Inside the Lab Studying Why Women Face Greater Alzheimer’s Risk

Why are women more likely than men to develop Alzheimer’s disease? Mount Sinai neurologist Dr. Fanny Elahi is on a mission to find out.

Elahi, an associate professor of neurology, leads a multidisciplinary lab focused on modeling disease, spotting early biomarkers, and identifying new treatment targets for dementia. Her research zeroes in on the connection between vascular health and neurodegeneration — and how midlife changes like menopause and the drop in estrogen can affect brain function.

In this conversation with Being Patient founder Deborah Kan, Elahi unpacks the science behind sex-specific risks, from hormonal shifts that alter blood vessel function to biological differences that could shape how we approach prevention and treatment. She also shares actionable steps women can take now — including regular exercise, sleep assessments, and informed discussions about hormone replacement therapy — along with how emerging early-detection tools could make interventions more personalized and effective.

Being Patient: What do we know about women’s susceptibility to dementia versus men?

Dr. Fanny Elahi: I’ll take one step back and say we didn’t set out to ask the question of why women are more susceptible to dementia than men. We took everyone for whom we had samples and data. We started analyzing the risk of brain dysfunction and degeneration by measuring molecular abnormalities related to vascular dysfunction, building predictive models, and found that biological sex and age were important factors in these models. The directionality of the model was different if you were a younger woman versus an older woman, or a younger man versus an older man. So there was an interaction of sex and age.

I’m a woman, and I’ve known the statistics that women are at higher risk of specifically Alzheimer’s disease and that there are sex differences to think about across neurodegenerative disorders, but I wasn’t a sex differences researcher. I was fascinated with how vasculature contributes to dementia, but our data took us to face this huge biological effect. We started thinking about this. It’s still at the hypothesis level, and we have a lot of experiments in the making to start generating data toward this.

One thought I have is that in midlife, there’s a huge physiological shift for women due to menopause. Menopause is a very complex biological phenomenon, but to simplify, one major difference is that estrogen levels go down. Estrogen has a potent effect on cellular function across the board — not just neurons, glia, vascular cells, immune cells or bone cells. But one of the cells that is quite vulnerable to estrogen, with receptors, is endothelial cells, the inner lining of most blood vessels.

“We … found that biological sex and age
were important factors in these models.”

Despite the fact that neurodegeneration is ultimately dysfunction and degeneration of neurons, how a brain starts degenerating may be a chain of causes. One factor in this causal pathway that we study is the changes at the level of the barriers of the brain.

Being Patient: What types of comparisons were you making? Were the people studied more likely to have higher blood pressure? Were there any symptoms that might have manifested into this risk?

Elahi: We tried to make it as unbiased as possible. No research cohort is truly unbiased unless you’re sampling the population and bringing in people who wouldn’t otherwise participate. There are probably biases in every research cohort, but we had access to two different sample sets. We’ve continued to look at this across any sample set we have access to, and we continue to see the effect.

What we ended up finding is basically changes in plasticity of blood vessels, or their flexibility. It can mean a lot of different things from a biological perspective. These molecules that we measured are tightly associated with the adaptability of blood vessels and their function, relating to the smallest blood vessels in the brain and the largest.

Being Patient: Do we know the role of estrogen in vascular health, or does that still need to be studied?

Elahi: We know some. There was this directionality in younger women, and it was flipped in older women. In that study, we couldn’t measure hormone levels. We didn’t know when people went through menopause or whether they were on hormone replacement therapy — a lot of missing information. But there was a hint that there’s something happening in that midlife period of women’s lives.

Based on existing literature, estrogen is important for the function of vasculature, especially the endothelial cells. We are now prospectively, in in vitro and in vivo models, asking exactly what estrogen is doing to the cells that compose vasculature and how the presence or absence of estrogen is changing the cellular phenotypes. How are those changes related to downstream degenerative pathways?

It’s possible we’ll find women who are resilient to this absence, to a lesser or greater extent, and some who are very vulnerable. We need better ways to stratify women. Not everyone can be on hormone replacement therapy, and it may not help everyone to the same extent. One of the things we want to understand is, can we understand the biology such that we can drug it, not just with hormones, but other potent therapeutics.

In some ways, it’s telling us what may be important, and by understanding that more, we can reestablish balance or homeostasis — maybe in an even better way than just giving back hormones.

