Women and Alzheimer's: Brain Health News Update 2021 Part 1, The Estrogen Hypothesis
Written by Annie Fenn, M.D.
Pop quiz: What are the two most common risk factors for Alzheimer’s? Is it lack of exercise and poor diet? What about smoking and a genetic predisposition? Or, lack of sleep? While these all contribute to Alzheimer’s risk, being female and aging are the two most common predictors. In fact, it has been known for decades that women are more likely to develop Alzheimer’s than men. Two thirds of Alzheimer’s patients are women.
Could this just be due to that fact that women live longer than men? It’s true, women do outlive men by a slight margin, giving the disease more time to develop. However, the lifespan gap between men and women is narrowing to just a few years, and no longer accounts for the discrepancy in case numbers.
Researchers are looking for reasons why women are more vulnerable to this neurodegenerative disease through myriad approaches, including the biological differences between women’s and men’s brains. Why, for example, do men and women seem to be on different timelines of brain aging? As it turns out, women’s brains metabolize glucose differently than men’s, which becomes glaringly apparent during the menopausal transition. Women’s brains also attract different pathological proteins that can create an inflammatory, dementia-provoking state. Finally, women and men respond differently to carrying the Alzheimer’s risk gene Apolipoprotein E4 (ApoE4).
In this 3-part series, I discuss three scientific papers that shed light on the unique vulnerabilities of the female brain and the impact of hormones on the aging brain. The influence of estrogen, in particular, is an intense area of investigation, and I'll explore how it's a key player in the brain in this first article.
The Estrogen Hypothesis
Estrogen is emerging as a neuroprotective hormone.
The first step to understanding the role of gender differences in Alzheimer’s is to dive into the “Estrogen Hypothesis.” This concept centers the female sex hormone as central to healthy brain aging in addition to its role in reproductive health. In the paper Sex and Gender Driven Modifiers of Alzheimer’s: The Role of Estrogenic Control Across Age, Race, Medical and Lifestyle Risks, published by Dr. Lisa Mosconi, Dr. Aneela Rahman, and colleagues in the journal Frontiers in Aging Neuroscience in 2019, estrogen is recognized as a key player in numerous areas of the brain, impacting cognitive function, affect, and behavior.1
As a vital communicating hormone in the brain, estrogen passes into the brain from the bloodstream through the blood brain barrier, where it links up with specific receptors on brain neurons. From there, this connection directly impacts the production of proteins and other bioactive substances that help cells fend off oxidative stress. Estrogen also enhances how many synapses a neuron has, determining how connected it is to other cells.
Estrogen influences how the brain utilizes glucose, its primary source of fuel. When the brain is low on estrogen, the brain can replenish the hormone by using endogenous cholesterol (not the dietary kind, but the type the body makes) as a building block. However, when estrogen levels plummet dramatically, as they do during the menopausal transition, the brain can’t keep up. That’s why researchers consider menopause a time of bioenergetic crisis in the brain. Translation: as estrogen fluctuates, a woman’s brain struggles to have enough energy to meet its demands. Low estrogen triggers classic menopausal symptoms like hot flashes and night sweats, but also cognitive symptoms like short-term memory loss and difficulty retrieving words, what Dr. Roberta Brinton calls “the whatchamacallit syndrome.”
The research suggests that the more years of her life a woman has estrogen reaching her brain, the lower her likelihood of developing Alzheimer’s. Most women produce all the estrogen the brain needs from the time they start menstruating until the time they go through perimenopause. The more years a woman has of these estrogen-producing cycles, the lower her overall risk. Going through natural menopause late (the average age is 51.5 years), for example, bodes well for overall risk. Conversely, early menopause (defined as loss of ovarian function prior to age 40) increases risk. When researchers looked at women who had undergone surgery that induced early menopause (usually removal of the ovaries with or without the removal of the uterus), they were more likely to be diagnosed with Alzheimer’s, especially if they didn’t receive hormone replacement therapy.
The Take-Away for Brain Health
The Estrogen Hypothesis maintains that estrogen plays a protective role in the brain, working to help fend off Alzheimer’s dementia. When a woman experiences periods of reduced estrogen, like during menopause, this triggers or exacerbates the process of developing Alzheimer’s.
- Rahman, A., Jackson, H., Hristov, H., Isaacson, R.S., Saif, N., Shetty, T., Etingin, O., Henchcliffe, C., Brinton, R.D., and Mosconi, L. Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks. Front. Aging Neurosci., 2019, 11, 1–22.