Among the three ApoE isoforms, ApoE4 is a major risk factor for sporadic AD due to its impact on amyloid beta (Abeta) clearance and plaque formation. Although extensive research has connected ApoE to various AD-related pathologies beyond Abeta, its association with ApoE isoforms remains an area that requires further investigation. This study aimed to elucidate the effects of ApoE isoforms on AD pathology using human ApoE Knock-In (KI) AD mouse models. First, we generated an APPNL-G-F;hApoE (ApoE Double KI) mouse model by crossing human ApoE3 or ApoE4 KI mice with APPNL-G-F KI mice. Additionally, to investigate the association of gamma-secretase and ApoE, we generated APPNL-G-F;PSEN1M146V;hApoE (ApoE Triple KI) models by crossing ApoE Double KI with PSEN1M146V KI mice. Behavioral experiments showed cognitive decline in ApoE4 mice compared to ApoE3 mice, with biochemical analysis indicating increased neuroinflammatory markers and Abeta deposition in the brains of ApoE4 mice, along with elevated plaque volume and microglia association. Next, we conducted RNA sequencing and analyzed DEGs that were either upregulated or downregulated in ApoE4, exploring the genes overall expressed in response to ApoE4 in the context of AD pathology. Conversely, we examined DEGs with contrasting results in both models to investigate the genes influencing the correlation between PSEN1 mutants and ApoE isoforms.In conclusion, this study comprehensively investigated the impact of APOE genotypes on various aspects of AD pathology using a newly developed human ApoE Knock-In AD model. This study provides insight into the multifaceted influence of APOE genotypes on AD pathology.