That New Study on Menopausal Hormone Therapy and Alzheimer’s Disease

What is says, and more importantly, what it doesn't

Whenever a new study comes out that suggests menopausal hormone therapy may be helpful, but is in no way definitive, there are always some menopause influencers who cherry pick a line or two from the study and use it to further what appears to be an agenda of estrogen for everyone. Not only does this approach over-sell the benefits of estrogen, it makes those who can’t take it fearful, as if they are doomed to a miserable existence and an early death, all for the want of estrogen. It also creates conflict between providers who follow evidence-based guidelines and patients, because people believe these influencers.

And of course that is what happened with the recent publication of the study titled Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. There were Instagram posts from some doctors, functional nutritionists, and others who style themselves as menopause experts claiming this study was proof that estrogen protects the brain and hence everyone should be taking it.

But extraordinary claims require extraordinary proof, and while this study is very interesting and may be another important piece of the puzzle, the conclusion is not that every woman should be on estrogen. If the study really reached that conclusion, that would be big enough news that it would be the front page in many newspapers, and not just something promoted by a few people who feel that hormone scares are good for business. (Disclosure: I do prescribe hormones for my patients when indicated. However, in my practice, I do not make any more or any less if I prescribe estrogen, recommend gabapentin for hot flashes, or talk about the value of exercise. I have no financial incentive either way.)

Tell Me More

This study looked at women who were already enrolled in the European Prevention of Alzheimer’s Dementia (EPAD) project, which started in 2015. This study is following people over time to learn more about Alzheimer’s Disease and what interventions could be preventive. 

Women have a higher incidence of Alzheimer's compared to men and there is a lot of controversy in the literature about the role of menopausal hormone therapy in reducing that risk. To try and shed light on this potential estrogen-brain benefit researchers used data from EPAD, specifically looking at women with a genetic variation that increases the risk of Alzheimer’s and what happened to them over time, based on whether they received estrogen or not.  The researchers looked at results from cognitive testing as well as MRI scans that evaluated an area of the brain responsible for memory function.

What is the Genetic Variation in Question?

The APOE gene provides the instructions for making a protein called apolipoprotein E that is involved with packaging and transportation of cholesterol and other fats. There are three variations of the APOE gene, E2, E3 and E4, and we all have two copies of the gene, inheriting one from each parent. The E3 variation has no impact on Alzheimer’s risk, and about 60% of people have two copies of the E3 variation. The E2 variation reduces the risk while the E4 version increases the risk for late-onset Alzheimer’s disease (which occurs over the age of 65). Overall, about 25% of people have one copy of the E4 variant and 2-3% have 2 copies. One copy of E4 increases the risk of developing late-onset Alzheimer's about threefold, and two copies about 8-12 times over baseline. Carrying an APOE4 variation increases the risk of late-onset Alzheimer’s but it does not guarantee that you will develop it. 

What Did the Study Find?

Among those who carried APOE4 variations there was less loss of brain volume and fewer memory issues for those who took menopausal hormone therapy versus those who didn’t. And the earlier estrogen was started, the greater the effect on brain volume. There was no difference for those who did not have the APOE4 variation. And while these changes are interesting, this study does not prove that estrogen was the cause of this difference for those who are APOE4 carriers.  

This is because this is an observational study, meaning people chose to be on hormones or not and then they were followed, they weren’t randomly assigned to estrogen or a placebo therapy. This is important, because observational data typically can’t prove causation, just correlation. Now correlation is important, but it’s important to look at study results for what they actually are. 

While one conclusion could be that estrogen in menopausal hormone therapy is protective brain-wise for APOE4 carriers, it’s equally possible that the benefit shown is spurious, meaning there are potentially other reasons that people who take estrogen might have better outcomes brain-wise. For example, taking estrogen might be a marker for being more engaged with other activities that we know reduce the risk of dementia, but were not tracked in the study. Basically, choosing to take estrogen results in a healthy-user bias.

What Else Do We Know About Estrogen and Brain Health?

One observational study shouldn’t change anything. In fact, a recent observational study from Taiwan showed an increased risk of dementia with menopausal hormone therapy, and the higher the dose the greater the risk. This study doesn’t mean everyone should stop estrogen, rather, observational data on estrogen and brain health is tricky. 

We have data that shows that dementia is increased when estrogen is started after age 65. This should not be extrapolated to mean that estrogen doesn’t help younger women, but it means that all the guidelines recommend against starting hormones at or after age 65. (Yes, I know there are some self-described menopause experts who say otherwise, and they are incorrect. Whether they can’t read the literature and follow guidelines or think they are above all that, I don’t know.).

The idea that estrogen might be beneficial when started early, right around the final period, a time known as the “critical window”, has been tested in randomized controlled trials, specifically the Early Versus Late Intervention Trial With Estradiol (ELITE), the Kronos Early Estrogen Prevention Study (KEEPS), and the Women’s Health Initiative Memory Study of Younger Women (WHIMSY) trial.  None of these trials showed a benefit for memory or prevention of dementia. However, they may not have been long enough to show that effect and we don’t know if the results might have been different for those who had the APOE4 variation.

What Should I do?

