Single cell RNA sequencing and emerging transcriptomic technologies in Alzheimer's disease cerebral organoids: a mini...

Alzheimer's disease (AD), the most common cause of dementia worldwide, presents a formidable challenge due to its complex, multifactorial etiology, and limited translational success of existing models. Recent advances in stem cell biology have enabled the generation of three-dimensional human cerebral organoids which exhibit multicellular complexity and self-organisation, recapitulating key aspects of fetal brain development in vitro. This mini review highlights the landscape of AD modelling in human cerebral organoids. While studies using single cell RNA sequencing (scRNA-seq) form the core of this review, we also discuss single-nucleus RNA sequencing, computational deconvolution, and spatial approaches as translationally relevant extensions. We categorise current organoid research into distinct model types: (1) familial AD models driven by APP, PSEN1, and PSEN2 mutations; (2) sporadic AD models incorporating genetic APOE variants and environmental risk factors (serum exposure, pollutants, and viral reactivation); (3) tauopathy models highlighting astrocyte-driven metabolic disruption; (4) models featuring glial-immune interactions; and (5) emerging models of mitochondrial dysfunction as an early disease initiator. Across these categories, single cell technologies reveal critical alterations in lipid metabolism, synaptic programs, and glial-immune crosstalk. Finally, we review methodological innovations-drawing on non-AD developmental organoid studies such as region-specific patterning, morphodynamic control, and enhanced cellular diversity, which offer a roadmap for improving the physiological fidelity of next-generation AD organoid models. Ultimately, integrating these advanced cerebral organoid platforms with single cell technologies offer a powerful toolkit to dissect early disease mechanisms and accelerate the development of personalised therapeutics.