Alzheimer’s Hope

From an Unexpected Source

What is good for your heart is also good for your brain—at least when it comes to some medications. Scientists at Case Western Reserve University have found that drugs developed to treat the hardening of arteries, or atherosclerosis, have the unexpected ability to clear the telltale protein deposits found in patients with Alzheimer’s disease. This action could slow disease progression and even reverse its course.

Gary Landreth, director of the Alzheimer’s Research Laboratory at Case Western Reserve, first got the idea to test the drugs six years ago. While having dinner with a colleague, he learned that certain proteins called LXRs (short for liver X receptors) could reduce inflammation. “This was an unusual activity for these molecules,” recalls Landreth. LXRs were only known to boost levels of high density lipoprotein (HDL), or “good” cholesterol, in the blood.

Because inflammation in the brain has long been thought to play a role in Alzheimer’s disease, Landreth decided to treat animals with a similar disease with an LXR agonist—a drug that activates LXRs. Several companies had already developed LXR agonists as a possible treatment for atherosclerosis. As Landreth had anticipated, giving the LXR agonist to mice improved symptoms of Alzheimer’s. But, what he had not expected was that this effect was not simply due to reduced inflammation. “We spent the next five years trying to figure out what this drug was doing,” he says.

The effort paid off.

His group discovered that the LXR agonist stimulated production of a protein called apolipoprotein E (ApoE), which is a component of HDL and a prime suspect in Alzheimer’s disease. In humans, there are three different versions of the ApoE gene; for some reason, people with one of these versions, ApoE4, have a higher risk of developing Alzheimer’s.

In a recent publication in the journal Neuron, Landreth showed that when more ApoE-containing HDL is produced, it mops up the protein deposits in a brain affected by Alzheimer’s. “This is a completely unexpected action of ApoE,” says Landreth. Most researchers believe that reduction or removal of the brain deposits would result in improved memory and learning in patients.

Drug companies are now busy developing new LXR agonists with fewer side effects. Landreth is testing these new drugs in mice and, depending on the results, hopes to soon move to studies in human patients. “If it works in mice it should work in humans and our data provide proof of principle for the potential therapeutic utility of these drugs in Alzheimer’s disease,” he says