Can HRT Help Protect Women From Alzheimer’s and Dementia?

Reviewing studies on menopausal hormone replacement therapy

Carol and Barbara are two of my superstar Brain Health Retreaters in Sicily

Hello, everyone. I write to you from Sicily in the midst of the Brain Health Retreat. We are having a lot of fun eating, cooking, and touring around, but we are also immersed in brain health topics. Last night at dinner we had an in-depth discussion about sleep, menopausal symptoms, and menopausal hormone therapy (HRT). The topic of HRT and brain health usually brings a lot of confusion in its wake. One day you may read that taking HRT can protect the brain from Alzheimer’s. Then a new study will come out to say that HRT causes dementia. A recent study from Denmark  has prompted me to write about this again today. Sensational headlines only added to the confusion and incited a new wave of fear about taking HRT for women and their physicians. 

While it seems like the topic of HRT and brain health is a hot (flash) mess, there is actually a lot of solid information here that may be helpful. As you are probably aware, women are at heightened risk for Alzheimer’s: two-thirds of those living with the disease are female. And, all women go through menopause and are faced with the decision to take HRT. Getting the story straight on whether or not HRT can protect the brain is crucial. 

So, today, I’d like to share my thoughts on the Danish study and briefly summarize what we know now about how HRT (estrogen alone or estrogen + progestin) impacts the brain. It may be helpful to go back and read this post I shared a few months ago about a different new study—a groundbreaking one on how HRT shows promise in female carriers of ApoE4 at menopause—and I gave you some practical tips about talking to your doctor about menopause. So gather around and let’s dig in.

Lunch at an almond farm yesterday.

Estrogen and the Brain 101

Estrogen is synthesized primarily in the ovaries, where it then travels throughout the body and passes the blood brain barrier. But estrogen is also made in the brain. This “central” estrogen stays in the brain and exerts many actions on brain cell function. For example, estrogen influences higher cognitive function, pain, fine motor skills, mood, susceptibility to seizures, and neuroprotection in response to brain damage. Estrogen also regulates glial cells—the immune cells of the brain—and is a key player in how brain cells communicate.

In the brain health world, estrogen is considered neuroprotective. The Estrogen Hypothesis is a key concept arising from the evolving science that shows this hormone has a central role in healthy brain aging in women. And when I say “estrogen” I mean both the natural kind your body makes and other forms that can be supplemented through a pill, patch, or cream. 

Here’s what we know now based on dozens of studies on this topic:

• Lack of estrogen at midlife is associated with an increased risk of Alzheimer’s later in life. This could be from going through natural menopause, surgical menopause (a hysterectomy with ovaries removed), or drug-induced menopause (such as chemotherapy) without taking HRT. 

• The earlier a woman goes through menopause, the greater her risk of Alzheimer’s. (The average age of menopause is 51.4.)

• Going through puberty early (average age is 11) leads to reduced dementia risk later in life.

• The more full-term pregnancies a woman has, the lower her risk of dementia.

• Six studies show that women are less likely to develop dementia if they ever took birth control pills before menopause. One of these showed a reduction of 50% in ever-users of the pill. A few other birth control pill studies were inconclusive in preventing dementia, yet none showed an increased risk. 

• Women who have one or both ovaries removed before going through menopause are more likely to develop dementia later in life. 

In general, the more years a woman is exposed to estrogen, the lower her risk of all types of dementia, including Alzheimer’s. This pertains to both the estrogen the body makes and any estrogen taken as HRT.

What the studies say about taking HRT and Alzheimer’s risk

With this solid foundation of estrogen basic science, you would think that the issue of taking HRT and brain health would be clear. But HRT and menopause are challenging topics to study. 

Menopausal symptoms themselves, for example, are confounding factors. Just having severe symptoms like hot flashes and brain fog at menopause may be associated with an increased risk of neurodegenerative diseases later in life. That’s because severe hot flashes are a marker for underlying cardiovascular disease, a major risk factor for Alzheimer’s later. Hence, those women who opt to take HRT may already be at increased risk. 

Also, formulations vary. The studies run the gamut of looking at women taking natural vs. synthetic hormones, estrogen alone vs. with a progestin, patch vs. pill. This leads to an apples vs. oranges situation without a clean way to compare one study to the next. 

Finally, not all studies take into account whether the participants are ApoE4 carriers. I went into what you need to know about this Alzheimer’s gene variant here. ApoE4 is extremely common: 25% of people living in the U.S. carry one or two copies. If a study does not account for those who have ApoE4, results will be erroneously skewed. So, while the existing HRT and dementia data does not line up as nicely as we would like, there is a general positive trend in the major trials to date:

• These studies support that taking HRT has a protective effect on cognitive health and reduces Alzheimer’s risk by 30 to 50%: Baltimore Longitudinal Study of Aging, Cache County Study, Leisure World Cohort Study, Kaiser Permanente Study. Note that the Cache County study included 379,352 women, so while it is observational by design, the shear number of participants lends it power. 

