what, doesn’t increase his risk
[This was the subject of episode #310 ]
No, of course not
We do androgen deprivation therapy
But once a man has surgical therapy for his prostate cancer, guess what?
We resume testosterone replacement therapy
He had prostate cancer, we’re giving him testosterone; but guess what, doesn’t increase his risk

Here’s why Peter believes we’re so brain damaged on this topic

The urologist has a marked advantage over the clinician who treats breast cancer, and it comes down to a very simple protein called PSA It’s the PSA that gives the urologist and the urologic oncologist a marked advantage, which is we can always follow PSA
So when you have a man who has a Gleason 3+3 (which is a cancer), and you’re trying to decide, “ Okay, he has prostate cancer, but is it the kind that’s going to kill him or is it the kind that’s just going to stay in his gland and stay localized? ” You watch and wait those men
We don’t operate on a Gleason 3+3 even though it’s cancer
But do we chemically castrate that man? Not a chance
If his testosterone is 900, we rejoice
If his testosterone is 300 and he’s feeling symptoms of hypogonadism, do we give him testosterone? Absolutely, we do And we follow the PSA and we follow the MRI And if we need to do a biopsy, we do a biopsy And if his cancer changes, we treat him
Peter thinks it’s the fact that we don’t have the equivalent of the PSA for breast tissue
And in fairness to those who have to make these decisions, we miss the blood biomarker that allows us to cheaply and easily track the disease
But that doesn’t change the underlying pathophysiology
Peter has nothing against SERMs
He didn’t mean to get on his soapbox, but he doesn’t want women to come away from this discussion thinking estrogen is bad
It’s the PSA that gives the urologist and the urologic oncologist a marked advantage, which is we can always follow PSA
You watch and wait those men
And we follow the PSA and we follow the MRI
And if we need to do a biopsy, we do a biopsy
And if his cancer changes, we treat him

Women should be coming away with the opposite, which is estrogen is very important for their brains

Lisa adds, “ Estrogen is currently on the table. ”

We have put ourselves in a difficult situation where now we need to re-educate not just the patients, but also the entire medical and scientific community based on newer data

Lisa doesn’t know how this really happened, but we have been stuck with the Women’s Health Initiative for decades

She asks, “ It doesn’t happen in other fields of research, don’t you think? ”

No, it did
Think about the literature or think about the phobia around dietary cholesterol Think about how much you can’t eat the yolk of an egg, you can’t eat shrimp
Dietary cholesterol raises cholesterol in the blood that causes heart disease
Think about how much you can’t eat the yolk of an egg, you can’t eat shrimp

Lisa asks, “But did it all come down to one trial? Because this is just one trial.”

That’s a fair point. You’re right.

Peter compares it to dietary cholesterol and ASCVD risk

In the case of dietary cholesterol, it came down to a couple of epidemiologic studies, a couple of clinical trials, none of which asked the question exactly
But the public was either misled or confused about the difference between the chemical structure of dietary cholesterol, which is esterified versus non-esterified endogenously produced cholesterol
And the story is much more complicated

To Lisa’s point, the Women’s Health Initiative cost more than a billion dollars 25 years ago, and therefore, it’s not going to be replicated

It was a study that had at least 3 or 4 fatal flaws in the design Some of which Peter thinks are justifiable The most fatal flaw in his mind is they just used a garbage formulation of estrogen and progestin It was not the only thing they had, but they made the decision to use what doctors were prescribing most frequently It was the sponsors That was a forgivable mistake
The real fault lies with the PIs and the media, who Peter believes very nefariously promoted a false agenda When was the last time the NIH did a press conference on a study? Post-game analysis. Really? That’s very strange There were certain members of the media who simply got it in their mind that this was the way it was, and they have been completely immune to any form of logical intervention to show otherwise Even when 7, 19 years later subsequent analyses find the same thing
Some of which Peter thinks are justifiable
The most fatal flaw in his mind is they just used a garbage formulation of estrogen and progestin
It was not the only thing they had, but they made the decision to use what doctors were prescribing most frequently It was the sponsors That was a forgivable mistake
It was the sponsors
That was a forgivable mistake
When was the last time the NIH did a press conference on a study?
Post-game analysis. Really? That’s very strange
There were certain members of the media who simply got it in their mind that this was the way it was, and they have been completely immune to any form of logical intervention to show otherwise
Even when 7, 19 years later subsequent analyses find the same thing

Peter points out, “ 19 years later … we’re seeing not one additional woman died of breast cancer in the CEE plus MPA group relative to placebo. And that’s even with the MPA. Where’s the press release on that? ”

Lisa thinks there’s a tendency to amplify the negative results as opposed to the positive result

Even with the association with Alzheimer’s, there are a few studies that came out of Northern Europe showing that hormone therapy… Those are retrospective studies that looked at women who have Alzheimer’s today and were taking hormone therapy starting before the Women’s Health Initiative crash
And in those studies, there is an association between taking hormone therapy at any age and an increased risk of dementia
Those are retrospective studies that looked at women who have Alzheimer’s today and were taking hormone therapy starting before the Women’s Health Initiative crash

They’re 2 studies all over the news: hormone therapy causes Alzheimer’s; but there are 10 studies that show the opposite

There are studies with half a million women from the United States where, by the way, the vast majority of studies shows a protective association that just never make the news
Lisa thinks this is a pity because it leads to a very unbalanced conversation where so many women today are like, “ Oh, I need to go off hormone therapy because of this observational stud y” That is a correlational study, not even a trial
That is a correlational study, not even a trial

“ I think it’s so hard to disentangle scientific information when it’s a headline. ”‒ Lisa Mosconi

You’re hit by the headline, and it’s very hard to really understand the context and the nuances and just the fact that even in these studies that make the headlines, those women were taking hormones before the Women’s Health Initiative crashed

You can see that they start with a certain number of women in the study, and then the number just plummets
So at the end, you’re left with this subpopulation of women who just happen to be still on hormones

Peter won’t even pretend to disentangle that he could predict the biases that are inherent in that type of study

Observational research is hard
Peter finds that to be the worst example of observational epidemiology He couldn’t disentangle that He couldn’t even tell you what corrections you need to make
He couldn’t disentangle that
He couldn’t even tell you what corrections you need to make

Why better biomarkers are central to advancing women’s Alzheimer’s research [A: 1:38:30, V: 1:44:09]

Peter thinks Lisa’s intuition a few moments ago was the right one, which is the only way we’re going to get better data on this is by generating the right data

We don’t need more observational epidemiology on this question
What we need are better and better biomarkers that allow us to do more rigorous prospective randomized control trials
We need RCTs, and we’re not going to get hard outcomes because it takes too long and it’s going to cost too much It’s not feasible
It’s not feasible

Biomarkers we could look at

C 2 N , p-tau
Any of the other brain metabolomics
Most people listening to this aren’t going to have access to an estrogen tracer They would have to be in a clinical trial or in the studies Lisa is doing
They would have to be in a clinical trial or in the studies Lisa is doing

Clinically, what do you think of C 2 N, what do you think of the commercially available versions of p-tau and these other studies?

Do you think that these are ready for prime time?

Do you think that physicians and women could use these as tools to track interventions that they’re making?

Oh yes, totally
This is what Lisa is doing with CARE
We are using the same machines used by commercial entities to run their own assays
We are using those as surrogate outcomes of Alzheimer’s risk
We’re using not just the brain scans, but also the blood-based biomarkers because they’re much cheaper, they’re minimally invasive, they’re easier to read
We do need to have more long-term data to really establish their predictive value for each individual
Right now, they’re being used either diagnostically (which Lisa thinks is very smart) or for research to try and better understand if we can use those markers to really predict: Who is at risk and who is not And what is the positive predictive value and negative predictive value for any given individual
Lisa thinks studies like CARE and other prospective cohort studies and large-scale biorepositories are so important Like the UK Biobank, thousands and thousands and thousands of blood samples that can be used and analyzed for these purposes
One way to maximize the potential of observational research in a 3-year span is to leverage data from all over the world
Because a lot of the information we have comes pretty much always from the same studies Mainly North America, some European studies And the population in those studies tends to be quite homogeneous, predominantly white individuals with a certain level of education, overall healthy
Who is at risk and who is not
And what is the positive predictive value and negative predictive value for any given individual
Like the UK Biobank, thousands and thousands and thousands of blood samples that can be used and analyzed for these purposes
Mainly North America, some European studies
And the population in those studies tends to be quite homogeneous, predominantly white individuals with a certain level of education, overall healthy

Lisa explains about CARE, “ What we’re trying to do is to get data from all over the world .”

