BACKGROUND: Combination treatments based on pharmacological interactions at α7 nicotinic acetylcholine receptors (nAChR) are promising therapeutic approaches for neurocognitive disorders. METHODS: Here, we tested the cognitive efficacy of combinations of memantine with an α7 nAChR-selective agonist (PHA-543613) in naturally aged rats. Age-related changes in the expression of some key genes and proteins were also measured using quantitative PCR and ELISA. RESULTS: Aged rats showed marked cognitive decline in the novel object recognition test, and they also exhibited cholinergic changes such as mRNA upregulation of α7 nAChRs. Upregulation of interleukin-1β, MIP-1α, CX3CL1, ICAM-1 and CNTF mRNA were also detected in aged rats. Combination treatment of memantine and PHA-543613 successfully alleviated the age-related decline of recognition memory of rats by exceeding the effects of the corresponding monotreatments. CONCLUSIONS: Results indicate a positive interaction between memantine and PHA-543613, which also reflects a putative role of α7 nAChRs in the cognitive enhancer effects of memantine. These findings may facilitate the development of combination therapies for age-related neurocognitive disorders.