Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, thus few studies pointed at immune dysfunctions as a contributing factor. We tested this hypothesis in an α-synuclein (αSyn)-based model of PD obtained by the intranigral infusion of human α-synuclein oligomers (H-SynOs). Three months after infusion rats developed mild cognitive deficits sustained by an altered electrophysiological activity in the anterior cingulate cortex (ACC). The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in the same region, in the absence of any evident neuronal loss, supporting the role of neuroinflammation in cognitive decline.Moreover, the transcriptomic analysis of the ACC showed that 51 genes were differentially expressed between vehicle and H-αSynOs treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related to immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Altogether results show that H-αSynOs trigger neuropathological dysregulation on multiple levels in cognition-related areas, providing a pathological substrate for MCI associated with early PD.