Alzheimer's disease (AD) is the most widespread late-life dementia and involves the prefrontal cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. To understand the molecular differences between the effects of aging and AD on the prefrontal cortex, this study characterized the age-dependent changes in gene expression in Wistar rats (control) and OXYS rats (rodents that simulate key characteristics of sporadic AD) using RNA sequencing. We found that major altered biological processes during aging in Wistar rats were associated with immune processes. Gene expression changes during development of AD-like pathology as well as at the preclinical stage were related to neuronal plasticity, catalytic activity, lipid and immune processes, and mitochondria. A comparison of genes between data sets "OXYS rats" and "human AD" revealed similarity in expression alterations of genes related primarily to mitochondrial function; immune, endocrine, and circulatory systems; signal transduction; neuronal and synaptic processes; hypoxia; and apoptosis. Expression changes in mitochondrial processes identified in OXYS rats by RNA sequencing were confirmed by ultrastructural neuronal organelle alterations and low activity of respiratory chain complexes I, IV, and V in cortical mitochondria, suggesting that mitochondrial dysfunction appears to mediate or possibly even initiate the development of AD.