Mouse studies have shown that small doses of an HIV drug boost the brain’s ability to clear cholesterol. Now, a Case Western Reserve University team has identified how the drug works, suggesting it could be effective in delaying or preventing Alzheimer’s disease in humans.

Scientists from the National Institute of Standards of Technology found that the approved HIV drug efavirenz binds to an enzyme, CYP46A1, that breaks down 80% of cholesterol in the brain, according to a statement. A Case Western team carried out follow-on experiments to examine why a low dose of the drug revved up the enzyme’s activity, while higher doses inhibited it.

In low doses, efavirenz molecules bind to a site on the enzyme, spurring cholesterol breakdown at other sites on the enzyme’s surface. But at higher doses, drug molecules start to compete with cholesterol molecules for sites where cholesterol usually attaches, blocking its ability to process cholesterol at all.

The researchers tapped a team from the Institute for Bioscience and Biotechnology Research, who used HDX mass spectroscopy to study how the enzyme changes its shape when alone, with cholesterol, with efavirenz and with cholesterol and efavirenz. They found the exact site where the drug latches onto the enzyme as well as how the cholesterol-binding site changed in response. The changes caused by the drug allowed the enzyme to bind cholesterol molecules more tightly than it could without the drug.

In mouse studies, the drug increased cholesterol breakdown in and removal from the brain by 40%. The effect is likely to be more marked in humans, because the enzyme plays a larger part in clearing cholesterol in the human brain, said Irina Pikuleva, who led the Case Western team. The evidence “strongly” suggests that efavirenz might be an effective therapy for improving cholesterol removal from the brain and delaying or preventing Alzheimer’s disease, she said. And it can do it at doses a hundred times lower than those used to treat HIV. Her team is seeking funding to bring the drug into clinical trials.