Comparison of the ApoE allelic variants in the formation of intracerebral Aβ deposits.

The Apolipoprotein E (APOE) isoforms APOE2, APOE3 and APOE4 differentially modulate risk of Alzheimer's disease (AD). Despite established evidence for APOE's impact on Aβ deposition, the differential effects of APOE genotypes on distinct forms of amyloid pathology remain poorly understood. The three primary types of amyloid pathology in the brain are dense-cored fibrillar plaques, diffuse Aβ deposits, and vascular deposits in the form of cerebral amyloid angiopathy (CAA) and their relative distribution is thought to be important in determining the phenotypic outcomes in AD and related dementias. Here, we used different mouse models of AD-amyloidosis to ask two main questions: (1) does human APOE4 promote the deposition of all these subtypes of types of amyloid pathology, and (2) does presence of APOE4 influence the morphological transformation of diffuse Aβ deposits into dense-core neuritic plaques? In the SAA-APP knock-in model of dense-cored Aβ deposits resulting from accumulation of protofibrillar-favoring Aβ42, we observed that crossing in human Apoe reduced amyloid burden. Among the three human APOE alleles, APOE4 produced the highest plaque burden and size, relative to APOE3 and APOE2 in the SAA-APP mice. Though all three human APOE isoforms showed comparable levels of colocalization with individual plaques, focused genomic analysis at early stages of pathology revealed that neural connectivity pathways were affected in mice with human APOE4 compared to human APOE3, implicating mechanisms of early neuronal dysfunction. In the slowly-developing APPsi model, characterized by predominantly diffuse Aβ deposits and cerebral amyloid angiopathy (CAA) emerging at older ages, we also found that mouse Apoe showed the greatest amyloid burden, followed by human APOE4 and APOE3. CAA deposition was noted in aged APPsi mice with mouse Apoe or human APOE4 mice but rarely in APPsi mice with human APOE3. Finally, neonatal Aβ seeding in APPsi mice revealed that APOE4 accelerated parenchymal Aβ deposition compared to APOE3 mice, though seeding in the presence of APOE4 did not alter the inherent diffuse morphology of the Aβ deposits. Collectively, these results demonstrate that APOE genotype influences the deposition of all types of amyloid pathology, including dense-cored, diffuse and vascular pathology. Notably, only the amount of amyloid was modified by APOE variants, while the type of amyloid pathology inherent in each model was not altered. Together these findings implicate a key role for apoE as a modifier of all types of Aβ deposition with limited potential to modify plaque compaction or morphology.