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New perspective needed for role of major Alzheimer's gene
Date:5/7/2013

d how the harmful forms of APOE increase risk of the disease.

"APOE is a major player in Alzheimer's, there's no question about that," said Philip Verghese, PhD, a postdoctoral research associate. "We did some additional studies in mice and cell cultures that suggested the APOE protein may be blocking a pathway that normally helps degrade amyloid beta."

APOE is involved in the metabolism of fats, cholesterol and vitamins throughout the body. Scientists have identified three different forms of the gene that each make a slightly different version of the protein.

One version, APOE 2, produces a protein that significantly reduces Alzheimer's risk. Another, APOE 4, increases risk. Each person has two copies of the gene, and if both copies are APOE 4, the chance of developing Alzheimer's rises dramatically.

"About 60 percent of the patients we see in the Alzheimer's clinics have at least one copy of APOE 4," Holtzman said. "In contrast, only about 25 percent of cognitively normal 70-year-olds have a copy of APOE 4."

Verghese tested cerebrospinal fluid samples from people who had either two copies of APOE 4 or two copies of APOE 3, another form of the gene that is not associated with increased Alzheimer's risk.

"We also found that APOE 2, the protective form of the protein, doesn't bind to amyloid beta in body fluids," Verghese said.

In follow-up studies, Verghese showed that APOE and amyloid beta "compete" to bind to a receptor on support cells in the brain known as astrocytes.

"Studies by other researchers have shown that astrocytes can degrade amyloid beta," Verghese said. "The receptor we identified may be important for getting amyloid beta into the astrocyte so it can be broken down. It's possible that when the harmful forms of APOE bind to the receptor, this reduces the opportunities for amyloid to be degraded."

The researchers are planning follow-up studies of the effects of APOE-bl
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Contact: Michael C. Purdy
purdym@wustl.edu
314-286-0122
Washington University School of Medicine
Source:Eurekalert

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