Denali-WashU team clears Alzheimer’s plaques in mice by targeting a faulty APOE gene

Alzheimer’s researchers have long understood that a buildup of the beta-amyloid protein in the brain causes the formation of plaques, which in turn leads to the debilitating symptoms of the disease. But efforts to target those plaques with drugs have failed so far.

Now, researchers at Washington University School of Medicine believe they’ve found a more effective way to clear amyloid plaques: by targeting the gene APOE, variants of which are known to raise the risk of Alzheimer’s.

Although amyloid is the main component of brain plaques that form in the disease, small amounts of the APOE protein that the gene produces are also present. And targeting the APOE protein with an antibody clears a significant amount of plaques in mouse models of Alzheimer’s, the scientists found.

Using mice with human APOE genes, the team tested several antibodies that were designed to target the protein. They developed the antibodies in conjunction with Denali Therapeutics, a South San Francisco company that’s building an Alzheimer’s pipeline. They gave the mice either a placebo or an antibody in weekly injections for six weeks, measuring their brain plaques along the way.

One of the antibodies, called HAE-4, lessened the plaque load by half, the researchers reported in the Journal of Clinical Investigation.

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What’s more, the antibody only affected APOE levels in the brain—not in the bloodstream. That’s important because APOE helps the body process fat and cholesterol, so removing it would create unwanted off-target effects.

"It turns out that the APOE in the plaques has a different structure than the form of APOE found in the blood," said senior author David Holtzman, M.D., head of the department of neurology at Washington University, in a statement. "The HAE-4 antibody recognized only the form found attached to the plaques in the brain."

Antibodies targeting amyloid have been disappointing in clinical trials so far. Biogen’s and Eisai’s anti-amyloid beta drug BAN2401 is the most recent under-performer, with the companies announcing in December that 12-month data from a phase 2 trial didn’t look promising. The companies will make a decision about whether to proceed to phase 3 after looking at the 18-month results.

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Another concern with anti-amyloid antibodies is that they could cause brain inflammation. Washington University’s Holzman is optimistic that an antibody targeting APOE will have fewer side effects because there is so little of the protein in amyloid plaques that the drug wouldn’t bind to them quite so tightly.

"This means we may find less immune activation, and we might not see the unwelcome side effects," he said.

The next step for the research team is to test similar antibodies and to design further trials to determine whether they’re safe in people.