• These studies don’t support a protective effect of taking HRT, but don’t show an increased risk of dementia either: WHIMS of Younger Women (WHIMS-Y), Kronos Early Estrogen Prevention Study (KEEPS), Early versus Late Intervention Trial with Estradiol (ELITE). In this meta-analysis of 29 studies, for example, taking HRT was not overall helpful but not harmful either.

• Studies generally report a protective effect of HRT on cognitive health if started early in the menopausal transition. This is the Critical Window Hypothesis: starting HRT early is key; late starters may not get the same benefits and are more likely to have adverse effects.

• Female carriers of ApoE4 who take HRT early in the menopausal transition may have key benefits, such as: better memory testing and word retrieval, and larger brain volume in the hippocampus (important for short term memory) and the amygdala (which has a central role in anxiety and stress response). 

• Taking estrogen alone (without progestin) generally shows more positive effects on cognitive health.

• Newer estrogen formulations (such as natural estradiol in patch form) may be better for cognitive health than older formulations (synthetic estrogen and progestin in pill form) used in older studies. 

The Danish Study: Menopausal hormone therapy and dementia: nationwide, nested case-control study

On the heels of this mostly positive stack of data leaning towards HRT being very good for women’s brains, this study out of Denmark dropped in July with seemingly opposite findings. This was based on insurance claim records from a single insurance company of a large group of women. It’s a nested, case-controlled study, meaning they matched participants with another larger group with similar characteristics to draw conclusions. 

The finding that made headlines was that women taking HRT had as much as 20% more likely to develop dementia than women who did not. The study loses credibility however, when you dig into the details. For example, they draw a conclusion that taking HRT for one year at menopause increases risk 20 years later, something that is not physiologically plausible. Based on everything we know about Alzheimer’s and dementia, the disease evolves over decades, not months. There’s also the problem of medical surveillance—women in the study were more likely to be diagnosed early with dementia because they were receiving medical care, unlike the nested comparison group. Also, if there was a slight increase in dementia in this population of women, it may be because the predominant type of HRT taken was the older formulations that have been shown to reverse some of the cardiovascular benefits of taking HRT.

So the Danish study, while novel in its design and ambitious in its scope, has most gynecologists and Alzheimer’s experts wondering how it could be so out of line of what has already been shown. In other words, it’s an outlier that shows the opposite of what other better (larger or randomized controlled) studies have shown. The bottom line: this study does nothing to help a woman decide if taking HRT may or may not be beneficial for brain health. 

Alzheimer’s starts at menopause and other takeaways

Even though the data on this topic is still evolving, and not as quickly as we’d like, there are key takeaways here for women of all ages. 

• Alzheimer’s starts at menopause. Women have a unique trajectory to Alzheimer’s when compared to men. If a woman is at heightened risk for Alzheimer’s because she carries an ApoE4 gene, or has other risk factors, the perimenopausal period is a vulnerable time. This is when structural changes in the brain begin.

• Estrogen is neuroprotective. While the studies about HRT and Alzheimer’s protection are messy, the basic science is more clear. Estrogen protects the brain in many ways. A woman’s most powerful source of this hormone is her ovaries, which should be kept intact for as long as possible. (Tip: if you are facing gynecological surgery, be sure to discuss what will happen to your ovaries with your surgeon.)

• ApoE4 carriers: taking HRT early in perimenopause has unique brain health benefits.  Approach this time of life proactively. Gather a health care team to see if HRT is right for you.

• It’s too early to prescribe HRT for all women exclusively for the purpose of brain health. The science is still evolving, and it’s still not overwhelmingly in favor of preventing Alzheimer’s with HRT. That’s why organizations like the North American Menopause Society do not recommend prescribing HRT to prevent Alzheimer’s. Yet. 

• If you take HRT, think of potential brain health benefits as an additional perk. Most women sleep better, think better, and have sharper memories if taking HRT for menopausal symptoms. All of this is beneficial for short- and long-term brain health. 

• Protecting the brain later in life may be one of the important side benefits of taking hormonal contraception (birth control pills) at any time in a woman’s life. Taking birth control pills protects health later in many ways. It reduces the need for surgically removing ovaries (by reducing severity of endometriosis and ovarian cysts). It reduces the risks of ovarian and uterine cancers later in life. And taking the pill has been shown to reduce the risk of developing dementia later in life. Not everyone is a candidate for the pill because they’ve had blood clots, breast cancer, or other situations, but the pill is extremely safe and also brain protective.

If you want to read one scientific article on this topic, I recommend this review article by Drs. Lisa Mosconi, Richard Isaacson, Roberta Brinton, Kellyann Niotis, Steven Jett, and others: Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention. And if you are interested in the basic science research of how estrogen impacts the brain at menopause, check out this one: Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. 

Ciao For Now

All smiles after teaching a class with the amazing Sicilian chef and culinary instructor Alessia.

Today the Brain Health Retreat is headed to the Mt. Etna area in northern Sicily, where some of the best wines in Italy grow in the soil around this active volcano. I’ll be back this weekend with my Sicily Diary to show you more of what we have been doing and learning here. I hope it’s a great week wherever you are. Ciao!

Love,

Annie