Integration of transcriptomic and genomic data provide insight into the molecular mechanism of ApoE4-mediated pathogenic action.

Genetic factors such as the presence of the apolipoproteine e4 (APOE4) allele strongly increases an individual's risk for developing late-onset Alzheimer’s disease. Despite decades of research and thousands of studies, the pathogenic role of ApoE4 in Alzheimer’s disease has not been clearly elucidated. In order to clarify the role of APOE4 in the pathogenesis of Alzheimer’s disease, a systems biology approach was applied to transcriptomic and genomic data of APOE44 carriers affected by Alzheimer’s disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in ageing-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by ageing.
Integration of genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carries with Alzheimer’s disease. Interestingly, also PSEN1 and APP, genes mutated in the early onset AD, are closely linked to this pathway. Thus, in conclusion, ApoE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of AD.

Fig.1. Schematic representation of the network analysis workflow. The molecular biomarker associated to ApoE44-AD was extracted from transcriptomic data of post-mortem cerebral cortices of AD affected individuals carrying the APOE33 or APOE44 alleles. Network analysis was then performed using Netwalker technique with the reference protein-protein interaction (PPI) network derived from HPRD data. The functionality of the network was then performed by testing over-represented Gene Ontology biological process terms and pathways. Genomic data analysis was then performed with the analysis of genes in the network displaying a genetic interaction with APOE.

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Fig. 3: Flow diagram representing the molecular interactions in the Notch pathway (modified from KEGG database). The Notch pathway is enriched with the network proteins, labeled in orange (panel A). In panel B, the sub-network of the genes belonging to the Notch pathway and their interaction with the epistasis genes.