According to the findings, the researchers identified an antibody which clears the sticky plaques formed in the brain and also Alzheimer's protein APOE nestled within the plaques to prevent or treat the Alzheimer's disease


The sticky clumps, known as amyloid plaques, are composed primarily of a brain protein called amyloid beta. But nestled within the plaques are small amounts of another Alzheimer's protein: APOE.

"Many people build up amyloid over many years, and the brain just can't get rid of it," said senior author David Holtzman, MD. "By removing plaques, if we start early enough, we may be able to stop the changes to the brain that result in forgetfulness, confusion and cognitive decline."

Variants of the gene APOE are the single most substantial risk factor for Alzheimer's disease. In earlier work, Holtzman and colleagues have shown that a DNA-based compound that targets APOE can lessen the injury caused by amyloid plaques.

But getting rid of the plaques likely would protect the brain better than blunting the plaques' destructiveness. To find out whether the plaques could be removed, researchers focused on antibodies that recognize and bind to APOE.

Once antibodies attach themselves to their APOE target, they attract the attention of roving immune cells, which carry both antibodies and target off to be destroyed. The researchers reasoned that nearby amyloid might be cleared away along with APOE.

The researchers tested several antibodies that recognize human APOE in mice genetically predisposed to develop amyloid plaques. The APOE genes of the mice had been replaced with a human APOE gene.

For six weeks, the mice were given weekly injections of placebo or antibodies against APOE. Then, the researchers measured the number of plaques in their brains. One antibody – called HAE-4 – cut the level of plaques by half.

Moreover, HAE-4 did not affect APOE levels in the blood. APOE plays a vital role in transporting fats and cholesterol in the body, so removing it from the bloodstream could create side effects. The failure of the antibody to lower levels of APOE in the blood was, therefore, a good sign. 

"It turns out that the APOE in the plaques has a different structure than the form of APOE found in the blood," Holtzman said. "The HAE-4 antibody recognized only the form found attached to the plaques in the brain."

No treatment exists to prevent or delay onset – or slow the trajectory – of Alzheimer's disease. But a few antibodies that clear plaques by targeting amyloid beta are being evaluated in clinical trials. While such antibodies are promising, they sometimes come with the side effect of inflammation and swelling in the brain.

"The anti-amyloid antibodies are going to be binding to most of the molecules that are in the plaque, but the anti-APOE antibody would target a very small component of the plaque," Holtzman said. "This means we may find less immune activation, and we might not see the unwelcome side effects."