A study is shedding light on how APOE genetics may shape Alzheimer’s disease inside the brain. Researchers compared human astrocytes carrying APOE3 and APOE4 in chimeric mouse models. They found that APOE genotype can influence not only astrocyte behavior, but also Alzheimer-related pathology and microglial responses. The results point to a more specific disease mechanism in which APOE4-expressing astrocytes alter the local brain environment and reshape microglial responses to Alzheimer’s pathology, highlighting astrocyte-microglia interactions as a potential intervention point in APOE4-associated disease. (https://doi.org/10.1016/j.celrep.2026.117803)