With CARE, we have access to female-specific data from 6 continents (we don’t have it from Antarctica)
And all together with the other scientists involved in CARE, we are estimating receiving data from over 20 million women, especially longitudinal data

So that’s going to be a treasure box of data for scientists who are interested in addressing these questions

And yes, that’s what we’re going to do.

⇒ The first component of CARE is to firmly establish neuroendocrine aging and really reproductive history for women

All these different factors that seem to emerge already at puberty
And then are perhaps even more unmasked during pregnancy in the postpartum period
And then tend to repeat themselves around menopause
There seems to be a continuum, you can kind of leverage a woman’s reproductive history

“ It’s a potential stress test for future cognitive decline in Alzheimer’s disease or the opposite, cognitive resilience .”‒ Lisa Mosconi

This is something that has never quite been done formally and in a standardized fashion, so we are trying to do it now

For instance, high blood pressure is a risk factor for Alzheimer’s for both men and women

It may be even worse for women, some studies suggest (it is a suggestion) that preeclampsia during gestation When a woman is pregnant is effectively a stress test on the body It gives you a preview of whether or not you may have chronic hypertension when you’re older And usually, if it starts during pregnancy, it may present itself again during menopause, and then it may remain stable
Same for mood changes If during puberty your neuroendocrine system is activated in such a way that you are more likely to suffer from anxiety or from depressive episodes or from mood changes, then things may stabilize as you get older But then they could actually come back during pregnancy, and that could be unmasked again during menopause
It’s so common for women, and we know that midlife depression is a risk factor for Alzheimer’s, more for women than for men
When a woman is pregnant is effectively a stress test on the body
It gives you a preview of whether or not you may have chronic hypertension when you’re older
And usually, if it starts during pregnancy, it may present itself again during menopause, and then it may remain stable
If during puberty your neuroendocrine system is activated in such a way that you are more likely to suffer from anxiety or from depressive episodes or from mood changes, then things may stabilize as you get older
But then they could actually come back during pregnancy, and that could be unmasked again during menopause

So we’re trying to put it all in context, not just what happens to you today, but what happened to you in the past

Lisa believes that hormonal history should be considered a vital sign

Modifiable risk factors for dementia, the limitations of risk models, and questionable conclusions drawn from observational data [A: 1:44:15, V: 1:50:20]

Let’s take the blood pressure example: hypertension is a risk factor for Alzheimer’s disease in men and women And vascular health in general
And vascular health in general

Do we know if when we see hypertension being a greater driver of risk in women than in men that we’re not picking up the same underlying risk that is being driven by something else such as the neuroendocrine system?

We do not know that
We don’t know if independently these are all the case
There are very few studies that have looked at neuroendocrine variables at all, very few
If you look at the Lancet Commission for those interested in Alzheimer’s disease, whenever it comes to Alzheimer’s prevention, we look at the recommendations of the Lancet Commission, which every few years produce an update [modifiable risk factors identified are shown in the figure below]
[modifiable risk factors identified are shown in the figure below]

As of 2024, we have this risk model that accounts for approximately 45% of all Alzheimer’s cases

Figure 2. 14 modifiable risk factors in dementia . Image credit: The Lancet 2024

⇒ There are 14 modifiable risk factors that have been established to be meaningful and replicable by the Lancet Commission that altogether account for about 45% of Alzheimer’s risk, and those are sex-aggregated risk factors; they’re valid for both men and women

Lisa points out, “ What is completely missing there is anything that is female-specific or male-specific. ”

They have a section about menopause and hormone therapy, and they conclude that hormone therapy may increase the risk of Alzheimer’s, especially for women with an oophorectomy

