Identification of KIAA0513 and Other Hub Genes Associated With Alzheimer Disease Using Weighted Gene Coexpression Network Analysis

Alzheimer disease (AD) is the most common cause of dementia and creates a significant burden on society. As a result, the investigation of hub genes for the discovery of potential therapeutic targets and candidate biomarkers is warranted. In this study, we used the ComBat method to merge three gene expression datasets of AD from the Gene Expression Omnibus (GEO). During combined analysis, we identified 850 differentially expressed genes (DEGs) from the temporal cortex of AD and cognitively normal (CN) samples. We performed weighted gene coexpression network analysis to build gene coexpression networks incorporating these DEGs to identify key modules and hub genes. We found one module most strongly correlated with AD onset as the key module and 19 hub genes in the key module that were down-regulated in AD brains. According to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, DEGs were mostly enriched in synapse function, and genes in the key module were mostly related to learning and memory. We selected five little-studied genes,AP3B2,GABRD,GPR158,KIAA0513, andMAL2, to validate their expression in AD mouse model by performing quantitative real-time polymerase chain reaction. We found that all of them were down-regulated in cortices of 8-month 5xFAD mice compared to those of wild-type mice. We then further investigated their correlations with beta-secretase activity and A beta 42 levels in AD samples of different Braak stages. We found that all five hub genes had significant negative associations with beta-secretase activity and thatAP3B2andKIAA0513had significant negative associations with A beta 42 levels. We tested the differential expressions of the five hub genes in two AD GEO datasets from the blood and found thatKIAA0513was significantly up-regulated in patients with both mild cognitive impairment (MCI) and AD and was able to differentiate MCI and AD from CN in the two datasets. In conclusion, these five novel vulnerable genes were involved in AD progression, and KIAA0513 was a promising candidate biomarker for early diagnosis of AD.