APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). LOAD patients carrying or not carrying APOE4 manifest distinct clinico-pathological characteristics. APOE4 has been shown to play a critical role in the pathogenesis of AD by affecting various aspects of pathological processes. However, the pathogenesis involved in LOAD not-carrying APOE4 remains elusive.We aimed to identify the associated genes involved in LOAD not-carrying APOE4.An integrated genomic analysis of datasets of genome-wide association study, genome-wide expression profiling and genome-wide linkage scan and protein-protein interaction network construction were applied to identify associated gene clusters in APOE4 non-carriers. The role of one of hub gene of an APOE4 non-carrier-associated gene cluster in tau phosphorylation was studied by knockdown and western blot.We identified 12 gene clusters associated with AD APOE4 non-carriers. The hub genes associated with AD in these clusters were MAPK8, POU2F1, XRCC1, PRKCG, EXOC6, VAMP4, SIRT1, MME, NOS1, ABCA1 and LDLR. The associated genes for APOE4 non-carriers were enriched in hereditary disorder, neurological disease and psychological disorders. Moreover, knockdown of PRKCG to reduce the expression of protein kinase Cγ isoform enhanced tau phosphorylation at Thr181 and Thr231 and the expression of glycogen synthase kinase 3β and cyclin-dependent kinase 5 in the presence of APOE3 but not APOE4.The study provides new insight into the mechanism of distinct pathogenesis of LOAD not carrying APOE4 and prompts the functional exploration of identified genes based on APOE genotypes.