Effects of APOE Genotype and Sex on the Plasma Lipoprotein Profile of the EFAD Mouse
Authors: Panchapakesan Kailash , Saleh Yaseen , Xiang Bingtao , Valencia‐Olvera Ana Carolina , LaDu Mary Jo , Karstens Aimee 
Published: June 2021

Alzheimer's disease (AD) is the 6th leading cause of death in the United States with no cure, few palliative treatments, and no prognostic biomarker. The lack of a surrogate biomarker that is both reliably prognostic and sensitive to changes over time has limited drug discovery and will be a barrier for targeted treatment of at‐risk populations. The greatest genetic risk factor for AD is APOE4, increasing risk 5‐ to 15‐fold compared to the common APOE3, while APOE2, though rare, reduces risk. Importantly, female APOE4 carriers have a greater lifetime risk and rate of cognitive decline compared male APOE4 carriers. Apolipoprotein E (apoE), encoded by APOE, is a protein component of both plasma lipoproteins and the only apolipoprotein expressed in the brain. In the CNS and periphery apoE helps to regulate cholesterol transport. Typically, blood lipid panels report total lipid levels and lipids levels associated with isolated lipoproteins, specifically VLDL, LDL and HDL, with an emphasis on cholesterol HDL/LDL ratios, with higher being better. In contrast to blood lipid panels, plasma lipoprotein profiles elute intact lipoprotein particles from largest to smallest i.e., Chylomicrons/VLDL, LDL, HDL‐2, HDL‐3, and free proteins that can be further analyzed for lipid/protein content (e.g., cholesterol, apoE). This profile and its lipid content is altered by APOE genotype. The signature of the APOE genotype effect on plasma lipoprotein profiles and the ability to detect shifts (i.e., leftward indicating a worse profile) over time may act as a surrogate blood biomarker for AD. We hypothesize that the plasma lipoprotein profile is a prognostic biomarker for AD, reflecting the AD risk associated with age, APOE4 genotype, and female sex. In the novel EFAD mice (over‐expressing specifically Ab42 via the 5xFAD background) with human APOE knocked‐in (E2FAD, E3FAD, E4FAD), our lab previously showed that the plasma lipoprotein profiles of E4FAD mice exhibit less co‐elution of cholesterol in HDL classes and older mice exhibit increased co‐elution of cholesterol in Chylomicrons/VLDL. The current study will extend this work to include the effect of sex, thus the interaction among age (6‐ and 18‐months), APOE genotype (APOE3 vs. APOE4), and sex (male vs. female) on the plasma lipoprotein profile can be determined. Plasma lipoprotein profiles were quantified using fast protein liquid chromatography and the fractions were further analyzed using cholesterol assays. Female sex appears to exacerbate the separate effects of APOE genotype and sex on the plasma lipoprotein profiles and the co‐elution of cholesterol. In conclusion, this work in combination with future studies in human samples will help establish whether the plasma lipoprotein profile is a surrogate biomarker for cognition in AD.

Support or Funding Information

LaDu lab funding includes the University of Illinois College of Medicine, UIC Honors College Grant, and the University of Illinois at Chicago ADRD Trainee Grant.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.