Women's risk of Alzheimer's disease and cognitive decline linked to gene sequence

SAN DIEGO—Women who have a particular gene sequence are
at a higher risk of developing cognitive impairment and
Alzheimer’s disease, according to a study from researchers
at UCSF and the Veterans Affairs Medical Center (SFVAMC).

These inherited sequences, which create small differences
in the receptor that binds estrogen, were linked with
increased risk of Alzheimer’s or of declining performance
on tests of cognitive function over several years, said
lead author Kristine Yaffe, MD, chief of geriatric psychiatry
at SFVAMC, and UCSF assistant professor of psychiatry,
neurology and epidemiology.

“In this study of older women, there wasn’t that big a
difference in the initial cognitive scores.  But over time,
the women with these certain sequences had much more cognitive
impairment.  And they also had a much higher risk of being
diagnosed with Alzheimer’s disease,” she said.

The study conducted by Yaffe and her colleagues at UCSF and
Axys Pharmaceuticals, was presented here at the Society for
Neuroscience Annual Meeting today, November 14.

The researchers focused on two regions of the estrogen receptor
gene that vary greatly from person to person.  These gene regions,
generally known as polymorphisms, had previously been linked to
risks of osteoporosis, endometriosis and breast cancer, Yaffe said.

The study, which followed more than 2,800 women over roughly
seven years, found that women with the high risk polymorphism
were about 30 to 40 percent more likely to either suffer a major
decline in test scores, or be diagnosed with Alzheimer’s disease.

So far, there’s no clear explanation for how these very small
differences in the estrogen receptor gene actually influence
the fate of women’s brains, Yaffe said.  A few studies suggest
that the polymorphisms may change the function of the receptor. 
“We really need more research in this area,” she said.

The estrogen receptor gene is only one of many that are likely
to influence the risk of Alzheimer’s disease, Yaffe said.  “We
know about several genes that are linked to Alzheimer’s or appear
to be, but it’s estimated that we have only found about 50 percent
of these genetic risk factors,” she said.

Previous studies have shown that estrogen and its receptors play
a major role in women’s brains.  “We know there are estrogen
receptors throughout the brain, particularly in the areas involved
in learning and memory,” Yaffe said. Also, estrogen therapy after
menopause appears to protect women from cognitive decline, she said.

Yaffe’s co-author’s on the study included: Li-Yung Lui, MS, and
Katie Stone, PhD, researchers in UCSF’s department of epidemiology
and biostatistics; Deborah Grady, MD, professor and vice chair of
epidemiology and biostatistics at UCSF, and a physician at SFVAMC;
and Philip Morin, PhD, at Axys Pharmaceuticals in La Jolla, Calif.

The study was supported by grants from the National
Institutes of Health.