Alzheimer’s disease (AD) is the most common neurodegenerative disease. It produces atrophic changes in the brain which cause dementia. The incidence of AD is increasing with life expectancy and the gradual aging of the population in the developed countries. There are no effective prophylactic interventions because of the insufficient understanding of the AD pathogenesis and the absence of adequate experimental models. Recently, we showed that the senescence-accelerated OXYS rats represent a promising model of AD; in these rats, accelerated aging of the brain is accompanied by the typical signs of AD: degenerative alterations and death of neurons, a decrease in synaptic density, mitochondrial dysfunction, hyperphosphorylation of the tau protein, an increased level of amyloid β (Aβ1–42), and the formation of amyloid plaques. To elucidate how these signs develop, we used a next-generation RNA sequencing technique (RNA-Seq) to study the prefrontal-cortex transcriptome of OXYS rats during the manifestation of AD signs (at the age of 5 months) and during their active progression (at the age of 18 months), using age-matched Wistar rats (parental strain) as controls. At the age of 5 months, there were significant differences between OXYS and Wistar rats (p 2000 genes at the age of 18 months) in the prefrontal cortex. Most of these genes were related to neuronal plasticity, protein phosphorylation, Са2+ homeostasis, hypoxia, immune processes, and apoptosis. Between the ages of 5 and 18 months, there were changes in the expression of 499 genes in Wistar rats and changes in the expression of 5500 genes in OXYS rats. Only 333 genes were common between these sets. This finding points to differences in the mechanisms and rates of agerelated changes in the brain between normal aging and the period of development of AD-specific neurodegenerative processes.