Modeling Alzheimer’s Disease in Cerebral Organoids: From Amyloid β Accumulation to APOE4-Specific Drug Responses
Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, amyloid pathology, and limited treatment options. Conventional models fail to fully capture the complexity of human-specific mechanisms, prompting the development of cerebral organoids derived from induced pluripotent stem cells (iPSCs) as disease-relevant platforms. We thus established AD organoid models capable of recapitulating hallmark features of pathology, including extracellular amyloid β (Aβ) cluster formation and elevated levels of Aβ peptides detectable in culture media. Using organoids carrying familial AD mutations in PSEN1, single-cell RNA sequencing revealed accelerated neuronal differentiation, consistent with previously reported hyperexcitability phenotypes in AD models. We further extended our work by initiating a single-cell sequencing atlas of AD cerebral organoids, enabling detailed characterization of disease-associated transcriptional programs. Importantly, we show that AD pathology can be reproduced across multiple genetic backgrounds, including SORL1 variants. Lastly, beyond modeling, we employed organoids for therapeutic testing and demonstrated that Tramiprosate exerts selective effects on APOE4 organoids, altering lipid metabolism, while leaving APOE3 organoids largely unaffected. Our findings thus highlight cerebral organoids as a robust platform for modeling genetic risk factors, dissecting molecular mechanisms of AD, and evaluating genotype-specific drug responses. This approach bridges the gap between fundamental research and translational applications, advancing our understanding of Alzheimer’s disease at the single-cell level.
