Background: Inflammation is associated with A beta pathology in Alzheimer's disease (AD) and transgenic AD models. Previously, it has been demonstrated that chronic stimulation of the immune response induces pro-inflammatory cytokines IL-1 beta and TNF-alpha which contribute to neurodegeneration. However, recent evidence has shown that inducing the adaptive immune response reduces A beta pathology and is neuroprotective. Low concentrations of IFN-gamma modulate the adaptive immune response by directing microglia to differentiate to antigen presenting cells. Our objective was to determine if exercise could induce a shift from the immune profile in aged (17-19 months) Tg2576 mice to a response that reduces A beta pathology. Methods: TG (n = 29) and WT (n = 27) mice were divided into sedentary (SED) and exercised (RUN) groups. RUN animals were provided an in-cage running wheel for 3 weeks. Tissue was harvested and hippocampus and cortex dissected out. Quantitative data was analyzed using 2 x 2 ANOVA and student's t-tests. Results: IL-1 beta and TNF-alpha were significantly greater in hippocampi from sedentary Tg2576 (TG(SED)) mice than in wildtype (WT(SED)) (p = 0.04, p = 0.006). Immune response proteins IFN-gamma and MIP-1 alpha are lower in TG(SED) mice than in WT(SED) (p = 0.03, p = 0.07). Following three weeks of voluntary wheel running, IL-1 beta and TNF-alpha decreased to levels indistinguishable from WT. Concurrently, IFN-gamma. and MIP-1 alpha increased in TG(RUN). Increased CD40 and MHCII, markers of antigen presentation, were observed in TG(RUN) animals compared to TG(SED), as well as CD11c staining in and around plaques and vasculature. Additional vascular reactivity observed in TG(RUN) is consistent with an alternative activation immune pathway, involving perivascular macrophages. Significant decreases in soluble A beta(40) (p = 0.01) and soluble fibrillar A beta (p = 0.01) were observed in the exercised transgenic animals. Conclusion: Exercise shifts the immune response from innate to an adaptive or alternative response. This shift in immune response coincides with a decrease in A beta in advanced pathological states.