Adenosine suppresses immune responses through the A(2A) receptor (A(2A)R). This study investigated the interleukin 10 (IL-10) genetic profile and the expression of A(2A)R in peripheral blood mononuclear cells (PBMCs) of patients with mild cognitive impairment (MCI), Alzheimer disease (AD), and age-matched controls to verify, if they may help distinguish different forms of cognitive decline. We analyzed the IL-10 genotype and the expression of A(2A)R in 41 subjects with AD, 10 with amnestic MCI (a-MCI), 49 with multiple cognitive domain MCI (mcd-MCI), and 46 controls. There was a significant linear increase in A(2A)R mRNA levels and A(2A)R density from mcd-MCI to a-MCI, with intermediate levels being found in AD. The IL-10 AA genotype frequency was 67% in a-MCI, 46% in AD, 35% in mcd-MCI, and 20% in controls. These data suggest that the assessment of the IL-10 genotype and the expression of A(2A)R in PBMCs may be a valuable means of differentiating between a-MCI and mcd-MCI.