Title: O5-03-01: Apolipoprotein E Genotype Differentially Modulates Effects of ANTI-AB Immunotherapy
Abstract: APOE genotype is the foremost genetic risk factor for sporadic Alzheimer’s disease (AD) and influences the load of β-amyloid (Aβ) deposition in the brain. To investigate how APOE genotype modulates response to anti-Aβ immunotherapy we administered 10D5 anti-Aβ monoclonal antibody (mAb) to APPSW/PS1dE9 (APP) AD model mice with targeted replacement (TR) of the murine Apoe gene for various human APOE alleles. APP/APOE-TR mice received 10D5 mAb or TY11-15 isotypal control IgG between the age of 12 and 15 months. In vivo μMRI was used to monitor Amyloid Related Imaging Abnormalities (ARIA) in APP/ε4 mice undergoing the treatment. Postmortem evaluation included assessment of parenchymal Aβ plaque load, microglia response, vascular Aβ deposition, and perivascular hemosiderin deposits reflecting ensued microhemorrhages. Occurrence of new microhemorrhages (ARIA-H) was infrequently detected by μMRI in APP/ε4 mice undergoing 10D5 mAb treatment and we found no evidence of “vasogenic edema” (ARIA-E). Although relative reduction in the parenchymal Aβ plaque load in response to 10D5 mAb immunization was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute values of Aβ plaque load, given their highest baseline. 10D5 mAb promoted microglia activation, which in APP/ε4 mice was the most robust and out of proportion to the post-treatment Aβ plaque load suggesting defective Aβ phagocytosis associated with the ε4 allele. Perivascular hemosiderin deposits were associated with vascular Aβ deposition and were ubiquitous in control mice of all APOE genotypes although in APP/ε3 mice their incidence was significantly lower than that in APP/ε2 and APP/ε4 mice. 10D5 mAb but not TY11-15 treatment effected significant reduction in the load of vascular Aβ deposition but increased the occurrence of perivascular hemosiderin deposits across all APOE genotypes with the most robust and the weakest effects seen in APP/ε2 and APP/ε3 mice, respectively. APOE genotype differentially affect microglia activation and Aβ plaque load reduction resulting from anti-Aβ passive immunization. The APOE ε3 allele shows strong protective effect against vasculotropic complications of anti-Aβ immunization, while conversely the APOE ε2 allele is associated with significantly increased risk of cerebral microhemorrhages.