Alzheimer’s disease (AD) is the leading cause of age-related dementia, in which neuroinflammation is highlighted to play a critical role in driving neurodegeneration. Emerging evidence has demonstrated crucial roles for peripheral immune cells in AD pathology by direct infiltration into brains and regulating brain-resident immune cells, including microglia. However, many critical questions remain unaddressed. This is partly due to the lack of an effective and reliable model to capture the complex interactions between the various human cellular components of the brain and the peripheral immune system. Drawing upon our considerable experience in AD biology, 3D modeling of AD in a dish, microfluidic systems and cellular engineering, we recently developed a human neuroimmune axis model to gain a deeper understanding of peripheral immune cells’ biology and their disease-modifying role in AD. We found that CD8+ T-cells infiltrate specifically into AD cultures and exacerbate neuroinflammation and neurodegeneration by interacting with microglia. Mechanistically, we found that the CXCL10-CXCR3 axis plays a critical role in regulating CD8+ T-cell infiltration and T-cell-mediated neurodegeneration in AD. The overarching goal of this proposal is to use our unique multicellular neuroimmune axis model to gain a greater understanding of the crosstalk between CD8+ T-cells and brain glial cells in driving AD pathogenesis.