Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-Î² (AÎ²) accumulation, extracellular deposition of AÎ² peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of AÎ² in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.