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 torcetrapib–turned 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.