APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-β42 Levels in Non-Hyperlipidemic Mice

APOE2 lowers Alzheimer’s disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-β peptide (Aβ) (EFAD) to evaluate the effect of APOE2 dosage on Aβ pathology. We found that heterozygous mice do not exhibit hyperlipidemia. Hippocampal but not cortical levels of soluble Aβ₄₂ followed the order E2/2FAD > E2/3FAD≤ E3/3FAD and E2/2FAD > E2/4FAD < E4/4FAD without an effect on insoluble Aβ₄₂. These findings offer initial insights on the impact of APOE2 on Aβ pathology.