Lisa shares, “ We were all like, ‘What happened?’ ”

Lisa is not dismissive, she’s really like, “ What can we do to change this? Because it’s so important with women who do get an oophorectomy to also be aware of hormone therapy. ”

Peter wants to understand, “ They’re claiming that it’s not the oophorectomy, that it’s the hormones that follow the oophorectomy? ”

We do know that undergoing an oophorectomy before menopause is associated with an increased risk for Alzheimer’s [see studies listed in the “selected links” section]
But what they say is that hormone therapy can also increase the risk of Alzheimer’s disease, especially for women

Peter asks, “ What’s the data on that? ”

There’s a couple of studies [see also Lisa’s 2025 review on this topic]
Peter’s point is it’s total nonsense The studies that suggest that if a 40-year-old or a 35-year-old woman undergoes an oophorectomy that she’s better off without hormones than she is with hormones He just doesn’t believe those studies, he doesn’t believe those observational data
The studies that suggest that if a 40-year-old or a 35-year-old woman undergoes an oophorectomy that she’s better off without hormones than she is with hormones
He just doesn’t believe those studies, he doesn’t believe those observational data

“ I think observational research needs to be cautious .”‒ Lisa Mosconi

What would you recommend for your 35-year old sister?

If your 35-year-old sister was in a car accident or had an ovarian cyst rupture or something like that and needed to undergo an oophorectomy
She’s now sitting in front of you in menopause, she’s mechanically chemically in menopause and she’s got hot flashes and she’s got all the symptoms that a 35-year-old woman would absolutely have in spades because of the abruptness of this
And she came to you and said, “ Do you think I would be better off with or without hormones? ” What would you suggest?

Lisa thinks she would be better off with hormones ‒ this is standard at this point

But do you think you would be increasing her risk of Alzheimer’s disease by telling her that?

No, that’s why Lisa is so puzzled
That’s is Peter’s point ‒ they’re in alignment

Lisa explains, “ Whatever we know about hormone therapy is that is especially beneficial for women who experience early menopause and especially when early menopause is triggered by an oophorectomy. This is in professional guidelines .”

Peter’s point is that these commissions sometimes cherry-pick the data to fit their agenda

That’s Lisa’s problem

Why is it even an agenda?

Lisa doesn’t know

Lisa makes the point, “ What is concerning to me is that neuroendocrine factors, that are important for women, I think it’s undeniable, and not part of these recommendations for Alzheimer’s prevention. ”

For menopause hormone therapy, it’s not positioned as a recommendation It’s more like we don’t know enough
It’s more like we don’t know enough

GLP-1 agonists and brain health: exploring potential neuroprotective effects of GLP-1 agonists beyond metabolic benefits [A: 1:49:00, V: 1:55:48]

Do you believe that independent of weight loss and insulin sensitivity, GLP-1 agonists are going to have a protective effect in the brain?

Lisa thinks it’s really interesting and it makes sense

“ That’s the thing, biological plausibility needs to be present for any study to be done. ”‒ Lisa Mosconi

Lisa completes her train of thought

When you do observational research, which is also relative to the GLP-1s, you need to have a hypothesis that is based on something
You can’t just do a fishing expedition
You need to have pre-clinical work showing, for instance, that once you have an oophorectomy, estrogen is beneficial if you start right after the surgery, you keep taking it until the natural age of menopause That we know from pre-clinical research That is your biological plausibility
Then you do translational research
That we know from pre-clinical research
That is your biological plausibility

You power your observational study to assess a hypothesis that is based on pre-clinical work, that is still observational but is solid

Lisa explains when there is a problem, “I f instead your study is showing the opposite, there’s some issue there .”

So that is Lisa’s concern when it comes to some kind of research that gets published It gets published because that’s the data that you have And regardless of whether or not your conclusions are in alignment with pre-clinical research, you publish it anyway That’s a question mark for her
And everybody falls back on the Women’s Health Initiative Once they find an increased risk, it’s like, “ Well, the Women’s Health Initiative found so-and-so, even though it goes against biological plausibility. ”
It gets published because that’s the data that you have
And regardless of whether or not your conclusions are in alignment with pre-clinical research, you publish it anyway
That’s a question mark for her
Once they find an increased risk, it’s like, “ Well, the Women’s Health Initiative found so-and-so, even though it goes against biological plausibility. ”

For the GLP-1s, there’s a lot of potential

Lisa knows someone who is developing ligands or tracers for GLP-1s in the brain, and she thinks that’s going to be really interesting

Do you have a sense of what the mechanism of action would be beyond two things that are important, which are metabolic?

