APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation

Introduction – Disruption of brain glucose and lipid metabolism contributes to Alzheimer’s disease (AD) and often emerges before clinical symptoms. Women are at increased AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women’s risk of AD is further exacerbated by the APOE4 allele, the strongest genetic risk factor for late-onset AD. Methods – To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages from pre- to postmenopause. Results – APOE3/3 mice exhibited dynamic regulation of metabolic systems that supported postmenopausal brain bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice exhibited accelerated and compromised metabolic adaptation, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and compromised brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits. Discussion – Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.