<p>Alzheimer’s disease (AD) is the most common cause of dementia worldwide, characterized by accumulation of amyloid-β protein and hyperphosphorylated tau protein in the brain. Neuroinflammation, resulting from chronic activation of brain-resident innate immune cells as well as enhanced peripheral leukocyte access across the blood–brain barrier, crucially affects AD progression. In this context, TNFSF10, a cytokine substantially expressed in the AD brain, has been shown to modulate both the innate and the adaptive branches of the immune response in AD-related neuroinflammation. In this study, we explored whether a TNFSF10-neutralizing treatment could represent a tool to re-balance the overall overshooting inflammatory response in a mouse model of AD. Specifically, 3xTg-AD mice were treated sub-chronically with an anti-TNFSF10 monoclonal antibody for three months, and were then sacrificed at 15&#xa0;months. TNFSF10 neutralization reduced the expression of the inflammatory marker CD86, inversely related to levels of the anti-inflammatory marker CD206 in the brain of 3xTg-AD mice, suggesting a switch of microglia towards a neuroprotective phenotype. Similar results were observed in the splenic macrophage population. Moreover, flow cytometry revealed a significant decrease of CD4⁺CD25⁺FOXP3⁺ T regulatory cells as well as reduced number of CD11b⁺LY6C^high proinflammatory monocytes in both the brain and the spleen of 3xTg-AD mice&#xa0;treated with anti-TNFSF10 monoclonal antibody. Finally, the treatment resulted in lower count of splenic CD4⁺ and CD8⁺ T cells expressing PD1. The data suggest that TNFSF10 system-targeted treatment effectively restrain overshooting central and peripheral inflammation by rebalancing the overall immune response, mitigating the&#xa0;progression of AD&#xa0;pathology. </p> Graphical Abstract <p></p>