A team of researchers from USC has unlocked the details of a cellular pathway that triggers cellular inflammation and aging and is linked to Alzheimer’s disease, particularly among those who carry the APOE4 genetic risk. They have also found a way to return cells to a healthy state, revealing a new potential approach to treatment. Past research found that a shortage of HDL cholesterol in the brain raises a person’s risk for Alzheimer’s disease. That risk is related to problems with ABCA1, which produces HDL when working properly. To discover what is going wrong with ABCA1 and how it increases risk, scientists used a range of methods to pinpoint the processes unfolding inside brain cells. They found that in brains of people affected by Alzheimer’s disease or who carried the APOE4 gene putting them at higher risk for the disease, ABCA1 increased, but became trapped in a part of the cell that typically clears waste. That change was linked to a rise in a modified form of cholesterol known as oxysterol. Lowering oxysterol, in both animal models and human stem cells, freed the trapped ABCA1 and restored the pathway to its healthy state. Lowering oxysterol could be a new way to prevent or treat Alzheimer’s disease in its earliest stages.