Omic Data Mining And Drug Target Finding Of Alzheimer’s Disease Based On APOE ε4 Status

Alzheimer’s Disease (AD) is one of the most leading causes of dementia among people aged 65 and older with distinctive genetic etiology. AD is characterized by cognitive decline with distinctive brain pathology such as amyloid plaques (Abeta) and neurofibrillary tangles (Tau). Etiology of the most common form of non-familial late-onset AD (LOAD) appears to be more complicated. Although many genetic loci have been identified to be risk factors of LOAD through genome-wide association studies (GWAS), only APOE ε4 has been generally accepted as a risk factor in LOAD. LOAD patients carrying or non-carrying APOE ε4 show many clinico-pathological distinctions. Moreover, the drug responses in APOE ε4 carriers and non-carriers are different. Thus, the integrated analysis and precision medicine for LOAD are indispensible. The emergence of omic data and databases for LOAD provides opportunity for unraveling LOAD on systematical level and mining new drug targets.We utilized GWAS, genetics, systems pharmacology, statistics, graph theory to analyze the databases of AD and molecular biological technologies for verification (1) to construct differential coexpression and protein-protein interaction networks and explore the differences between the two subtypes of LOAD patients based on APOE ε4 status, and (2) to illuminate the genetic and gene expression distinctions and (3) to find the specific drug targets between LOAD APOE ε4 carriers and non-carriers and a potential APOE s4-specific siRNA drug.The results included that:①distinctive genetic differences between LOAD APOE ε4 carriers and non-carriers were found with specific susceptible loci rs6816078 and haplotype block rs28604990-rs7955747 of LOAD APOE ε4 non-carriers were associated with CSF biomarkers (Abeta and Tau).②Specific coexpression modules (violet and darkmagenta modules of carriers and lightcyan module of non-carriers) within LOAD APOE ε4 carriers and non-carriers were identified through Weighted Gene Coexpression Network Analysis (WGCNA). Modules of LOAD APOE ε4 carriers contained strong genetic basis. These specific modules (violet, darkmagenta and lightcyan) consisted of different potential LOAD-associated drug targets. ③ Many distinctive susceptible genes were identified between APOE ε4 carriers and non-carriers. Hub gene FYN and CAMK2A/2B of LOAD APOE ε4 carriers were influenced by APOE ε4, and FYN siRNA could reverse APOE ε4 toxicity on neuron.This study systematically showed the genetic and gene expression differences and also the different potential drug targets between LOAD APOE ε4 carriers and non-carrier. The above findings provided insight into the stratification and systems pharmacology for LOAD.