Less cholesterol = Less Alzheimer's


In Alzheimer's disease and related dementias, cognitive decline is driven by the overaccumulation of a normal brain protein known as tau. Wherever tau builds up, nearby brain tissue starts to degenerate and die.

Now, researchers at Washington University School of Medicine in St. Louis have found — in mice — that Alzheimer's-like tau deposits in the brain lead to the accumulation of a form of cholesterol known as cholesteryl esters, and that lowering cholesteryl ester levels helps prevent brain damage and behavioral changes.

The biggest genetic risk factor for Alzheimer's is APOE, a gene involved in activating the brain's immune cells. When such cells are activated in the wrong way or at the wrong time, they can damage brain tissue. But APOE also has another important job in the body: It carries cholesterol and other lipids around in the blood. In this capacity, it plays a role in atherosclerosis.

Investigation revealed that APOE4 is linked to distorted lipid metabolism in the brain.

Therefore, clearing out lipids potentially could reduce brain inflammation and neurodegeneration, he said.

To find out, the investigators used an LXR agonist, a member of an experimental class of drugs that lowers lipid levels in cells. The researchers fed the drug, called GW3965, to tau mice carrying APOE4, starting at 6 months of age.

Mice that had received the drug retained significantly more brain volume than those that had received a placebo. They also had lower levels of tau, fewer inflammatory cells and less inflammation, less loss of synapses in their brains, and were better at building nests.


Washington University School of Medicine