Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling. It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them. Apolipoprotein E polymorphism, combined with environmental stresses and/or age-related alterations, influences the risk of developing late-onset Alzheimer’s disease. In this review, we discuss our current knowledge of how apolipoprotein E homeostasis, i.e. its synthesis, secretion, degradation, and lipidation, is affected in Alzheimer’s disease.