Are Women the Key to Unlocking Alzheimer's?

By Brenda Goodman, MA
WebMD Health News

Reviewed by Michael W. Smith, MD

Feb. 25, 2016 -- Alzheimer's disease hit the Schafferman siblings hard. Audrey was the first. She was diagnosed at age 65, about 3 years before her younger brother Gene. Audrey died in 2007. Gene would follow 5 years later.

Gene's daughter, Donna Shore, recalls that the disease looked a lot different in her father than it did in her aunt.

"It seemed like Aunt Audrey went a lot faster than my father did," says Shore, 58, of Littlestown, PA. She took care of Gene. He was so spry and vibrant that he was able to continue his favorite hobby -- dancing -- until just a year before his death. The nursing home staff called him "Gene, Gene, the Dancing Machine."

Shore is especially grateful that her dad never forgot who she was, calling her by her nickname, Sparky, right up until his death.

Audrey's loss, by contrast, seemed crueler. The unfailingly kind and loving mother and grandmother became paranoid. She accused her daughters of stealing her glasses and her social security checks -- when she could remember who her children were.

"I would have to go to the bathroom and cry, because I wasn't used to my mother talking to me that way," says Robin Broyles, 62, of Baltimore, MD.

When Audrey began sneaking out of the house and started confusing a closet for the bathroom, the family made the wrenching decision to put her in a nursing home. She died 18 months later.

Though the experience of the disease is highly individual, researchers think what happened in the Schafferman family may be part of a larger pattern, one that puts women in the epicenter of the Alzheimer's epidemic.

Studies show that by age 65, women have about twice the risk of getting the condition. About 1 in 6 women will get Alzheimer's after age 65, compared to about 1 in 11 men. About two-thirds of people in the U.S. with the disease are women.

Not only are women more likely to get Alzheimer's than men, but recent studies suggest the disease does its work more swiftly in women, causing them to decline faster -- and farther -- than men do, at least in the beginning.

Alzheimer's in Women: What's the Risk?

It's long been thought that the main reason for women's increased risk was age. Women simply live longer than men do, and Alzheimer's is a disease of aging. The longer you live, the more likely you are to get it.

But researchers say age alone doesn't entirely explain the extra risk.

In a recent study, researchers at Duke University looked back at the medical histories -- documented by written tests and brain scans -- of almost 400 women and men enrolled in a long-running study of brain function. All the study participants were showing early changes in memory and thinking that often, but not always, progress to Alzheimer's disease.

What the researchers found was striking. Women with early memory changes declined about twice as fast as men did, and they ended up worse off, too.

"Our findings suggest that men and women at risk for Alzheimer's may be having two very different experiences," says Katherine Lin, a senior at Duke and lead researcher of the study.

Lin says it's possible there's something unique to women's biology or life experiences that makes them more vulnerable to the disease than men.

"Uncovering those factors should be a high priority for future research," she says.

The Alzheimer's Association, a national nonprofit advocacy group, agrees.

In May 2015, the association launched the Women's Alzheimer's Research Initiative, or WARI, which will focus on funding studies to tease out what those as-yet-unknown risks may be.

They plan to announce the first round of study grants this spring. It won't be an easy task, as they have to pick just six to eight projects out of more than 120 applications from 17 countries. Each project will get $250,000 in research funding.

"It's not just that women are living to be older. There's something else going on in terms of the biology, the environment, for women compared to men that may make them at greater risk, or if they have some symptoms, change the progression," says Kristine Yaffe, MD, a professor of psychiatry, neurology and epidemiology at the University of California, San Francisco.

Roberta Diaz Brinton, PhD, is a neuroscientist at the University of Southern California and a leading voice for studying the disease in women. She finds it puzzling that most Alzheimer's research has been gender-blind, when women are in the majority of people with the disease.

"With AIDS, the AIDS research community did not look across the entire spectrum of everyone who was having sexual intercourse," Brinton says. Instead, researchers focused on gay men having unprotected sex. "Focus on the people who have the biology," she says.

New Clues in Women

One of the biggest risk factors for Alzheimer's disease -- in men or women -- is a gene that carries instructions for a protein called apolipoprotein E, which ferries cholesterol and beta-amyloid in and out of cells. Beta-amyloid are sticky fragments of proteins that build up in the brains of people who have Alzheimer's disease.

QUESTION

One of the first symptoms of Alzheimer's disease is __________________. See Answer

Inheriting just one copy of the APOE4 gene results in a two to four times greater risk of Alzheimer's disease. Inheriting two copies raises the risk nearly 15 times.

That higher risk doesn't appear to be shared equally by men and women. A 2014 study of more than 8,000 people found that APOE4 had a stronger effect in women. For healthy men, having one copy of the gene only slightly increased the risk of memory problems compared to other men. For women, a single copy nearly doubled their risk of the brain changes and eventual Alzheimer's compared to other women.

Other studies have questioned whether lifestyle factors and experiences particular to women may be playing a role. Women are more likely than men to get depression, which increases the risk for Alzheimer's disease.

Education, it turns out, has a powerful connection with brain health. The more education a person has, the lower their risk for getting Alzheimer's, leading researchers to wonder whether knowledge and learning may build the brain up, almost like a muscle, making it harder for the disease to wear it away. Historically, women haven't been as well-educated as men.

Exercise protects the brain from Alzheimer's, and studies have shown that at least in the past, women haven't been as physically active over the course of their lives as men are.

Even surgery is riskier for women.

A little confusion can be normal after general anesthesia, and most people recover from the experience with no lasting problems. But some people never quite recover, and older adults are known to be particularly vulnerable to long-term effects after surgery.

Researchers at Oregon Health & Science University found that men and women who'd been put to sleep for surgery did worse on tests of thinking and memory compared to similar adults who didn't have surgery. But the declines were bigger and more rapid for women. Women also had more brain shrinkage on MRI scans after anesthesia than men did.

The more procedures a person had, the bigger the brain problems after surgery. And it didn't seem to matter what anesthesia drug doctors used.

Hormones: Help or Harm?

Another major puzzle about Alzheimer's has been the role of hormones, and whether hormone replacement therapy hurts or helps a woman's memory as she ages.

Estrogen plays a large role in brain health. It boosts levels of a chemical that helps nerve cells talk to each other.

It also plays a role in how the brain uses the sugar glucose, its main fuel.

During the period just before menopause, when estrogen levels naturally start to fall, many women complain of problems with foggy thinking and scattered attention.

So doctors wondered whether giving hormones back to women might keep their memory sharp.

But in a large, government-funded study, use of estrogen and progesterone after menopause was found to increase the risk for Alzheimer's and other kinds of dementia. In taking a closer look at the results, though, researchers saw that most of the women in the study were getting hormones when they were well past menopause, long after the body had stopped making them naturally.

That made doctors wonder if giving the hormones closer to the time when the body had stopped making them naturally, around age 50 instead of 65, might make a difference, an idea called "the timing hypothesis."

Several studies have now checked out that theory and come up empty.

"I'm pretty confident that the data suggest no effect. No evidence of benefit or harm. If a woman is thinking about hormone therapy for whatever reason, there are a lot of things to consider in that decision, but whether or not it's going to make someone a little smarter or a little duller, I don't think there's much of an effect there," says Victor Henderson, MD, a professor of health research and policy and neurology at Stanford.

But researchers haven't given up on the hope that estrogen might help protect some women's brains.

"Now, I think, the question has become more refined over time. Is there even a subset of individuals we should focus on in the critical-window period, and if so, who would that subset be?" says Sarah Janicki, MD, a neurologist at Columbia University.

Personalized medicine may make it possible. Janicki led a study that looked at the genes that tell the body how to make estrogen receptors. Estrogen receptors are docking sites on cells all over the body -- including cells in the brain -- that recognize and respond to estrogen. She found that four gene changes to those receptors were linked to a nearly doubled risk of getting Alzheimer's.

She says figuring out why could help target women who might benefit or be harmed from hormone therapy. And because men also have estrogen receptors on their brain cells, her research could eventually help them, too.

Menopause isn't the only time in a woman's life when her brain goes through big changes. Pregnancy also has an impact.

