Gene Variant Could Lower Alzheimer's Risk

TUESDAY Jan. 12, 2010 -- A gene variant that is good for the heart also appears to be good for the brain, slowing age-related decline in mental function and cutting the odds for Alzheimer's disease, a study indicates.

"If you carry two copies of the favorable form of the gene, it reduces the risk of Alzheimer's disease by 70 percent," explained study lead author Dr. Richard B. Lipton, professor and vice chair of neurology at Albert Einstein College of Medicine in New York City.

Drugs that mimic the activity of the gene variant already are being developed, said Lipton, whose group reported the finding in the Jan. 13 issue of the Journal of the American Medical Association.

A 2003 study by Lipton and his associates identified a variant of the gene for cholesterol ester transfer protein (CETP) -- involved in carrying cholesterol in the bloodstream -- as being associated with a longer life span. "The longer you live, the more common is the favorable variant," Lipton noted. "The incidence is 5 percent at age 50 and 35 percent at age 95."

The new study followed 523 people, all age 70 or older, for four years, testing their mental function and relating it to the variant of the CETP gene they carried.

Participants who carried two copies of the variant gene experienced an age-related decline in mental function that was about half as rapid as people with two normal versions of the gene, the study found.

Individuals with two copies of the favorable CETP variant also had a reduced risk of developing Alzheimer's disease compared to those with two normal versions of the gene, the study found.

Besides its effects on the brain, the favorable CETP gene variant also appears to boost blood levels of HDL ("good") cholesterol, which helps prevent artery-blocking clots from forming.

How does the gene variant work its magic? Lipton put forth two theories.

"We know that it protects against disease in blood vessels," he said. "It lowers the risk of heart attack and stroke, and stroke is a risk factor for cognitive decline. So it protects the brain against atherosclerotic disease.

"The other mechanism is more speculative. It might protect against formation of proteins involved in Alzheimer's disease, such as beta-amyloid," Lipton said. The buildup of beta-amyloid protein plaques within brain tissue has long been a hallmark of Alzheimer's disease.

One expert found the study results intriguing.

"It's a great candidate gene for research on Alzheimer's disease and dementia," said Dr. James Burke, director of the Memory Disorders Clinic at Duke University Medical Center in Durham, N.C.

The benefit probably does not come from improved blood flow to the brain, he said. "I think it's related to lipid-cholesterol transport and metabolism," Burke said. Drugs that raise HDL level in the same way as the variant gene might therefore be useful against Alzheimer's disease, he reasoned.

According to the researchers, the CETP gene variant was first identified in a population of Ashkenazi Jews, descendents of western and central Europeans. The current study was done among an ethnically diverse population of people living in the Bronx who have been followed for 25 years.

It remains a small study that requires verification in broader research, Lipton said. "We have enrolled 600 additional people who we are following and we hope to enroll other groups," he noted.

Most studies of the genetics of Alzheimer's disease have concentrated on genes associated with increased risk, such as the ApoE-a4 gene, which also is involved in cholesterol metabolism, Lipton pointed out. "We hope that by understanding the genetics of the condition we can improve diagnosis or treatment or both," he said.

More information

There's more on Alzheimer's disease at the Alzheimer's Association.

Posted: January 2010


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