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.
“This has important therapeutic implications,” said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. “The compound we used in this study has side effects that make it unsuitable for use in people. But if you could develop a therapy that reduces cholesteryl esters inside brain cells without unacceptable side effects, it would be a promising candidate to test in neurodegenerative diseases.”
The findings are published Nov. 22 in the journal Neuron.
The link between cholesterol and dementia is not as far-fetched as it might seem. 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.