Aspirin is one of the most widely used drugs. Besides providing pain relief, it has been shown to reduce the risk of colon cancer and heart attacks. Some suggest that aspirin might also protect against Alzheimer’s disease because the disease is less common in aspirin users than nonusers. But without proper clinical trials, the link is still uncertain. A new study led by Kalipada Pahan of Rush University Medical Center may provide mechanistic clues that underpin that link (Proc. Natl. Acad. Sci. USA 2018, DOI: 10.1073/pnas.1802021115). Using computer modeling and biochemical experiments, the researchers found that aspirin binds to a receptor called peroxisome proliferator-activated receptor α (PPARα), which is involved in fatty acid metabolism. When PPARα is activated by aspirin binding, it triggers a cascade of signaling events that lead to increased connections between nerve cells in the hippocampus, a brain region key for memory formation. In mice that are genetically engineered to have Alzheimer’s-like symptoms, a low dose of aspirin improved the animals’ spatial learning via PPARα signaling, the team reports. Pahan says the ultimate goal is to test whether low doses of aspirin could prevent Alzheimer’s disease in clinical trials.