Peter thinks it’s logical that even if you have some insulin resistance , absent diabetes, making that better is going to make it better
Lisa agrees
Peter adds that obesity is accompanied by inflammation , even if it doesn’t come with diabetes Vascular inflammation
Vascular inflammation

If someone like you, in perfect health were at high risk of Alzheimer’s disease, would there be a benefit to taking a micro dose of tirzepatide ?

A low enough does that you wouldn’t lose any weight

Is that going to provide protection for your brain?

This is the study Peter wants to see done
You can only study this prospectively with very good brain biomarkers
We’re not going to be able to do this study for 20 years and follow a bunch of women
But Peter thinks we’re getting to the place where we have really good biomarkers

Can we start to ask this question scientifically?

We can start

The question is never interest, the problem is always funding

So many scientists are interested in testing it
It’s really expensive to do this kind of research and do it well
And who is going to sponsor it?
Hopefully, the NIH… historically, the NIH has been the biggest source of research funding in the United States
This is clearly a national level problem, it’s a bipartisan problem
Hopefully, this is happening

This not Lisa’s field necessarily, but even just the fact that people are developing ligands and tracers for GLP-1s everywhere in the body, including the brain, she thinks is a strong indication that there is a lot of interest

Lisa concludes, “ As of today, I don’t know how to answer .”

Peter has seen some unpublished data that looks promising

You have to take that with caution (there’s lots of things you have to be mindful of)

This data suggests that 2.5 mg of tirzepatide (a very low dose) is meaningfully reducing blood-based and CSF-based markers of neuroinflammation and protein aggregation

The study had very small numbers, a n of 20
It’s a pilot study
You have to start somewhere

The importance of lifestyle factors in reducing risk of dementia: practical strategies for women to support brain health [A: 1:53:45, V: 2:01:21]

This has been a really interesting discussion for Peter
Unfortunately, he feels like we are still a little bit in the dark because while it appears that the neuroendocrine differences between men and women probably account for the majority of these differences, there may still be other things

We still don’t understand:

If women are more susceptible to hypertension, dyslipidemia, insulin resistance, sleep disturbances, all of the other risk factors
We don’t know if they’re disproportionately affecting women

Peter is left with the following question:

Ultimately, if you’re listening to this podcast, you might take interest in all the nuances we’ve talked about, but if you’re a woman, you want to know: What should I be doing differently?

If you’re already paying great attention to your sleep, if you’re already paying great attention to your nutrition, if you’re insulin-sensitive, if you’re managing all of these things that we’ve talked about

Is the big takeaway from this discussion that if you’re on the fence about hormone replacement therapy, it’s probably something that should be in your purview and you should probably think about it more seriously?

What would you say to a woman who’s either about to go through menopause, in menopause, or just out of menopause who’s coming at this purely through the lens of her brain?

Lisa doesn’t know that many women who really check all the boxes

Whenever patients come to the Alzheimer’s Prevention Clinic at Weill Cornell Medicine , which Richard Isaacson launched
Most of our patients come here because they’re really scared that they may be experiencing early-onset dementia
We go through a series of tests
And more often than not, these are midlife women, what they’re describing could be attributed to midlife changes, including menopause
In some cases, clearly there’s an increased risk of Alzheimer’s that needs to be mitigated

“ The ABCs, if you will, of Alzheimer’s prevention are lifestyle-based .”‒ Lisa Mosconi

At this point, what we do for Alzheimer’s prevention is predominantly behavioral

That includes managing medical conditions like high blood pressure, and insulin resistance, diabetes, obesity, all the cardiovascular risk factors
That can be done with a combination of tools that leverage diet, exercise, stress reduction, sleep hygiene, and whatnot, and also medical pharmaceutical routes when appropriate
For women, specifically midlife, Lisa does not think that having a serious menopause conversation is important not just for the short term Not just for the symptoms of menopause that one may be experiencing today But because the research is moving so fast.
Not just for the symptoms of menopause that one may be experiencing today
But because the research is moving so fast.

