Objective To determine the transcriptomic profile of AD mice and controls by RNA?Seq, in order to identify differentially expressed genes and reveal the molecular mechanism of AD. Methods Nine?month?old APP/ PS1 mice and age?matched wild?type C57BL/6 J mice were selected, with five female mice included in each group. Genome?wide analysis of mRNA expression in the prefrontal cortex of AD mice and controls was performed by RNA?Seq. qRT?PCR was used to verify the six key genes. Then, cluster analysis, Gene Ontology (GO) function enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to analyze gene function. Results The result showed that a total of 224 genes were differentially expressed in the two groups ( P < 0. 05, |logFC| > 1. 0): 205 genes were upregulated and 19 genes were downregulated. When qRT?PCR was used to validate the six key genes, the result were consistent with the RNA?Seq. GO enrichment analysis result showed that the differentially expressed genes are involved in immune response, inflammatory response, chemokine activity, and IgG binding. KEGG pathway enrichment analysis revealed that these genes participate in phagosome, lysosome, toll?like receptor signaling pathway, cytokine?cytokine receptor interactions, and the NF?κB signaling pathway. Conclusions Differentially expressed genes related to AD were obtained, which provides an important experimental basis for the usage of a double?transgenic mouse model to study AD?related mechanisms and pharmacological intervention.