Sex and the single gene

What if you carry the strongest genetic risk factor for Alzheimer’s?

At age 65, a woman’s chances of incurring Alzheimer’s disease are one in six: nearly twice that of a man’s estimated one in 11 likelihood. New studies of the strongest known genetic risk factor for Alzheimer’s — a gene called ApoE4 — provide insight into why women are more at risk and hints for a solution.

In general, people carrying a copy of ApoE4 are at a heightened risk — about two- to four-fold — of developing Alzheimer’s. Those with two gene copies encoding ApoE4 (one inherited from dad, one from mom) are at 10-fold risk and are likely to start showing symptoms earlier in life than most others.

But there’s obviously more to Alzheimer’s than just having that gene version. “An ApoE4 carrier can live to be 90 and still not get Alzheimer’s,” says assistant professor of neurology Mike Greicius, MD, medical director of the Stanford Center for Memory Disorders, and almost half of those diagnosed with Alzheimer’s don’t carry any copies of ApoE4 at all.

In a study published in Annals of Neurology in April, Greicius and his colleagues examined clinical and biochemical data on some 8,000 older people, many of whom showed no initial signs of dementia, and concluded that the increased Alzheimer’s risk conferred upon ApoE4 carriers is much greater in women.

That finding may have clinical ramifications. Another new brain-imaging study led by Natalie Rasgon, MD, PhD, professor of psychiatry and behavioral sciences and director of the Stanford Center for Neuroscience in Women’s Health, followed women who were at heightened Alzheimer’s risk because, for example, they had at least one copy of ApoE4 or a family history of the disease. Rasgon’s study found that those who adopt estrogen-replacement therapy consisting solely of estradiol (the dominant female hormone) shortly after the onset of menopause, when intrinsic estradiol production dives abruptly, suffer substantially less deterioration in key brain areas that, other studies have shown, faithfully predict clinically significant dementia by years and decades.

So is estrogen replacement the way to protect women from Alzheimer’s? It is for some, says Rasgon, but not all.

Estradiol’s effects on the body aren’t entirely benign. For example, she notes, exposure to the hormone raises the risk of breast and uterine cancer. “Perimenopausal women with risk factors for dementia should talk to their doctors about whether estradiol-based hormone therapy makes sense,” she says.

If these results wind up being replicated in a large sample of postmenopausal women not at risk for dementia, estradiol-based hormone therapy could become more broadly a treatment of choice to preserve optimal brain aging, she says.

Bruce Goldman

Bruce Goldman writes for Stanford University School of Medicine on immunology, infectious disease, neurosciences, radiology, cell biology and biochemistry. Although pretty much recovered from an ectopic philosophy degree sustained in adolescence that long plagued all who came near him, he persists in spotting tipping points in conventional wisdom before others do.

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