Our work shows that even in a relative circumscribed and limited part of Alzheimer’s disease pathogenesis, i.e., the formation of amyloid plaques and the microglia response to it, the different isoforms of APOE act in diverse and unanticipated ways, affecting amyloid plaques, Aβ soluble aggregates, but also the cellular reactions of microglia and astrocytes. The gene discussed is APOE; the disease is Alzheimer disease.