Lisa shares, “ As a midlife woman, I do pay attention to all the things you mentioned. I am extremely conscious about my lifestyle and so disciplined it’s almost ridiculous. This morning, I couldn’t find anything that I wanted to eat for breakfast, so I just skipped it because I’m not going to have a bagel first thing in the morning .”

Lisa wants to have all those answers, but we need to also wait for the research to get done so that we can then give women the right information

It’s the first principle of medicine: first of all, do no harm
As long as lifestyle is concerned, it is important to be very consistent
A lot of people, especially in this country, try a lot of different things And then maybe those things don’t work out, they feel like they’re not working out And they switch from a keto diet to veganism, and then go back to something else.
And then maybe those things don’t work out, they feel like they’re not working out
And they switch from a keto diet to veganism, and then go back to something else.

Lisa thinks consistency is important

We do know that some very specific patterns are conducive to brain health, and I think it’s important to embrace them and stick with them for long enough time
Like exercise , yes, but there’s so many different ways to exercise
That, at least, we have information that is specific to women, including women in midlife, which is the association between intensity and gains
But gains is not building muscle mass, but more like for health

Overall health follows almost like an inverted U shape where moderate intensity exercise, if performed frequently enough, is conducive to the greatest gains, which Lisa thinks is the Zone 2

Peter explains that this turns out to be a bit more complicated

In that intensity matters and duration matters
And it depends on how much time an individual has
The less time an individual has, the more they have to prioritize intensity
The more time they have, the distribution curve actually skews to lower intensity
But if you’re in sort of a sweet spot in the middle, then you’re probably going to get the most bang for your buck at a modest level of intensity, which might actually be even north of Zone 2

Peter adds, “ I’m overdue for a discussion on this because I feel like sometimes I talk about this and I ironically create confusion by not being nuanced enough, which is a rare accusation for me. ”

Peter’s takeaway from today’s discussion:

The single most important thing to do is maximize the known lifestyle levers because it buys us more time

Peter is more optimistic today than he was 5 years ago about treatments for dementia 5 years ago, he was in a state of despair; he thought, “ This is a disease that will never be treatable. ” He believed that once the proteins started folding in the brain, there was just nothing that could be done
Now when he looks at treatments like klotho [this was the subject of episode #303 ] Full disclosure, Peter is a co-founder of a company that is trying to develop a Klotho injection
And Peter looks at the potential around GLP-1 agonists
He looks at the ways that we’re getting better understanding of hormones
He looks at other molecules, exercise memetic proteins
He’s starting to think we just need to hold on long enough
5 years ago, he was in a state of despair; he thought, “ This is a disease that will never be treatable. ”
He believed that once the proteins started folding in the brain, there was just nothing that could be done
[this was the subject of episode #303 ]
Full disclosure, Peter is a co-founder of a company that is trying to develop a Klotho injection

If you can delay the onset of something by 10 years through all of these modifications, that could be the difference between a normal cognitive life and a cognitive life that is cut short

Unfortunately, that’s not the answer to the person who’s 75 today who has dementia And that is tragic
Peter wishes he could say, “ Don’t worry, tomorrow we’re going to have something that’s going to reverse this .” He doesn’t believe that personally Maybe that makes him a pessimist
But he absolutely believes that in a decade we’re going to have things that are going to make a real difference
And that is tragic
He doesn’t believe that personally
Maybe that makes him a pessimist

And therefore, if you’re sitting here and you’re 60 years old and you can keep checking all those boxes, as you said, that could be the difference between you being the candidate who gets the rescue before you’re fully in the throes of the disease versus not

Why long-term, consistent lifestyle habits are essential for building cognitive resilience and protecting brain health over decades [A: 2:01:15, V: 2:09:58]

Lisa completely agrees
Whenever she mentions lifestyle, people are always like, “ Oh yeah, sure. ”
But really, it’s so important
And not that many people are as consistent throughout the years

