AUTHOR=Jiang Shan , Tang Ling , Zhao Na , Yang Wanling , Qiu Yu , Chen Hong-Zhuan 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=8

YEAR=2016

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2016.00171

DOI=10.3389/fnagi.2016.00171

ISSN=1663-4365

ABSTRACT=<p><italic>APOE</italic> ε4 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 <italic>APOE</italic> ε4 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 <italic>APOE</italic> ε4 stratification. Two specific modules were identified in AD <italic>APOE</italic> ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD <italic>APOE</italic> ε4 carriers were <italic>ISOC1, ENO3, GDF10, GNB3, XPO4</italic>, <italic>ACLY</italic> and <italic>MATN2</italic>. The other module of AD <italic>APOE</italic> ε4 carriers consisted of 10 hub genes including <italic>ANO3, ARPP21, HPCA, RASD2, PCP4</italic> and <italic>ADORA2A</italic>. The module of AD <italic>APOE</italic> ε4 non-carriers consisted of 16 hub genes including <italic>DUSP5, TNFRSF18, ZNF331, DNAJB5</italic> and <italic>RIN1</italic>. The module of AD <italic>APOE</italic> ε4 carriers including <italic>ISOC1</italic> and <italic>ENO3</italic> and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the <italic>ISOC1</italic> and <italic>ENO3</italic> module of carriers was shown to be correlated in a time-dependent manner under <italic>APOE</italic> ε4 treatment but not under <italic>APOE</italic> ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers’ module was correlated under <italic>APOE</italic> ε3 treatment but not under <italic>APOE</italic> ε4 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 <italic>ISOC1</italic> and <italic>ENO3</italic> 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 <italic>APOE</italic> ε4 carriers involves more genetic factors and particular biological processes, whereas AD in <italic>APOE</italic> ε4 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 <italic>APOE</italic> ε4 carriers and non-carriers in AD.</p>