ApoE isoforms establish distinct antioxidant trajectories across the aging brain

Abstract

APOE {varepsilon}4 is the strongest common genetic risk factor for late-onset Alzheimers disease, but how ApoE isoforms shape physiology before disease remains unclear. Across the ancestral-to-derived ApoE4[->]ApoE3[->]ApoE2 sequence, we examined antioxidant regulation during aging. Young humanized ApoE4 mice had lower antioxidant protein abundance and oxidized phospholipid reduction before detectable oxidative damage, yet accumulated lipid peroxidation products with age despite antioxidant remodeling. ApoE4 cells mounted the strongest antioxidant transcriptional response to sulforaphane but accumulated less protein from targets supporting proteostasis, glutathione synthesis and ferroptosis suppression, alongside altered eIF2 signaling and translation kinetics. Antioxidant transcription shifted from an ApoE4 bias in youth toward ApoE2 with age, and adult APOE4-to-APOE2 switching redirected expression in astrocytes and microglia. Cognitively normal human brains showed regional reductions in nuclear Nrf2 and antioxidant proteins, with transcriptomic analyses supporting context-dependent organization. ApoE isoforms differentially couple stress-responsive transcription to protein output, linking age-dependent antioxidant adaptation to neurodegenerative vulnerability.