Lisa explains the importance of consistency for the brain

When we talk about brain health, it’s important to understand that the brain is not the same as the rest of the body And people are so used to seeing results quickly Within a matter of weeks, you can lose a couple of inches or you can grow muscle
The brain is built for stability, whereas the rest of the body is built for change
And people are so used to seeing results quickly
Within a matter of weeks, you can lose a couple of inches or you can grow muscle

Lisa advises, “ If you want to make an impact on your brain cells, you need to hit them frequently enough and long enough that that change is going to be recorded as an epigenetic mutation or as an epigenetic change or as something structurally permanent .”

And thank goodness, takes a really long time

So the good news is it takes a while to cause damage. The bad news is it takes a while to create resilience.

Lisa emphasizes that you can create resilience

This is not like a woo-woo, wishy-washy thing
It really can give your brain cognitive resilience and brain reserve, which is what you want in the end
You want your neurons to be strong

And you do that by having your body, for instance, move

⇒ We know the movements produces BDNF in the brain, produce uridine in the brain that support the health and growth of your dendritic… your synaptic extensions, for instance

⇒ We know that if you reduce inflammation, if you reduce oxidative stress, which is something you need to do from the outside, your brain will do better, will age less

These are all things that are very realistic, that every one of us can do on a daily basis
We can all make good choices that support the health of our brains in the long term or not, and then it will show
It may not show today, but it may show 10 years from now

“ This is really the time, I think, to invest in brain health because at the end of the day, we all want our cognitive lifespan to match our lifespan. ”‒ Lisa Mosconi

This is what Lisa is trying to do
And then we do research as fast as we can
She was so happy to have the opportunity to launch CARE because it’s very high speed research that should deliver in 3 years
Lisa joked with her daughter that by the time she goes through puberty, Lisa may be going through menopause Lisa wants answers by then
Peter is really grateful for the grant Lisa has
He did the math once, he believes the entire Manhattan Project in today’s dollars was about $3,4 billion $3 to $4 billion is a trivial investment for the United States government
Lisa wants answers by then
$3 to $4 billion is a trivial investment for the United States government

Peter would love to see an investment of that size to tackle this question

Because if you think about what you’re going to be able to accomplish in 3 years with $50 million, can you imagine what Peter hates to use the term because it’s so overdone What a moonshot would look like here?
And look, it might have to just come from the private sector as it has in Lisa’s case, through the Wellcome Trust
But nevertheless, he’s sure there’s somebody out there listening who’s thinking about what this type of a moonshot could look like
Lisa thinks that would be wonderful, and scientists from all over the world are ready to do this kind of work They really hope they would be able to do more
Peter hates to use the term because it’s so overdone
What a moonshot would look like here?
They really hope they would be able to do more

Selected Links / Related Material

Women’s Brain Initiative at Weill Cornell : Women’s Brain Initiative | Weill Cornell Medicine, Neurology | [1:00]

The CARE initiative : CARE: Cutting Alzheimer’s Risk through Endocrinology | Welcome Leap | [2:15, 1:07:45]

Imaging of women’s brains before and after menopause : Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery | PLoS One (L Mosconi et al. 2017) | [27:30]

First in vivo measurement of estrogen receptor density in midlife women : In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology | Scientific Reports (L Mosconi et al. 2024) | [38:30]

How estrogen impacts mitochondrial function : [54:30]

Estrogen Regulation of Glucose Metabolism and Mitochondrial Function: Therapeutic Implications for Prevention of Alzheimer’s Disease | Advanced Drug Delivery Reviews (R Diaz GBbrinton 2008)

Women’s Health Initiative Memory Study : Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women’s Health Initiative Memory Study: A Randomized Controlled Trial | JAMA (S Shumaker et al. 2003) | [1:12:30]

One study shows increased risk of dementia in women using menopause hormone therapy : Menopausal hormone therapy and dementia: nationwide, nested case-control study | BMJ (N Pourhadi et al. 2023) | [1:15:15]

