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Longevity Genes May Protect against Alzheimer’s

Drugs that mimic the molecular effect are under development.
January 13, 2010

A genetic variation previously linked to longevity may also protect against the development of Alzheimer’s disease and other types of dementia, according to a new study. The variant affects cholesterol metabolism, boosting levels of high density lipoprotein (HDL), also known as “good” cholesterol, but it’s not yet clear how it could promote healthy aging in the brain. The new findings are likely to heighten interest in finding ways to chemically enhance good cholesterol–experimental drugs that mimic the molecular effects of the genetic variant are already in clinical tests for heart disease.

Protecting the brain: Alzheimer’s disease is characterized by the buildup of protein plaques, shown here, in the brain. A genetic variation that boosts levels of “good” cholesterol appears to protect against the disease.

In a previous study of Ashkenazi Jews, researchers at Albert Einstein College of Medicine, in New York, found that a specific variation in a gene that codes for a protein called cholesteryl ester transfer protein (CETP) is more common in very long-lived people. Those older people who carried it also tended to have better cognitive function. (Ashkenazi Jews are often studied in genetic research because they originate from a relatively small founder population and possess less genetic complexity than other groups, making it easier to identify meaningful genetic targets.)

The new research, conducted by the same group on a more diverse sampling of people, found that those with two copies of the protective variant had a 70 percent lower chance of developing Alzheimer’s and other dementias, as well as a significantly lower rate of memory decline. “That’s a huge reduction,” says Richard Lipton, senior author of the study. “I’m not aware of other genetic factors that have that effect.” The research was published today in the Journal of the American Medical Association.

“It’s a striking reduction in the incidence of Alzheimer’s disease and dementia that they observe,” says Benjamin Wolozin, a neurologist at Boston University’s Alzheimer’s Disease Center, who was not directly involved in the research. “I think there is increasing evidence that factors that protect the cardiovascular system also protect against dementia.” Still, he cautions that other studies examining the same gene have had mixed results, so the findings are not yet conclusive.

The new findings are part of the Einstein Aging Study, an ongoing examination of a diverse group of people age 70 and older living in the Bronx. All were free of dementia when they enrolled in the study. Participants undergo regular cognitive testing, as well as annual medical and neurologic exams.

The frequency of the protective CETP variant in the general population is not well known. But Lipton says that his team’s previous studies have found that about 5 percent of 60-year-olds had it, and approximately 25 percent of centenarians–those age 100 or older. “It’s one of the more robust longevity genes we have identified,” says Lipton. The Einstein researchers are now trying to replicate the findings in another group. They also hope to find other genetic variants that protect against Alzheimer’s disease.

People with the protective variant produce a less active version of CETP protein, which in turn raises levels of HDL, or good cholesterol. HDL plays an important role in the membranes of nerve cells in the brain, but it’s not yet clear what role the genetic variation plays in the brain. “It may also cause particle sizes of certain lipoproteins in blood to be larger,” says Amy Sanders, a physician at Einstein and lead author of the paper. “But exactly how that helps isn’t known.”

“My speculation is that it helps get blood into the brain,” says Wolozin. “We do know that reduction in blood flow is one of the earliest changes in dementia, and anything that preserves blood flow to the brain is helpful.”

The findings support the link between cholesterol levels and dementia. Another genetic factor previously linked to Alzheimer’s risk, a gene called Apolipoprotein E (APOE), also affects cholesterol metabolism; a variant known as APOE4 substantially increases the risk of developing Alzheimer’s, while a much rarer version called APOE2 reduces the risk.

Pharmaceutical companies are already developing drugs, called CETP inhibitors, that mimic the effect of the protective variant in hopes of preventing heart disease. (Raising HDL has long been thought to protect the heart, though that link has yet to be conclusively proven.) The first CETP inhibitor to be tested in humans–a highly hyped drug from Pfizer called torcetrapibturned out to be a multibillion-dollar failure. Rather than helping heart health, it appeared to increase blood pressure, and testing was halted in 2006.

Scientists have since determined that the negative effects were likely due to the molecule itself rather than its method of action. A handful of other CETP inhibitors are now in clinical trials, including compounds from Roche (dalcetrapib) and Merck (anacetrapib). Both appear to raise good cholesterol without increasing blood pressure, though their long-term safety and effectiveness in preventing heart disease is not yet clear.

“Ultimately, I think people who are developing these drugs to raise HDL may end up adding cognitive measures to their studies to see if there is a protective effect on cognition,” says Lipton. Previous research on mice that were engineered to mimic Alzheimer’s found that CETP inhibitors provided modest protection against the disease.

Anders Olsson, a physician and researcher at the University of Linkoping, in Sweden, is testing Roche’s CETP inhibitor in people with heart disease. He says that these patients probably aren’t the best subjects to tests cognitive function. “But this type of finding suggests these end points should be included,” he says.

While there are a number of drugs available to treat Alzheimer’s disease, none are approved to prevent the onset of the disease. “But given that there are four million Americans with Alzheimer’s and the number is likely to skyrocket as the population ages, there is a huge societal and public health need to develop agents that will prevent the disease,” says Lipton.

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