Human iPSC-Derived Brain Organoids: A Disease-Oriented Evaluation of Modeling Fidelity.

Two-dimensional (2D) cell culture systems and conventional animal models have been crucial in the study of central nervous system (CNS) pathology. However, they are limited in their abilities to elucidate human-specific neurobiology and disease etiology. Human induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a complementary platform that offers a three-dimensional (3D) structure and human-specific environment. They exhibit cellular heterogeneity, apical-basal polarity, and the ability to perform tissue-specific functions such as absorption, secretion, and electrophysiological activity. This review critically evaluates the use of iPSC-derived brain organoids as a disease-focused approach to study neuroinflammation, neurodegeneration, infection, and aging. Organoids provide a model for early pathogenic events, cellular interactions, and human-specific responses, providing insights into disease hallmarks such as tau and amyloid pathology, the vulnerability of dopaminergic neurons, and host-pathogen interactions. However, they are limited by developmental immaturity, inadequate systemic integration, and heterogeneity across models, which hinders their ability to represent late-stage disease progression and human level physiology. Therefore, their primary use lies in modeling human-specific early disease mechanisms, while integration with animal models and in vitro systems is crucial for progressing translational neuroscience.