ApoE isoforms establish distinct antioxidant trajectories across the aging brain

ApoE4-linked aging in young humanized ApoE4 mice shows reduced antioxidant protein abundance and oxidized phospholipid reduction early, yet increased lipid peroxidation products with age despite antioxidant remodeling.

• Why it matters: APOE ε4 is a major genetic risk factor for late-onset Alzheimer’s, but how ApoE isoforms shape antioxidant physiology before detectable oxidative damage is unclear.
• What they did: The study tracked antioxidant regulation across the ancestral-to-derived ApoE4→ApoE3→ApoE2 sequence in humanized mice, ApoE4 cells exposed to sulforaphane, and cognitively normal human brain regions using protein, lipid, and transcriptomic analyses.
• The result: Antioxidant transcription shifts from an ApoE4 bias in youth toward ApoE2 with age, and adult APOE4-to-APOE2 switching redirects astrocyte and microglia expression, linking age-dependent antioxidant adaptation to neurodegenerative vulnerability.

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