HLA is a potent immunoinflammatory target in asymptomatic Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease, neuroinflammation is an early pathological feature of AD. However, the alteration of the immune microenvironment in asymptomatic AD was not fully explained. In this study, we aimed to utilize the transcriptome data of AD patients in public databases to reveal the change of immune microenvironment in asymptomatic AD and screen the potential anti-AD drug. Through a series of bioinformatics analyses, differentially expressed genes (DEGs) screening, enrichment analysis, PPI network construction, and hub gene identification were done. Meanwhile, the hub genes were validated in APP/PS-1(AD) mice. Importantly, seven enrichment pathways and eight hub genes associated with inflammation were identified in asymptomatic AD. Early AD patients presented infiltration of immunoinflammatory cells to varying degrees in the four representative brain regions. Correspondingly, more hub genes changed in the hippocampus in AD mice compared to the other four brain regions. Accompanied by the activation of microglia and astrocytes, the inflammation cytokines were increased in the hippocampus of AD mice. Moreover, HLA-C was correlated with the activation of microglia, HLA-DRB1 with IL-6 and OAS2 with TGF-β1 in the hippocampus. Five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone and Pradaxa) were predicted as the common drug-targeted HLA-C and HLA-DRB1 by molecular docking. Taken together, the changes in the immune microenvironment of asymptomatic AD, and provided a new perspective for the development of anti-inflammatory drugs for AD early treatment.