Study on Largest Genetic Risk Factor (APOE4 Variant) for Alzheimer’s Points Toward New Drug Target

If you’re one of the nearly 25 percent of people with the gene variant known as APOE4, you have a higher-than-average chance of developing Alzheimer’s disease. But while scientists have long known that APOE4 leads to changes in the brain that can contribute to dementia, the exact mechanism of that effect has been unclear. Now, scientists at Gladstone Institutes in San Francisco have discovered that APOE4-producing neurons release an immune signaling molecule called HMGB1 at much higher rates than neurons producing other APOE variants. Upon release, HMGB1 activates brain immune cells called microglia, which then trigger inflammation and the degeneration of neurons. As described in their study published on October 19, 2023 in Cell Reports, when the researchers blocked the release of HMGB1 with a mixture of two experimental drugs, mouse models producing APOE4 and other dementia-causing factors showed much less microglial activation and neurodegeneration in the brain. The open-access article is titled “APOE4-Promoted Gliosis and Degeneration in Tauopathy Are Ameliorated by Pharmacological Inhibition of HMGB1 Release.”