Frontiers in aging neuroscience · 2026
APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation.
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Wang Tian, Shang Yuan, McLean John W, Yin Fei, Brinton Roberta Diaz
Аннотация
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.
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.