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Common genetic Alzheimer's risk factor disrupts healthy older women's brain function, but not men's

For every two men diagnosed with Alzheimer's there are three women who have it. The primary risk factor for Alzheimer's is, of course, old age - and it's true that women tend to live longer than men. But even after correcting for this longevity difference, the ratio of female to male Alzheimer's patients remains skewed toward women.

A just-published Journal of Neuroscience study led by Stanford's Mike Greicius, MD, may go a long way toward explaining why that's the case. Greicius's team, which included researchers from Stanford and the University of California-San Francisco, is the first to demonstrate a gender difference in brain function in healthy older people who carry at least one copy of ApoE4, a common gene variant known for predisposing people to Alzheimer's disease. (Both men and women who inherit two copies - one from each parent - of ApoE4 are at extremely high risk for Alzheimer's.)

Specifically, the team used an advanced brain-imaging technique to show that in older female - but not male - ApoE4 carriers with apparently normal cognitive skills for their age, a particular constellation of diverse brain regions that ordinarily operate in synch was showing signs of deteriorating synchronization. The same signs, in fact, that Greicius and colleagues had observed in Alzheimer's patients in an earlier study.

To confirm the new findings, which I describe in a [[press release]], the team resorted to an independent database that contained records of another set of healthy older subjects' spinal-tap results. Analyzing these records by gender, Greicius and his associates were able to find significant differences in levels of a telltale protein called tau in the cerebrospinal fluid of male versus female ApoE4 carriers. High levels of tau are an indication of Alzheimer's disease.

Alzheimer's affects about 5 million people in the United States and nearly 30 million worldwide. But that's just the tip of the iceberg, as this insidious disease starts knocking out nerve cells long before the emergence visible symptoms. The more we can find out about its pre-symptomatic development, the more capable we will be of arresting it before it commits violent crimes against memory, thought and emotion.

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