A Systems View of the Differences between APOE ε4 Carriers and Non-carriers in Alzheimer's Disease

APOE epsilon 4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and accounts for 50-65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE epsilon 4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE epsilon 4 stratification. Two specific modules were identified in AD APOE epsilon 4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE epsilon 4 carriers were ISOC1, ENO3, GDF10, GNB3, XP04, ACLY and MATN2. The other module of AD APOE 4 carriers consisted of 10 hub genes including ANO3. ARPP21, HPC4 RASD2, PCP4 and ADORA2A. The module of AD APOE epsilon 4 non carriers consisted of 16 hub genes including DUSP5, TNERSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE epsilon 4 carriers including ISOC1 and ENO3 and the module of of the genes in the cluster of the ISOC1 and EN03 module of carriers was shown to be correlated in a time-dependent manner under APOE epsilon 4 treatment but not under APOE epsilon 3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers' module was correlated under APOE epsilon 3 treatment but not under APOE epsilon 4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson's disease. These data demonstrate that AD in APOE epsilon 4 carriers involves more genetic factors and particular biological processes, whereas AD in APOE epsilon 4 non carriers shares more common pathways with other types of diseases. The study reveals differential genetic bases and pathogenic and pathological processes between carriers and non-carriers, providing new insight into the mechanisms of the differences between APOE epsilon 4 carriers and non-carriers in AD.