Plasma metabolomic profiles of aged, humanized APOE mice and behavioral correlates

Background Apolipoprotein E (APOE) plays a critical metabolic role by facilitating the binding of lipid complexes to cell surface receptors, providing tissues with energy substrates. The APOE‐ε4 (APOE4) polymorphism is the predominant genetic risk factor for late‐onset Alzheimer’s Disease (LOAD), while APOE3 is considered risk‐neutral. Female biological sex also nearly doubles LOAD risk. This study utilizes the JAX humanized APOE knock‐in mouse model to investigate the contributions of chromosomal sex and APOE genotype to plasma metabolic profiles, along with potential correlates to cognitive performance in a novel objection recognition (NOR) task. Method Male and female mice aged 23‐25 months old (37M/32F) with humanized APOE3/3, APOE3/4, and APOE4/4 genotypes underwent blood plasma extraction and subsequent metabolic profiling via mass spectrometry using the Biocrates MxP® Quant 500 platform. A subset of animals (34M/28F) additionally performed an NOR paradigm prior to metabolic profiling. Two‐way ANOVA and post‐hoc t‐tests were utilized to determine data significance. Result Metabolomic analyses indicated that male mice exhibited relatively higher levels of glucogenic amino acids, including glycine, asparagine, and histidine. In contrast, female mice had higher levels of TMAO and ADMA along with lower levels of phosphatidylcholines, cholesteryl esters (CE), and triglycerides. In males, APOE3/4 and APOE4/4 genotypes were associated with lowered CE levels. APOE3/4 female mice had the lowest CE plasma concentrations. Female APOE4/4 mice had increased concentrations of several diglyceride and triglyceride species, relative to APOE3/3 and APOE3/4 female mice. Behavioral correlates indicated that triglyceride levels negatively correlated with locomotion throughout the NOR paradigm. Memory performance, as determined by the discrimination index, positively correlated with plasma concentrations of glycine and negatively correlated with hydroxy acylcarnitine levels. Conclusion In mice aged to resemble a ∼70‐year‐old human population, these results suggest that biological sex affects peripheral metabolic profiles greater than APOE genotype. Male metabolism was characterized by elevated glucogenic amino acid levels; female metabolic profiles demonstrated increased TMAO and lower phosphatidylcholines and triglycerides, suggesting differences in lipid metabolism. APOE3/4 genotype was associated with lowered CE in both sexes while APOE4/4 females had higher triglyceri