Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.

Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer's disease (AD), thus addressing long-standing translational obstacles posed by the disease's complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-region-specific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including Aβ plaques, tau tangles, neuroinflammation, and blood-brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype-phenotype relationships for major AD genes (APP, PSEN1, PSEN2, and APOEε4), enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific "avatar" models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks-including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization-limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications.