Integrated Genomic Analysis Revealed Associated Genes for Alzheimer's Disease in APOE4 Non-Carriers

Background: 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. Objective: We aimed to identify the associated genes involved in LOAD not-carrying APOE4. Methods: 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. Results: 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 C gamma isoform enhanced tau phosphorylation at Thr181 and Thr231 and the expression of glycogen synthase kinase 3 beta and cyclin-dependent kinase 5 in the presence of APOE3 but not APOE4. Conclusion: 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.