Researchers have uncovered a molecular pathway in neurons that shines new light on how the biggest genetic risk factor for Alzheimer’s disease may contribute to the disorder. Thomas C. Südhof and colleagues of Stanford University Medical School describe a clear link between apolipoprotein E activity and the production of amyloid-β, the peptide that forms the characteristic plaques that develop in the brains of people with the disease (Cell 2017, DOI: 10.1016/j.cell.2016.12.044). The gene that codes for apolipoprotein E comes in three forms, each with different probabilities for developing Alzheimer’s: People with ApoE2 have a lower risk, those with ApoE3 have an average risk, and people with ApoE4 have a greatly increased risk. By using neurons derived from human embryonic stem cells to eliminate noise from other cells and molecules found in the brain, the researchers found that ApoE proteins bind receptors on the neuron surface and activate an “unusual” signaling pathway. The final step of the pathway turns on transcription of the amyloid-β precursor gene, with ApoE4 proteins causing the highest amyloid-β levels and ApoE2 proteins the lowest, “paralleling their relative effects on Alzheimer’s disease risk,” Südhof says. Jungsu Kim of the Mayo Clinic calls the details of the unexpected pathway “exciting,” adding that it “may provide a new therapeutic target” for Alzheimer’s.