Investigation Of Alzheimer’s Disease Based On Omics Data Integration And Analysis

Alzheimer’s disease (AD) affects a significant portion of elderly people worldwide. Scientific investigationes on AD have been proved to be important. First, defining the RNA transcriptome in Alzheimer Disease (AD) will help understand the disease mechanisms and provide biomarkers. Though the AD blood transcriptome has been studied, effects of white matter hyperintensities (WMH) were not considered. This study investigated the AD blood transcriptome and accounted for WMH. RNA from whole blood was processed on whole-genome microarrays. A total of 293 probe sets were differentially expressed in AD versus controls,5 of which were significant for WMH status. The 288 AD-specific probe sets classified subjects with 87.5% sensitivity and 90.5% specificity. They represented 188 genes of which 29 have been reported in prior AD blood and 89 in AD brain studies.-Regulated blood genes included MMP9, MME (Neprilysin), TGFb1, CA4, OCLN, ATM, TGM3, IGFR2, NOV, RNF213, BMX, LRRN1, CAMK2G, INSR, CTSD, SORCS1, SORL1, and TANC2. The results demonstrate that RNA expression is altered in AD blood irrespective of WMH status and some genes are shared with AD brain. Second, the brain transcriptome of Alzheimer’s disease (AD) reflects the primary disease mechanism at the gene expression level. However, thousands of genes have been reported to dys-regulated in AD brains in previous studies, and the consistency or discrepancy among these studies has not been thoroughly evaluated. For the aim, we conducted a comprehensive survey on the brain transcriptome datasets for AD and other neurological diseases. We first demonstrated that the frequency of observed genes dys-regulation in AD was highly correlated with their reproducibility of the DEgs dys-regulation in another independent dataset. Due to this observation, we selected one hundred genes with the highest frequency of dys-regulation to understanding the major perturbation of AD brains. The dys-regulation of these genes was validated in another independent datasets studied for AD. We further identified 12 genes with strong correlation between gene expression and disease progression. The relevance of these genes to disease progression was also validated in an independent dataset. Interestingly, we found that there was a transcriptional "cushion" by these 100 genes shown in the less vulnerable visual cortex region, which could be a critical component of the protection mechanism for less vulnerable brain regions to some extent. Third, though web database on genetics research for Alzheimer’s disease have been published online, alzBase is a database focused on gene expression level that provides multiple information supported and annotated genes dysregulation in Alzheimer’s disease user-friendly. It can afford researchers helps in selecting candidate genes for further Alzheimer’s studies, finding vital genes of the disease progress, and understanding disease mechanisms on gene level. The alzBase differs from previous published alzheimer’s databases on several features below:1) To focus on genes dysregulation in Alzheimer’s disease (AD), other than the single nucleotide polymorphisms (SNP) sites which are associated with AD in big scale population.2) Genes dysregulation in AD recorded in alzBase are multi-datasets result supported, and also demonstrated by in situ hybridization experiment to a certain extent.3) A wealth of information is provided to annotate and prove the genes, which includes SNPs, eQTL, several clinic symptoms and chemicals related to the disease.4) The situation of co-pattern and co-expression about the dysregulated genes are also exhibited to help user understand it better. In summary, alzBase provides multiple evidences, more comprehensive and user-friendly information about genes dysregulated in AD and will be beneficial to researchers in selecting candidate genes for further molecular biological mechanism studies on AD and understanding the disease in depth. In this paper, we release the database alzBase that focused on AD study, freely available at http://alz.big.ac.cn/alzBase/, which has its unique characters in comparison with the previous database on AD.