3D HUMAN NEUROIMMUNE ORGANOID MODEL OF SPORADIC ALZHEIMER’S DISEASE REVEALS AMYLOID-DRIVEN NETWORK DYSFUNCTION

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, yet the sporadic form of the disease remains inadequately modeled due to the limited translational relevance of existing animal models and in vitro systems. Most current models rely on familial mutations or synthetic amyloid species and fail to capture human-specific amyloid pathology, microglial interactions, and associated neuronal network dysfunction. Here, we present a human 3D neuroimmune organoid (NIO) model that recapitulates key pathological and functional features of sporadic AD. Long-term human iPSC-derived brain organoids were generated and integrated with microglial progenitors, resulting in stable microglial population distributed throughout the tissue To induce patient-relevant amyloid pathology, organoids were exposed to brain extracts from patients with beta-amyloid pathology in combination with nanoparticles that facilitate amyloid nucleation. This approach robustly induced amyloid-β aggregation within the organoids, whereas brain extracts or nanoparticles alone failed to trigger deposition. Functionally, amyloid-bearing AD-NIOs exhibited pronounced neuronal and network-level disturbances. Multielectrode array recordings revealed reduced firing activity and altered pharmacological responses, while whole-cell patch-clamp recordings demonstrated disrupted intrinsic membrane properties and an imbalance between excitatory and inhibitory synaptic activity. These changes mirror early functional alterations reported in human AD and directly link molecular pathology to impaired network behavior. Together, this AD-NIOs platform provides a human-relevant model of sporadic AD that integrates patient-derived amyloid pathology, microglial interactions, and functional neuronal readouts, offering a powerful framework to investigate early disease mechanisms and support therapeutic development.