Mitochondrial dysfunction is one of the key events in the pathogenesis of Alzheimer's disease (AD) that mediates cognitive impairment. In this study, we examined the extent to which the mitochondrial DNA (mtDNA) of APP/PS1 mouse strain is susceptible to damage accumulation and explored the potential relationship between mtDNA integrity and other physiological processes. The gut microbiome is known to largely determine the inflammatory status of the organism. However, although we found no significant differences in the bacterial composition of the gut microbiome at the phylum level between APP/PS1 and C57BL/6 mice strains, we found increased expression of the gene encoding the proinflammatory factor TNFα in the brain. This coincided with a decrease in expression of the transcription factor Nrf2, which is responsible for antioxidant protection of cells. We found decreased expression of genes responsible for glutathione and thioredoxin pathways of H2O2 utilization. In addition, we observed a decrease in the expression of some genes responsible for DNA repair. These processes appear to be the reason for the accumulation of oxidative damage in the mtDNA of the brain, and the damage accumulates predominantly in the cerebellum. Suppression of cerebellar output may facilitate freezing behavior, which we observed using the Barnes test. Freezing in APP/PS1 mice was a main reason for the increased average latency time to find the escape hole compared to C57BL/6 mice. Therefore, mitochondrial dysfunction at the level of changes in transcriptome and mtDNA integrity in some brain compartments may facilitate cognitive dysfunction in APP/PS1 mice.