APOE4 dual function: beneficial astrocyte anti-inflammatory signaling vs. patho…

APOE4’s beneficial immune function operates through enhanced astrocyte-mediated lipid metabolism and anti-inflammatory signaling, while its AD risk emerges from a microglial-specific gain-of-function that amplifies TREM2-independent lysosomal stress responses, elevates 4-hydroxynonenal (4-HNE) adduct formation, and drives chronic neurotoxic lipid peroxidation during aging. The protective astrocyte effects dominate in acute contexts but decline with age-related metabolic shift, while the pathogenic microglial lipid droplet accumulation becomes progressively more damaging. This cell-type-specific duality explains the apparent paradox: APOE4’s immune benefits reflect its astrocyte-mediated anti-inflammatory capacity, while AD risk stems from microglial lipid dyshomeostasis that overwhelms protective mechanisms and accelerates amyloid-independent neurodegeneration through lipid peroxidation chain reactions.