One powerful aspect of the current model is the spontaneous appearance of both [1] amyloid and tau pathology, and the distinct timeline on which these phenotypes appear. Modeling both these facets of AD has been challenging in mouse models. Most mouse AD models must carry multiple transgenes to achieve robust amyloid phenotypes, and rarely have significant tau pathology or neuronal loss (for review see [31]). Mouse models of tauopathy overexpress mutated human MAPT (which is causal for frontotemporal dementia, not AD) to induce tau pathology [80,81], and do not exhibit amyloid aggregation. Using the organoid model, we observed that amyloid pathology emerges prior to significant tau hyperphosphorylation in neural tissue derived from fAD patients carrying a duplication of the APP gene. While the sequential emergence of amyloid and tau pathology in human AD remains somewhat controversial [82–85], this timing is in close agreement with that observed in the scaffolded 3D cultures of Choi et al. 2014; [40]. Additionally, the inhibition of Aβ production using β and γ-secretase inhibitors reduced tau hyperphosphorylation only at the later time point of treatment, after
