Exciting News about Estrogen and Alzheimer’s

There are multiple causes of dementia, but Alzheimer’s is the most common. It is responsible for 60% of cases of late onset dementia. It is also the 6th most common cause of death in women and the only one of the top fifteen causes of death that the risk for women exceeds that of men. 

Here is what we know. Two thirds of Alzheimer’s patients are women, and it is not simply due to the fact that women live longer. According to imaging studies done by Dr. Lisa Mosconi, the female brain changes both in its structure and in its metabolism starting in perimenopause, and these changes continue after menopause. These changes in brain activity and structure are evident years, if not decades, before any clinically recognized cognitive deficits occur. Black women are twice as likely to develop Alzheimer’s as white women. Black women also experience menopause earlier, are more symptomatic and take longer to transition to menopause. Also, women who have early or premature menopause (either surgical or natural) have a higher lifetime risk of being diagnosed with Alzheimer’s. In fact, the North American Menopause Society recommends that women with early menopause (before 45) should take estrogen and progesterone (if they have a uterus) at least until the average age of menopause.

Understanding the causes and underlying risk factors for developing Alzheimer’s is essential to  preventing future cases. This is what we know thus far. The risks for developing Alzheimer’s are:

1. Being female

2. Having a family history of Alzheimer’s (with a mother imparting more risk than a father)

3. Menopause (the earlier the menopause the higher the risk)

4. Obesity

5. Hypertension

6. Diabetes

7. Sedentary lifestyle

If these risk factors look familiar to you, they should be. They are the same risk factors that increase your risk of cardiovascular disease. Brain health is heart health. Repeat after me. Brain health is heart health.

There is considerable evidence that there is an association between lowered estrogen states, menopause and the development of Alzheimer’s. And although the gold standard is a randomized, placebo controlled study in order to prove that estrogen therapy reduces the risk, it would take at least twenty years to collect that data. And to be sure, that study needs to be done and should have been done decades ago. For those of you who read the headlines from the Women’s Health Initiative that said that estrogen increases the risk of Alzheimer’s, consider this– this finding was only significant in women who started taking estrogen after the age of 65 who had been menopausal for upwards of 15 to 20 years. Talk about closing the barn door after the horse is already out!

So to answer the question that has been top of mind—does estrogen therapy after menopause decrease the risk of Alzheimer’s? The answer is we don’t know for sure, but the preliminary data suggests that estrogen, started early, is beneficial for brain function. Women who have had their ovaries removed or who have had hysterectomies demonstrated a lower risk of cognitive decline and dementia if estrogen therapy is initiated within five years. Just like for prevention of cardiac disease, timing matters. And it is shameful that not enough research has been directed in this area and that we don’t have a definitive answer by now.  

In a recent article published in Alzheimer’s and Dementia, investigators have been able to show, in a prospective study, that the bio-markers associated with Alzheimer’s were significantly decreased in women who took MHT. This finding is huge! We know that estrogen appears to have a protective effect on neurons in the brain, and that it decreases some of the inflammatory changes that damage the female brain. And I know, I’ve said many times before that association does not always equal causation, but the signals are starting to point in the same direction.

The development of Alzheimer’s Disease is a decades long process. Starting treatment after symptoms are present can only hope to slow the rate of cognitive decline. It does not reverse any damage already done. The Alzheimer’s medication Leqemba, recently approved by the FDA, touts a 27% slower rate of cognitive decline. What does that even mean? It means that after 18 months of study, patients on the medication scored a half point higher on an 18 point scale than patients who did not take the drug. A half point. See what you can do with statistics? 27% sounds way better than a half point improvement. Okay, but what happens after 18 months? Your guess is as good as mine. No one knows. And the cost for this medication is over twenty six thousand dollars a year.

This is what we know: estrogen therapy reduces the biomarkers associated with Alzheimer’s. We know that in Dr. Mosconi’s brain imaging studies, the structural changes associated with Alzheimer’s start appearing in perimenopause. Women with early menopause are at higher risk for developing Alzheimer’s. Black women who are more symptomatic, and least likely to be prescribed estrogen, have twice the risk of developing Alzheimer’s. Risk factors for cardiac disease and Alzheimer’s are one in the same and both increase dramatically at menopause. 

This is what I think– that estrogen therapy started early (within five years of menopause) may decrease the incidence of Alzheimer’s in women. Is there definitive proof? Not yet. Should we be investigating this? Absolutely. Like yesterday.

Sir William Osler, considered the father of modern medicine, once said  “Medicine is a science of uncertainty and an art of probability.” We all have to weigh the evidence before us and make decisions about the pros and cons of any therapy. But I think it is safe to say, and the North American Menopause Society agrees, that for healthy women who are symptomatic during the perimenopause and menopause, the decision to take menopausal hormone therapy is a no-brainer. And yes, the pun was intended.

Sources:

Depypere, Herman, et al. “Menopause Hormone Therapy Significantly Alters Pathophysiological Biomarkers of Alzheimer's Disease.” Alzheimer's & Dementia, 2022, https://doi.org/10.1002/alz.12759. 

Mosconi, Lisa, and Maria Shriver. The XX Brain: The Groundbreaking Science Empowering Women to Maximize Cognitive Health and Prevent Alzheimer's Disease. Avery, an Imprint of Peguin Random House LLC, 2020.

Scheyer, O., et al. “Female Sex and Alzheimer’s Risk: The Menopause Connection.” The Journal Of Prevention of Alzheimer's Disease, 2018, pp. 1–6., https://doi.org/10.14283/jpad.2018.34.

“FDA Grants Accelerated Approval for Alzheimer's Disease Treatment.” U.S. Food and Drug Administration, FDA, 6 Jan. 2023, https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment.