Why does the risk of Alzheimer's double or triple in elderly women compared to men? More important, can this decline be prevented or slowed?
Some clinical studies have suggested that menopause may be linked to memory decline, leading scientists to speculate that lower levels of estrogen might be at least partially responsible for turning the brain into a sieve that relentlessly leaks memories.
To address these questions, the center has launched Co-STAR, or Cognition in the Study of Tamoxifen and Raloxifene, stemming from the ongoing STAR trial, a multi-center, five-year study designed to compare the effectiveness of the drugs tamoxifen and raloxifene in preventing breast cancer in 22,000 women at increased risk for the disease.
Tamoxifen and raloxifene belong to a class of compounds known as SERMs (selective estrogen- receptor modulators), initially added to the arsenal of drugs for breast-cancer treatment. SERMs represent an alternative to traditional hormone-replacement therapy. Co-STAR adds a new dimension to the study by determining whether these drugs can slow the process of memory decline in postmenopausal women.
"It's an important area," said Joelle Machia, Co-STAR coordinator for the Clinical Research Division who works with the Puget Sound Oncology Consortium. She began working with women at high risk for breast cancer during her time as coordinator for the Breast Cancer Prevention Trial in 1991.
"Back then, one of the biggest questions with my women was, 'Can I go on hormones?'" she said.
Some of these participants were at a high risk for breast cancer, but the question of cognitive function came up as they considered their options.
Machia said that as a woman weighs her risks and benefits in taking hormones, she often comes to her physician asking, "Am I hurting myself by not taking hormones? Am I going to get Alzheimer's? Am I going to get worse cognitive function because I didn't take them?"
Lower Alzheimer's risk
Such questions stem from recent research suggesting that estrogen may protect the brain against memory decline. The Baltimore Longitudinal Study of Aging, for example, demonstrated a lower risk of developing Alzheimer's disease among women who had received hormone-replacement therapy compared with those who had not. Subsequent studies provided evidence that hormone-replacement therapy might protect against some types of normal, age-related memory decline.
Probing further the effect of estrogen on cognitive function is a Co-STAR neighbor, the Women's Health Initiative. As the largest randomized trial of its kind to date, WHI is anticipated to provide a wealth of data on estrogen's effectiveness in staving off cognitive decline.
Co-STAR purposely mirrors the WHI design to facilitate comparison between SERMs and traditional methods of hormone-replacement therapy on cognitive decline after menopause.
Some evidence suggests the potential for SERMs to lessen cognitive decline. Recently the Multiple Outcomes of Raloxifene Evalulation study showed small beneficial effects of raloxifene on a verbal memory task in the oldest group of women participating. Otherwise, the drug had no effect on cognitive function in women who took the drug compared to those who did not, as assessed by a series of tests used for Alzheimer's patients.
Further, a study published in the April Journal of the National Cancer Institute said tamoxifen may protect the brain from natural and disease-related brain damage. Though promising, the study was too small to draw firm conclusions.
The need for a large, controlled study led to Co-STAR, which is anticipated to offer unprecedented insights into SERM effect on cognitive function in aging women. Whether SERMs will affect cognitive function "is still a vague area," Machia said, "so we need to do the research to find out."
Machia and Melanie Forko, nurse in the Women's Health Initiative of the center's Public Health Sciences Division, have been trained in the Co-STAR protocols and are certified technicians in conducting a battery of cognitive tests.
After two days of training in Co-STAR headquarters in Winston-Salem, N.C., Machia returned to the center to bring the cognitive tests into action.
The first test establishes baseline cognitive function. Machia uses 14 tests of memory, thinking, mood and motor control, asking women to remember lists of words, compare the orientation of shapes and finger-tap a button repeatedly to assess fine motor control.
"Some of these tests are hard," Machia said. "It's such a long test. I practiced on my daughter who's 16, and even she had a hard time with it."
Participants take four more tests annually once they have begun taking medication.
Machia perceives that post-menopausal women involved in STAR are excited about their participation.
"It really is an incredible group, just remarkable - the commitment, the dedication," she said. "Their commitment is strong because they know our commitment to them is huge.
"I think they know that the more we do research the more we open the doors," she said, "so they're motivated in knowing that they're part of it. A lot of them feel as part of a team, this network of people who want to help."
[Danielle Ippolito is a graduate student in the University of Washington Department of Pharmacology.]