Age at Menopause, Delayed Hormone Therapy Linked to Elevated Levels of Tau Protein

In this video, Gillian T. Coughlan, MS, PhD, discussed her team's study results, which found that female sex, early-age menopause, and hormone therapy use beginning more than 5 years after menopause were associated with higher regional tau levels, particularly when β-amyloid is elevated. Tau protein and β-amyloid are two markers of Alzheimer disease.

Additional Resource:

Coughlan GT, Betthauser TJ, Boyle R, et al. Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography. JAMA Neurol. 2023;80(5):462-473. doi:10.1001/jamaneurol.2023.0455.

Gillian Coughlan

Gillian T. Coughlan, MS, PhD is a research fellow in the Department of Neurology at Massachusetts General Hospital and Harvard Medical School (Boston, Massachusetts).


Gillian T. Coughlan, MS, PhD: I'm Gillian Coughlan and I'm currently working at the Department of Neurology in Massachusetts General Hospital. I'm a research fellow.

Consultant360: What was the impetus for this research? So why now?

Dr Coughlan: So I guess more recently what we really wanted to understand in the lab is why women seem to be showing higher incidents of Alzheimer's disease relative to men. And so that was the motivation of the study. And what we've seen in our prior research is that even when women are cognitively normal, they're showing higher levels of Alzheimer's disease in the brain. And now Alzheimer's disease usually is present up to a decade before someone will show symptoms of Alzheimer's disease dementia. So we wanted to look at the factors that might be putting women at a higher risk of having Alzheimer's disease in the brain, even when they're cognitively normal still. And so we were interested in two things. We were interested in when women start menopause, so at the end of their reproductive life and how this might have implications for Alzheimer's disease in the brain later on. And then the second thing is menopausal hormone therapy. So how does the use of therapy implicate Alzheimer's disease pathology in later life?

C360: What was a key takeaway from the results of your study?

Dr Coughlan: So what we were showing is that basically if women use menopausal hormone therapy proximal to their menopause, so within five years after their menopause onset, they weren't showing higher levels of Alzheimer's disease or that neurotoxic tau protein in the brain. And this is what we would consider a good thing because, okay, menopausal hormone therapy might not be protecting women from dementia in later life, but it's not putting them at a higher risk either.

And this is important because many women, up to a quarter of all women, suffer from pretty severe menopausal symptoms, which can last for up to seven years. And menopausal hormone therapy is the most effective treatment for these troublesome symptoms. And so if women can use menopausal hormone therapy proximal to menopause, this is a good thing. Of course though, these findings are observational, meaning that we can't really make causal inferences. So it's really going to have to be another randomized controlled trial or RCT that can really test whether or not menopausal hormone therapy proximal to menopause really does have no implications for Alzheimer's disease neuropathology or that tau protein that you mentioned.

C360: Were there any surprises based on results from the study?

Dr Coughlan: Yeah. So in the early 2000s, there was a really huge study in women, a randomized controlled trial from the Women's Health Initiative that found menopausal hormone therapy doubled women's likelihood of probable dementia. And that's why rates of hormone therapy use, especially in the United States, declined so much through the early millennium. They also found it had risk for breast cancer and cardiovascular disease, et cetera. And so clinicians became very worried about prescribing menopausal hormone therapy to women. And on the flip side of that, there's a whole other body of research, particularly in observational studies that had suggested actually supplementing what estrogen should have very beneficial effects for the brain and should actually ameliorate cognitive impairment that tends present in menopausal women. So there was this very polarized field looking at hormone therapy, one side saying it can have potential bad ramifications for women and the other side saying, well, actually it can have potential positive effects for women in terms of cognition.

