Age, Sex, and APOE4: Insights into Metabolic Changes in a Novel Mouse Model of Late-Onset Alzheimer’s Disease

Abstract

Late-onset Alzheimer’s Disease (LOAD) is a progressive and irreversible neurodegenerative disease characterized by memory loss, cognitive decline, and brain atrophy. Age, chromosomal sex, and apolipoprotein E (APOE) genotype are well-documented risk factors for the development of AD, each having a systemic impact and significant implications for disease progression. Understanding the interactions among these risk factors is essential to elucidate the underlying mechanisms of disease development. Prior to clinical onset, LOAD is preceded by a decades-long prodromal phase. Previous studies have suggested that metabolic dysregulation during midlife aligns with this prodromal period. We hypothesize that age, APOE genotype, and chromosomal sex interact to drive AD risk through mechanisms that extend beyond traditional amyloid and tau pathology, involving systemic metabolic dysregulation. Specifically, we propose that these factors shape sex- and genotype-specific metabolic profiles, with female APOE4 carriers exhibiting metabolic dysregulation, and earlier than their male counterparts. To test this hypothesis, we utilized a novel mouse model combining humanized amyloid precursor protein (hAPP) and apolipoprotein E (hAPOE) to investigate sex- and genotype effects on metabolic profiles, evaluating energy metabolism and circulating lipids. Our findings revealed significant sex-driven differences, with females demonstrating earlier metabolic changes. Female hAPP+hAPOE4 mice exhibited disrupted glucose and lipid metabolism, and lower circulating cholesterol. This study provides a novel investigation into the effects of age, sex, and APOE genotype in a LOAD risk mouse model. By utilizing a preclinical model expressing humanized APOE and APP without dominant, disease-causing mutations, we examined the nuanced effects of APOE4 metabolic regulation across aging in a potentially more translational context. Furthermore, this work emphasizes sex-driven metabolic changes, providing additional insight into the increased vulnerability to LOAD in females.