Excerpts:

At a Glance

Researchers found evidence that the Alzheimer’s-related gene APOE4 disrupts cholesterol management in the brain and weakens insulation around nerve fibers.

A drug that affects cholesterol led to improved learning and memory in mice with the gene, pointing to a potential new approach for treating dementia in Alzheimer’s disease.

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To build on these findings, the team conducted a multi-pronged study that assessed gene activity of all major cell types in post-mortem human brain tissue from 32 men and women who had one, two, or no copies of the APOE4 gene. Results were published in Nature on November 24, 2022.

The researchers found that APOE4 affected gene expression across all measured cell types. The team then took a closer look at genes related to cholesterol and other lipids. Cholesterol-manufacturing genes were overly expressed, and cholesterol-transporting genes dysregulated, in brain cells called oligodendrocytes with the APOE4 gene. Oligodendrocytes are found in the brain and spinal cord. They make and maintain a fatty substance called myelin that surrounds and insulates long nerve fibers. The abnormalities were more extreme in oligodendrocytes with two copies of APOE4 rather than one.

To better understand how APOE4 affects oligodendrocytes, the scientists created laboratory cultures of the cells with and without the APOE4 gene. Oligodendrocytes with APOE4 tended to accumulate abnormal amounts of cholesterol within their cells, rather than using it to make healthy myelin sheaths around nerve fibers. When the scientists examined post-mortem human brains, they noted that myelin sheaths tended to be fewer and thinner in brains that carried the APOE4 gene.

The scientists next used model systems to test whether APOE4-related abnormalities might be reversed via drugs that affect cholesterol processing. They found that a drug called cyclodextrin, which promotes cholesterol transport, reduced cholesterol buildup and improved myelin sheath formation in cultured oligodendrocytes. It did the same in mice with two copies of APOE4. The mice also performed slightly better in learning and memory tasks after treatment with the drug.