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ObjectiveEvidence supports the important role of neuroinflammation in some types of dementia. This study aimed to evaluate the effect of epistasis of gene cytokines such as interleukin (IL)-α, IL-6, tumor necrosis factor (TNFα), and interferon-gamma (IFN-γ) on the susceptibility to the development of dementia.Materials and methodsIn the study, 221 patients diagnosed with dementia and 710 controls were included. The multifactor-dimensionality reduction (MDR) analysis was performed to identify the epistasis between SNP located in genes of IL-α (rs1800587), IL-6 (rs1800796), TNFα (rs361525 and rs1800629), and IFNγ (rs2069705). The best risk prediction model was identified based on precision and cross-validation consistency.ResultsMultifactor-dimensionality reduction analysis detected a significant model with the genes TNFα, IFNγ, IL1α, and IL6 (prediction success: 72%, p < 0.0001). When risk factors were analyzed with these polymorphisms, the model achieved a similar prediction for dementia as the genes-only model.ConclusionThese data indicate that gene–gene interactions form significant models to identify populations susceptible to dementia.