Being Patient: Can you explain more about what’s going on inside the brain from your data? What does that mean in terms of the vascular system and susceptibility?

Elahi: Exactly what’s happening is a question we’re trying to answer. All we’ve uncovered at this point is that blood vessels are changing, and that change is likely part of the brain’s vulnerability to tilt over into this degenerative pathway. Now we’re taking it apart to understand what’s the component of the vascular change that’s the most injurious to the brain.

If we can’t treat all aspects of the change — because there are a lot of things that happen with age to blood vessels — what can we go after?

A few things we know change with age: one is the leakage of the brain, or the communication between your body and the brain changes with age. Things are not getting in as efficiently, and things are getting in too easily that should be kept out of the brain. Another aspect is that we have circulating immune cells that are supposed to survey all of our organs, including the brain. We have the attachment of the circulating immune cells to endothelial cells in an abnormal way, and that can cause them to get into the brain more, or maybe not get out of the brain efficiently. So there’s this immunovascular communication that changes with age.

Being Patient: And that applies to both men and women in terms of aging, right?

Elahi: Yes. These are age-associated phenomena. The third is the communication between vascular cells and the neurons and glia. It’s called neurovascular coupling, meaning that when you and I are talking right now, there are parts of our brains that are more active than others, and there is an increased blood flow to those regions because there is a supply and demand. We know that with age, that also becomes less efficient.

Now, what we want to ask is what aspect of this is most affected in women, and what aspect of it is associated with these hormonal changes in midlife. Those are clues.

Being Patient: How long will it take to get those answers with research? What’s the next step? Are you running a trial?

Elahi: The great news is that we are not the only ones asking these questions. There has been a really exciting surge in the number of labs and researchers focusing on women’s risk of Alzheimer’s disease and degeneration. It’s maybe almost too late for how much data suggests that women are at higher risk — that we should study this higher-risk group — because information may even translate to men’s risk of Alzheimer’s disease.

The good news is that a lot more focus has been put on this question. That usually means there’s an ecosystem that gets built, so the data from our lab can motivate other research. We are inspired by other data that others are generating, either by directly working with them or indirectly reading each other’s work. This is really critical to how fast we can progress in discoveries.

As for clinical trials, I’m dying to run a clinical trial, but I think for that we want to do it with the novel techniques and tools we have at hand. We want to understand through these multimodal approaches — modeling in human samples, dissecting mechanisms in in vitro human cell models, and asking some questions in animal models — to become a little more precise with what should be the readouts.

What I don’t want is to have to run a really long, expensive trial with everyone, where not everyone would benefit. Also, what should be the readouts? If we do this trial in women in midlife, cognition may not be a good readout. Can we have molecular readouts of whether we’re having an effect on pathways important for this biology? We are in the phase of discovery science, and I hope before long we can start doing some interventions.

Being Patient: Is there a lifestyle hack that could actually make women less susceptible?

Elahi: What has been shown to have a lot of evidence across humans, female and male, is exercise. We need to take it seriously and make time for it. Maybe what wasn’t so clear when these interventions were focused on the heart is that it’s not just cardiovascular exercise — running or walking or getting your heart rate up and down — but also building muscle and strength training and bone health.

I always tell women: steady, continuous exercise — not just doing it for a month and then stopping. I think at least six months of continuous exercise before you start seeing benefits.

“What has been shown to have a lot of evidence
across humans, female and male, is exercise.
We need to take it seriously and make time for it.”

Sleep is very important. Sleep apnea can be insidious and quiet, so getting a sleep workup at some point in midlife may not be a bad idea, because treating that could prevent a lot of upstream risk factors.

A healthy diet — that’s easier said than done, and the most confusing for me. I think we know what not to eat — deeply fried food, simple sugars — but exactly what to eat may be variable and person dependent.

Stress can be really bad for aging trajectories. Interestingly, it’s more perceived stress than objective stress. Mindfulness and taking psychiatric health seriously is important.

The last one that is more specific to women is menopause. Be very intentional and have the conversation with your physicians about whether you should go on hormone replacement therapy or not. The data was confusing at one point, but at this stage we have suggestive, strong data to suggest that we want hormones for longer than when we go through natural menopause. If the person can, from a medical perspective, go on hormone replacement therapy, I think they should seriously consider that — unless there are contraindications.