This study is important for researchers, and adds to the growing body of data that APOE4 variations, menopause, and estrogen need further study. It is possible that down the road we will have precision medicine that we will have genetic tests can help us decide who will benefit the most from hormones, but it shouldn’t change what we think about who should get hormones at this time. Currently, the recommendations for menopausal hormone therapy are for hot flashes, night sweats, and for those at high risk of osteoporosis. There is also data supporting estrogen for mild depression in the early menopause transition and it may be worth an off label trial for things like joint pain or burning mouth (I’ve written previously about joint pain here).  

There are many modifiable things to do for brain health. In fact focusing on estrogen with all of its unknowns distracts us from the PROVEN interventions that protect brain health. 

So if you read anything about this observational study and panicked, let me review the things we know from good science that you can start doing for your brain:

1. Regular exercise. Think what you can do every day to meet this goal. I’ve recently made this a daily priority. It takes work, but I look at this as a daily preventative medication.

2. Avoid excess alcohol. I’m going to be honest, this is a big reason I cut back on my alcohol. Previously, I had about 7-8 drinks of alcohol a week, which is in the medically fine range, but with alcohol and health, less is better. Alcohol is also a carcinogen (the other reason I cut back). I felt it was absurd of me to worry about the slightly increased risk of breast cancer with long term estrogen use after menopause and not consider the fact that alcohol increases the risk for dementia and breast cancer, ya know? I’m down to 3-4 drinks most weeks, but sometimes its less. And I’m pleased to say there has been zero difference in my joy. 

3. Get tested for diabetes and work towards the best control you can if diagnosed. I was last screened about 2 years ago, and am going in next week to get rechecked. 

4. Get screened for high blood pressure and treating your blood pressure if it’s high. 

5. Treat hearing impairment. I recently had my hearing tested, and I have some loss in one ear. Not enough to intervene yet, but something to follow. 

6. Prevent head injury. Make sure to wear a helmet if biking or skiing and consider working on your balance, because falls are the leading cause of traumatic brain injury. 

7. Seek treatment for depression if you are diagnosed.

8. Stop smoking. I know this is hard, but the pay off is huge.

9. Frequent social contact. Low levels of cognitive engagement increase the risk of dementia, so stretching your brain by interacting with other people is a good thing. Considering how COVID affected and is still affecting many of us socially, I’m sure this is something many of us could work on. 

10. Consider losing some weight if your BMI is over 30. Even a 5 lb weight loss can help.

Should I Get Tested for the APOe4 Variation?

This is what the Alzheimer’s Association says:

“The Alzheimer’s Association cautions against routine genetic screening for risk of Alzheimer’s in healthy individuals. Genes are only one factor of many that contribute to a person’s risk, and researchers are still working to understand how they may impact risk across different groups and populations.”

They also add that many people with the APOE4 variation don’t develop Alzheimer’s and furthermore, if people do the testing and they are negative, they might falsely assume they won’t develop Alzheimer’s and so might be less likely to focus on the known actions that can reduce the risk of dementia. You can read more about what they have to say here. If you have a family history of dementia, then a genetic counselor and a neurologist are the best people to guide you about testing. If you don’t have a family history but have questions about testing, your family doctor/internist and/or a genetic counselor and/or neurologist who knows your medical and family history are also best people to help guide you further.

So…

No menopause society recommends estrogen for prevention of dementia for women in menopause at age 45 or later. For primary ovarian insufficiency or menopause before age 45 the recommendations are different, and in these situations taking estrogen until the average age of menopause, 51, is recommended and then at that point address estrogen as you would for anyone aged 51. 

There are a lot of PROVEN interventions to lower the risk of dementia, so focusing on an unproven one isn’t good medicine. 

When studies like this are amplified in the press and on social media it can feel like medical whiplash. I get it, what should you believe? But we need to accept each study for what it is, a piece of the puzzle, and then look at it in the context of what we know. That is the meandering path of science. 

References

Rasha N M Saleh, Michael Hornberger, Craig W Ritchie, Anne Marie Minihane. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. Alzheimers Res Ther 2023 Jan 9;15(1):10.

Yueh-Feng Sung, Chun-Teng Tsai, Cheng-Yi Kuo, et al. Use of Hormone Replacement Therapy and Risk of Dementia. A Nationwide Cohort Study. Neurology October, 2022; 99 (17).

Gleason CE, Dowling NM, Whartone W, et. al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med;2015 Jun 2;12(6):e1001833

Henderson St. John JA, Hodis HN, et. al. Cognitive effects of estradiol after Menopause. A randomized trial of the timing hypothesis. Neurology 2016. Aug 16;87(7):699-708.

Espeland MA, Shumaker SA, Leng I, et. al. Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013;173.

Mark A Espeland, Stephen R Rapp, JoAnn E Manson, et. al. Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups J Gerontol A Biol Sci Med Sci 2017 Jun 1;72(6):838-845. 

National Institute on Aging https://www.nia.nih.gov/news/study-reveals-how-apoe4-gene-may-increase-risk-dementia

Risk factors for dementia, Alzheimer’s Society Canada https://alzheimer.ca/en/about-dementia/how-can-i-prevent-dementia/risk-factors-dementia