Lisa’s systematic review and meta-analysis showed a reduced risk of dementia when menopause hormone therapy is started in mid-life : Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia | Frontiers in Aging Neuroscience (M Nerattini et al. 2023) | [1:15:30]

Benefits of hormone replacement therapy for reducing Alzheimer’s disease risk :

Timing of hormone replacement therapy could influence Alzheimer disease risk | Nature Reviews Neurology Research Highlight (H Wood 2025)
A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging | Neurology (C Kawas et al 1997)

Episode of The Drive with Rachel Rubin : #348 ‒ Women’s sexual health, menopause, and hormone replacement therapy (HRT) | Rachel Rubin, M.D. (May 12, 2025) | [1:23:30]

Phase I clinical trial of a neurological selective estrogen receptor modulator : Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial | Menopause (L Schneider et al. 2019) | [1:26:00]

No additional deaths from breast cancer observed in the Women’s Health Initiative cohort taking CEE + MPA : Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials | JAMA (R Chlebowski et al. 2020) | [1:35:45]

The Lancet Commission recommendations to prevent dementia : Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission | The Lancet (G Livingston et al. 2024) | [1:45:00]

Oophorectomy before menopause associated with increased risk of Alzheimer’s disease : [1:45:00]

Surgical menopause in association with cognitive function and risk of dementia: A systematic review and meta-analysis | Psychoneuroendocrinology (M Georgakis et al. 2019)
Association of Premenopausal Bilateral Oophorectomy With Cognitive Performance and Risk of Mild Cognitive Impairment | JAMA Network Open (W Rocca et al. 2021)
Premenopausal bilateral oophorectomy and Alzheimer’s disease imaging biomarkers later in life | Alzheimer’s & Dementia (K Kantarci et al. 2024)

Lisa’s review on menopause hormone therapy and risk of Alzheimer’s disease : New Horizons in Menopause, Menopausal Hormone Therapy, and Alzheimer’s Disease: Current Insights and Future Directions | Journal of Clinical Endocrinology & Metabolism (L Mosconi, M Nerattini, S Williams, M Gink 2025) | [1:49:45]

Alzheimer’s Prevention Clinic at Weill Cornell Medicine : Alzheimer’s Prevention Program | [1:55:15]

Lisa’s books :

The Menopause Brain by Lisa Mosconi and Maria Shriver (forward) (2024)
The XX Brain: The Groundbreaking Science Empowering Women to Maximize Cognitive Health and Prevent Alzheimer’s Disease by Lisa Mosconi, and Maria Shriver (forward) (2020)
Brain Food: The Surprising Science of Eating for Cognitive Power by Lisa Mosconi (2018)

People Mentioned

Mony de Leon (retired Professor of Neuroscience and Radiology at Weill Cornell, former faculty in Alzheimer’s Disease Research at New York University) [15:15]
Roberta Diaz Brinton (Director of the UA Center for Innovation in Brain Science at the University of Arizona Health Sciences; a leading neuroscientist in the field of Alzheimer’s, the aging female brain and regenerative therapeutics) [41:30, 54:30, 1:26:15]
Rachel Rubin (Urologist and sexual medicine specialist) [1:23:30]
Richard Isaacson (Director of the Atria Precision Prevention Program, previously founded and was the director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine in NY) [1:55:15]

Lisa Mosconi, PhD, is an associate professor of neuroscience in neurology and radiology at Weill Cornell Medicine and the director of the Women’s Brain Initiative and the Alzheimer’s Prevention Clinic at Weill Cornell Medicine/New York-Presbyterian Hospital. A world-renowned neuroscientist with a PhD in neuroscience and nuclear medicine from the University of Florence in Italy, Mosconi was listed as one of the seventeen most influential living female scientists by The Times and called “the Mona Lisa of Neuroscience” by ELLE International. She is the New York Times bestselling author of The Menopause Brain and The XX Brain . Lisa has dedicated her career to understanding how risk of memory loss and dementia can be mitigated through the combination of appropriate medical care and lifestyle modifications. [ Lisa Mosconi, PHD ]

Instagram: dr_mosconi

TED talk: How menopause affects the brain

Website: Lisa Mosconi, PHD

Transcript

Show transcript