Abstract
<jats:p>Genetic evidence implicates immune dysfunction in Alzheimer’s disease (AD), yet human-specific neuroimmune mechanisms remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates iPSC-derived microglia and CD8+ T cells to reconstitute multicellular Alzheimer’s disease pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this platform, we demonstrate that microglia mediate amyloid-β clearance and neuronal maturation but also drive inflammatory activation and recruit CD8+ T cells through CCL4/5-CXCL10 signaling via CCR1/5 and CXCR3, establishing a neuroinflammatory feedback loop. Pharmacological targeting of CCR5 or CXCR3 blocks T cell recruitment and modulates autophagy in a microglia-dependent manner. This modular organoid platform provides a versatile tool for dissecting neuron–immune interactions and enables cell-type-specific therapeutic screening in human neuroinflammatory disease models.</jats:p>