Brain organoids in Alzheimer disease and related tauopathies: Challenges and opportunities for translational readiness

A major hurdle in Alzheimer disease research is the failure of mouse models to capture complexities of the human brain that contributes to repeated clinical trial failure. Although the recent US Food and Drug Administration (FDA) Modernization Act 2.0 has enabled non-animal preclinical pathways, brain organoid models of tauopathies remain nascent compared with other disease areas. Here, we identify three challenges for their translational readiness, maturity, disease-relevant cellular complexity, and pathological accuracy, and examine current achievements and emerging solutions. We propose a ten-metric benchmarking framework and discuss the opportunities and remaining challenges for translational readiness in tauopathy modeling.