Brain organoids derived from hiPSCs provide human cellular models that closely resemble the 3D structure of the human brain and have proven valuable for studying neurodegenerative diseases.28–30,33,35,63 To simulate the phenotypes observed in the brains of patients with PSEN1 mutations, we generated brain organoids from both WT and PSEN1 mutant hiPSCs (Figure 7A) following our published protocol with modification.30 At day 70 of organoid development, we observed significantly higher levels of pTau in PSEN1 mutant brain organoids compared to WT brain organoids (Figures 7B and 7C). Here, PSEN1 is linked to neurodegenerative disease.