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Background: Current evidence suggests that systemic inflammation promotes Alzheimer's Disease (AD) and recent reports demonstrated that circulating neutrophils migrate into the AD brain inducing neuroinflammation and cognitive deficits in animal models of AD. However, how peripheral immune dysregulation occurs and promotes neuroinflammation and memory decline in AD is still unknown. Even though descriptive reports suggest the involvement of the microbiome in AD, the mechanisms behind AD pathology are not explored. In this context, we aim to better understand the dysregulation of leukocyte subpopulations in AD by addressing the gut‐blood‐brain axis. Method: By taking advantage of the 3xTg‐AD mouse model we addressed peripheral inflammation during early disease stages. To this aim, we performed: 1) an intestinal microbiota analysis; 2) characterization of circulating inflammatory mediators; and 3) immunophenotypization of peripheral blood. Result: In our study we show a clear intestinal dysbiosis in the 3xTg‐AD mice, characterized by higher abundance of taxa known to cause proinflammatory conditions. In agreement, we also found increased intestinal permeability and accumulation of immature precursors and aged neutrophils in circulating blood, suggesting a strong peripheral dysregulation in the early phases of the disease. Conclusion: Altogether, our data suggest microbiota as a modulator of leukocyte activation and migration into the brain. Therefore, targeting the gut‐blood‐brain axis in AD could lead to new immunomodulatory strategies for AD treatment. [ABSTRACT FROM AUTHOR]