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 drug targets. A series of bioinformatics analyses were done, including differentially expressed genes (DEGs) screening, enrichment analysis, PPI network construction, and hub gene identification. Meanwhile, the selected 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. Correspondingly, more hub genes were increased in the hippocampus in AD mice compared to the other four brain regions. Accompanied by the activation of microglia and astrocytes, the inflammatory cytokines were increased in the hippocampus of AD mice. Subsequently, the relationship between HLA-C and inflammation was evaluated in AD mice. HLA-C was correlated with the activation of microglia, and HLA-DRB1 with IL-6 in the hippocampus. Moreover, HLA-C is expressed in the microglia cells and astrocytes. Further, five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone, and Pradaxa) were predicted as the common drug targeting HLA-C and HLA-DRB1 by molecular docking. Taken together, the results revealed 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.