Basic Science and Pathogenesis.

Background: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD), increasing risk from 3-12-fold relative to the common ε3 allele. Seminal studies have revealed that age-related changes in blood-CNS communication regulate cognitive function. More recently, youth-associated blood-borne proteins revitalize the aged brain, improving hippocampal function and increasing adult neurogenesis and dendritic spine plasticity. Characterizing plasma proteomic changes across various systemic contexts may thus be critical for development of novel therapeutic strategies to combat AD. We hypothesized that the plasma proteome differs between APOE4 and APOE3 individuals, and these systemic changes account for differences in brain function according to APOE genotype.

Method: Using an aptamer-based platform to profile the plasma proteome from human APOE4/4 and APOE3/3 subjects, we identified allele-specific changes in protein expression and canonical pathways linked to CNS functions and processes. Next, we examined the plasma proteome in APOE knock-in mice expressing human APOE3 or APOE4 and evaluated those pathways that are conserved across species. To examine molecular processes within the brain regulated by opposing APOE alleles from the systemic environment, we characterized transcriptomic changes in the hippocampi of mice in which blood is shared between APOE4 and APOE3 mice by parabiosis relative to isogenic control pairs.

Result: In both mouse and human subjects, expression of APOE4 is associated with perturbations of plasma proteins related to extracellular matrix (ECM) and inflammation pathways relative to expression of APOE3. Several pathways shown to be associated with APOE3 expression in the hippocampus and disrupted in APOE4-KI hippocampus were found to be restored in APOE4-KI mice exposed to APOE3 blood via parabiosis. Specific deleterious phenotypes were identified in the hippocampi of APOE3 mice exposed to APOE4 blood, suggesting that APOE4-associated brain phenotypes are, in part, mediated by how APOE4 alters the systemic compartment.

Conclusion: We find that APOE alleles differentially alter the systemic environment to confer changes in brain phenotypes. Ongoing experiments focus on investigating the protective impact of the APOE3 systemic environment on molecular processes within the APOE4 hippocampus, which may ultimately inform our understanding of increased AD risk in APOE4 subjects.