How the APOE-E4 Gene May Raise Alzheimer’s Risk

November 13, 2012

People who carry the APOE-E4 gene, the most common known genetic contributor to Alzheimer’s, are at increased risk of developing the disease, though having the gene is no guarantee that you’ll get Alzheimer’s. Now scientists are uncovering new clues about how the gene may contribute to Alzheimer’s risk, work that may lead to new approaches to treating the illness.

APOE genes help the body process cholesterol, and people can inherit one of three main forms of the gene from their parents. APOE-E4 is the one that raises Alzheimer’s risk, though it’s important to note that it doesn’t cause the disease. (APOE-E2, the least common form, appears to protect against Alzheimer’s; whereas APOE-E3, the most common form, appears to have no effect on dementia risk.) Carrying one copy of the APOE-E4 gene raises Alzheimer’s risk by two- to three-fold. Carrying two copies of the gene raises the risk by up to 10-fold or more.

Now, researchers at the University of Rochester in New York and the University of Southern California and other medical centers have uncovered new clues about how APOE-E4 may increase Alzheimer’s risk. Through experiments in mice, they found that the APOE-E4 gene appears to cause the blood vessels that feed the brain to “leak,” allowing toxic substances in the bloodstream to infiltrate the brain.

Normally, the blood vessels in the brain are tightly sealed. The resulting blood-brain barrier allows nutrients to enter the brain, and keeps harmful substances out. But in animals that carried the APOE-E4 variant, the same blood vessels were leaky. This process appears to be mediated by a substance called cyclophilin A, levels of which were greatly increased in animals that carried APOE-E4.

“We are beginning to understand much more about how APOE-E4 may be contributing to Alzheimer’s disease,” said lead author Robert Bell of the University of Rochester. “In the presence of APOE-E4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer’s disease in the same way it does in cardiovascular disease.”

Cyclophilin A appears to trigger an inflammatory reaction that weakens the blood-brain barrier. Increasingly, inflammation is recognized as a contributor to Alzheimer’s disease, heart disease and stroke. The process likely begins years before symptoms like memory loss appear.

The current findings, published in the journal Nature, could lead to new approaches to treating Alzheimer’s disease. Developing new drugs that target cyclophilin A, for example, could help to stem the inflammatory cascade that leads to breakdowns in the brain.

“Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer’s in late-life,” said Suzana Petanceska of the National Institute on Aging, which helped fund the study. “We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer’s.”

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.

Source: Robert D. Bell, Ethan A. Winkler, Itender Singh, et al: “Apolipoprotein E Controls Cerebrovascular Integrity via Cyclophilin A.” Nature Vol. 485: Mayy 16, 2012, pages 512-516.


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