Alzheimer's disease (AD) is a critical neurodegenerative disorder with only a small number of effective disease-modifying therapies currently existing. Establishing a translational-relevant preclinical AD model is considered the bottleneck in AD drug development. Human brain organoids (hBOs) are suitable candidates to model AD in the context of human physiology. In recent years, hBO platforms have evolved to incorporate the robust population of microglia, astrocytes, and vascular endothelial cells. Concurrently, the adoption of innovative modeling strategies has expanded the realm of AD modeling in hBOs, extending from familial AD to sporadic AD and beyond. This review discusses recent advances in hBO designs for modeling AD, highlighting emerging strategies to model different facets of AD, and evaluates the current extent to which AD phenotypes are recapitulated in hBO systems. hBO models exhibit varying levels of recapitulation in AD phenotypes, with degrees ranging from strong, moderate, emerging but limited, weak but consistent, and weak and variable. Collectively, advances in AD modeling using hBOs have partially alleviated limitations related to cellular diversity and complexity, while expanding strategies for modeling distinct subtypes of AD. These advances have also been successful in strengthening the recapitulation of several AD phenotypes and unraveling emerging AD phenotypes in hBOs. However, early-generation AD hBO models lack cellular and physiological complexity, as well as modeling strategies for different AD subtypes. Future work is still required to enhance the robustness, credibility, and translational utility of AD hBO models in biomedical applications.
Citation: Wan Mohd Naim Wan Mohd Ruslan, Siti Zaleha Raduan, Maizatul Fazilah Abdul Razak. Advances in human brain organoids for Alzheimer's disease modeling[J]. AIMS Neuroscience, 2026, 13(4): 583-617. doi: 10.3934/Neuroscience.2026027
Alzheimer's disease (AD) is a critical neurodegenerative disorder with only a small number of effective disease-modifying therapies currently existing. Establishing a translational-relevant preclinical AD model is considered the bottleneck in AD drug development. Human brain organoids (hBOs) are suitable candidates to model AD in the context of human physiology. In recent years, hBO platforms have evolved to incorporate the robust population of microglia, astrocytes, and vascular endothelial cells. Concurrently, the adoption of innovative modeling strategies has expanded the realm of AD modeling in hBOs, extending from familial AD to sporadic AD and beyond. This review discusses recent advances in hBO designs for modeling AD, highlighting emerging strategies to model different facets of AD, and evaluates the current extent to which AD phenotypes are recapitulated in hBO systems. hBO models exhibit varying levels of recapitulation in AD phenotypes, with degrees ranging from strong, moderate, emerging but limited, weak but consistent, and weak and variable. Collectively, advances in AD modeling using hBOs have partially alleviated limitations related to cellular diversity and complexity, while expanding strategies for modeling distinct subtypes of AD. These advances have also been successful in strengthening the recapitulation of several AD phenotypes and unraveling emerging AD phenotypes in hBOs. However, early-generation AD hBO models lack cellular and physiological complexity, as well as modeling strategies for different AD subtypes. Future work is still required to enhance the robustness, credibility, and translational utility of AD hBO models in biomedical applications.
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Figures(2) / Tables(4)
Wan Mohd Naim Wan Mohd Ruslan, Siti Zaleha Raduan, Maizatul Fazilah Abdul Razak. Advances in human brain organoids for Alzheimer's disease modeling[J]. AIMS Neuroscience, 2026, 13(4): 583-617. doi: 10.3934/Neuroscience.2026027
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