During pregnancy, a woman's brain and her baby's get bombarded with a chemical called allopregnanolone, a brain hormone. It spurs the growth of the baby's new brain cells and protects them from harm. In Mom, researchers think it may reduce stress.

In mice bred to have a model of Alzheimer's disease, allopregnanolone sparked the growth of new brain cells and bulked up the brain's white matter -- the connections that help brain cells communicate. It also reduced the amount of beta-amyloid -- those sticky protein pieces -- that clog the brains of Alzheimer's patients. And it reversed the memory and thinking changes linked to the disease, so that Alzheimer's mice treated with allopregnanolone performed the same on memory and thinking tests as normal mice.

It's important to note that mice aren't people. Drugs that look promising in animals often do little or nothing for humans.

But Brinton thinks allopregnanolone has promise. She's testing the drug in people to determine the best dose and to try to get some clues about which patients could benefit from the medication. She won't know if it helps their memory or thinking for 2 to 3 more years, she says.

Another drug that has shown promise, at least for some patients, is leuprolide, or Lupron. It's already FDA-approved to treat endometriosis and shrink uterine fibroids.

In one study of more than 100 women with Alzheimer's, those who took a weekly injection of the drug, along with the Alzheimer's medication Aricept, saw almost no changes in their memory over the course of a year compared to women who took Aricept alone.

Lupron helps lower levels of follicle-stimulating hormone and luteinizing hormone, chemical signals that surge during menopause and stay high.

Craig Atwood, PhD, an associate professor of geriatrics at the University of Wisconsin School of Medicine, says the treatment helps the brain because it brings haywire hormones back into balance.

Atwood says they are looking at whether the elevated hormones are driving Alzheimer's disease. Suppressing them may prevent women from aging as rapidly.

But he admits that's just a guess. Right now, they really don't understand how the drug might be working or what it might be doing in combination with Aricept.

Atwood and his co-researchers hope to raise more money for a larger clinical trial, one that would test the treatment in men and women.

Families Wait, and Hope

While science churns slowly on, Audrey Schafferman's family is still struggling to cope without her.

When Audrey was 17, she married a man named Dennis Rose. After each child and grandchild was born, Audrey would proudly say, "It looks like the Roses!"

After Audrey's death in 2007, Jaime Stone and some of her other grandchildren formed a team to raise money for research into the disease. They walk under the name Audrey's Little Roses in the annual Walk to End Alzheimer's, sponsored by the Alzheimer's Association.

It's the best way they know to honor the matriarch who took so much with her when she left them.

"We used to be a really, really, really close family. But here in the last couple of years, nobody really wants to get together," Stone says.

Her grandmother, she says, was the glue that held them all together. "It's been difficult."

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References
SOURCES: Donna Shore, Alzheimer's caregiver, Littlestown, PA. Robin Broyles, Alzheimer's caregiver, Baltimore, MD. Katherine Lin, senior, Duke University, Chapel Hill, North Carolina. Roberta Diaz Brinton, PhD, Professor, Pharmacology and Pharmaceutical Sciences, Biomedical Engineering and Neurology, University of Southern California, Los Angeles, CA. Mary Sano, PhD, director, Alzheimer's Disease Research, The Mount Sinai School of Medicine, New York, NY. Kristine Yaffe, MD, professor, departments of psychiatry, neurology and epidemiology, the University of California at Berkeley, Berkeley, CA. Katie Schenning, MD, anesthesiologist, Oregon Health and Science University, Portland, OR.Sarah Janicki, MD, neurologist, Columbia University, New York, N.Y.Craig Atwood, PhD, associate professor, geriatrics, The University of Wisconsin School of Medicine, Madison, WI.Victor Henderson, MD, professor, health research and policy and neurology, Stanford University, Stanford, CA. Jaime Stone, granddaughter, Audrey Schafferman Rose. Annals of Neurology, April 2014. Alzheimer's & Dementia: Translational Research & Clinical Interventions, September 2015. Alzheimer's Association: "2014 Alzheimer's Disease Facts and Figures. "News briefing, Alzheimer's Association International Conference 2015.

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