And so the way that these two polarized sides of the coin have come together or what they potentially agree on is the timing of hormone therapy is important when it comes to implications or implications for women's health. So again, going back to time relative to menopause seems to be the determinant of outcomes. So if it's early or if menopausal hormone therapy is given early, we could have neutral outcomes or potential beneficial outcomes, although that hasn't been proven very well for cognition. And then if we use it late, that can have potential bad outcomes. And so I guess our findings weren't particularly surprising from that perspective, yet it is the first study to look at hormone therapy and actual AD neuropathology in vivo. And so whatever the results were, they were going to be novel from that perspective because it was the first time it was looked at.

C360: What gaps in our knowledge still remain after the results of your study and what studies would be needed to fill these gaps?

Dr Coughlan: Yeah. Well, another finding was that early menopause or premature menopause seems to have implications for women. So we did adjust for things like smoking, diabetes, cardiovascular risk, and whether or not this could explain the relationship between early menopause and Alzheimer's disease and none of those factors attenuated the effect of early menopause on Alzheimer's disease in the brain. But one thing we didn't look at is history of chemotherapy. So even though all the women who were in our study were cognitively normal at baseline, we didn't actually get to look at whether or not they could have potentially had chemotherapy earlier in life, which might have then resulted in early menopause. And then how would that potential chemotherapy implicate Alzheimer's disease down the line? And so that's something we might want to investigate in future studies.

When it comes to hormone therapy, I think it's important to look at how hormone therapy acts specifically on women who are suffering from severe symptoms. So if women take hormone therapy close to menopause and this protects them in terms of reduces insomnia or mood swings or the things that asthma motor symptoms would typically be accompanied with, could this potentially protect women down the line relative to women who didn't do anything about these kinds of severe symptoms and just lived with them for many years? And so we don't really know how hormone therapy might implicate women specifically in this category who are suffering from severe symptoms in terms of their AD outcomes later in life.

If you want to make any causal inferences, you have to do an RCT, but the first line of researching this could be an observational study. So for example, looking at just the association between chemotherapy, early menopause and Alzheimer's disease pathology. And then for hormone therapy, looking at subgroups of women with severe menopausal symptoms, subgrouping them into who took hormone and who didn't, and then looking at their Alzheimer's disease pathology later down the line. So that would be an observational study. If you were to do an RCT, it's a bit more complicated. You need to recruit women with severe menopausal symptoms, randomize them to hormone therapy versus no hormone therapy, and see how they do after treatment in terms of levels of Alzheimer's disease in the brain. So there are potential study designs.

So we're working on this in the future. We work a lot with existing datasets that are out there and pulling information on hormone therapy and menopause from these datasets. There's a lot of datasets now that have positron emission tomography scans. So those are the scans that we use to measure Alzheimer's disease in the brain. And so what we're doing is we're pulling all of these data sets together and then we're looking at how hormone therapy is associated with those PET scans across different cohorts or across independent cohorts of women. So replication is obviously important, so that's the first thing we want to do. In terms of RCT, we can also look at existing RCT data and we can potentially recruit women back from hormone therapy trials that were conducted years ago and see how they're doing in terms of their PET, what their PET scans look like. Or of course, we could just start a whole new RCT from scratch. But that's a couple of years down the line for us at the moment, we're just working with our observational datasets.

C360: What were the overall take-home messages from the study?

Dr Coughlan: Yeah. So one thing that I think is important is women taking control of their reproductive health and menopausal symptoms. It's surprising because you ask women when they come into research studies, what they've had done in terms of reproductive surgery, so removal of ovaries or half an ovary or removal of the womb, a hysterectomy, et cetera. A lot of women aren't really sure what they've had done if they have had surgery. And so I think that's quite telling and women really do need to pay attention to if they're getting surgery and why they're getting that surgery in the first place. Reproductive surgery, of course, can be important for certain reasons, but it can also have implications later down the line. And so it's important to have those kinds of conversations with your doctor around what potential implications having reproductive surgery are and whether or not this reproductive surgery might induce early menopause. And if it does, do you go on menopausal hormone therapy or not? And so it's important to talk about these things with your doctor.