Learn how menopause, estrogen can play a role in Alzheimer's disease

Estrogen, a steroidal hormone, which is produced in a woman’s ovaries and adrenal glands, is mostly known for its critical role in promoting female sex characteristics and reproduction. It also acts as a signaling molecule in genes, cells and organs. That's why many health  professionals are studying it now in relation to Alzheimer's disease since it's a critical regulator of metabolism in the female brain.

“I call estrogen the Queen of Darwin,” said Roberta Diaz Brinton, a professor at the University of Southern California’s School of Pharmacy who helped organize the Alliance of Women Alzheimer’s Researchers (AWARE), a professional interest group within the Alzheimer’s Association. She is pursuing clinical trials on a neurosteroid called allopregnanolone that holds promise for regenerating damaged brain tissue.

Brinton thinks the critical moment occurs after menopause, when a women’s estrogen levels drop, triggering a cascading series of effects. Among them is a radical decline in the brain’s ability to burn glucose for energy. Without glucose as a source of fuel, the brain shifts to a backup energy system that burns ketone bodies, which are compounds produced from carbohydrates and fat in the liver.

The backup energy system keeps brain circuits running, but at a cost. It is not as efficient and creates byproducts that ultimately damage brain cells. Brinton said this is the same fuel system seen in Type 2 diabetes, which also is a risk factor for Alzheimer’s.

“It’s kind of like burning rubber tires instead of propane,” said Suzanne Craft, a professor of gerontology and geriatric medicine at Wake Forest University’s School of Medicine and a founder of AWARE whose research concerns the way problems with metabolism can damage the brain. “You’ll get heat, but you’ll get a lot of toxic byproducts as well,” she said.

Estrogen has been of interest to Alzheimer’s researchers. Initially, many scientists suspected that because of its anti-inflammatory effects and other properties, estrogen might benefit brain health. Research also has found that the risks of dementia rise for women whose ovaries were removed.

But then the Women’s Health Initiative, a 15-year clinical trial involving tens of thousands of women, was stopped midway after researchers discovered that administering synthetic estrogen, along with progestin, increased the risk of breast cancer, heart disease and other circulatory disorders in postmenopausal women. The same clinical trial also found that older women — ages 65 to 79 — who received estrogen-only hormone therapy ran a higher risk of developing dementia, including Alzheimer’s.

Craft and others said those unexpected results temporarily derailed interest in the effect of hormones on the brain — an outcome that perhaps was exacerbated by human bias.

“I think the movement away from more understanding of hormones in the brain may arguably be partly due to the disproportionate number of men in higher echelons of Alzheimer’s research,” Craft said.

In recent years, however, the search for a possible link between estrogen and Alzheimer’s has received renewed attention.

In one recent study, written by Natalie L. Rasgon, director of the Stanford Center for Neuroscience in Women’s Health, researchers found that administering the hormone estradiol soon after menopause appeared to prevent deterioration in key areas of the brains of women at risk of dementia. Yet the same study found that combining estradiol with progestin canceled the estradiol benefit and accelerated deterioration. Premarin, an older form of estrogen therapy mixed with substances derived from mares and used by women in the Women’s Health Initiative, also appeared to accelerate deterioration.

Earlier this year, Rocca reported on several studies that suggest that the timing of hormone therapy is critically important to brain health. A 2012 study by Peter P. Zandi, a researcher at Johns Hopkins University’s Bloomberg School of Public Health, also found that the timing of estrogen therapy appeared to play a significant role in reducing the risk of Alzheimer’s.

Women who underwent estrogen replacement within five years of menopause seemed to reduce their chances of developing Alzheimer’s, while those who used estrogen more than five years later had no reduced risk. Women who used estrogen alone or with progestin late in life increased their risks of dementia, the study found.

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