Researchers used induced pluripotent stem cells (iPSCs) to study Alzheimer's disease, including both familial and sporadic forms. They reprogrammed fibroblasts from patients with familial Alzheimer's disease (caused by duplication of the APP gene), sporadic Alzheimer's disease (sAD), and non-demented controls into iPSCs. These iPSCs were then differentiated into neurons, which were purified and analyzed for Alzheimer's-related markers. The study found that neurons derived from patients with familial Alzheimer's disease and sAD showed significantly higher levels of amyloid-β (1–40), phospho-tau (Thr 231), and active GSK-3β compared to controls. These markers are associated with Alzheimer's pathology. Additionally, neurons from sAD patients exhibited phenotypes similar to those seen in familial Alzheimer's disease samples, suggesting that iPSC technology can reveal disease-related traits even when symptoms take decades to manifest. The study also showed that treatment with β-secretase inhibitors reduced levels of phospho-tau and active GSK-3β, indicating a direct relationship between APP processing and tau phosphorylation. Neurons from sAD patients had increased early endosome accumulation, which may contribute to Alzheimer's pathology. The research highlights the potential of iPSCs in modeling Alzheimer's disease and understanding its mechanisms, including the role of APP processing in tau phosphorylation and GSK-3β activation. The findings suggest that sporadic Alzheimer's disease may be influenced by genetic factors and that iPSCs can help identify genetic variants contributing to the disease. The study also emphasizes the importance of studying neuronal phenotypes in iPSC-derived neurons to better understand Alzheimer's disease progression and potential therapeutic targets.Researchers used induced pluripotent stem cells (iPSCs) to study Alzheimer's disease, including both familial and sporadic forms. They reprogrammed fibroblasts from patients with familial Alzheimer's disease (caused by duplication of the APP gene), sporadic Alzheimer's disease (sAD), and non-demented controls into iPSCs. These iPSCs were then differentiated into neurons, which were purified and analyzed for Alzheimer's-related markers. The study found that neurons derived from patients with familial Alzheimer's disease and sAD showed significantly higher levels of amyloid-β (1–40), phospho-tau (Thr 231), and active GSK-3β compared to controls. These markers are associated with Alzheimer's pathology. Additionally, neurons from sAD patients exhibited phenotypes similar to those seen in familial Alzheimer's disease samples, suggesting that iPSC technology can reveal disease-related traits even when symptoms take decades to manifest. The study also showed that treatment with β-secretase inhibitors reduced levels of phospho-tau and active GSK-3β, indicating a direct relationship between APP processing and tau phosphorylation. Neurons from sAD patients had increased early endosome accumulation, which may contribute to Alzheimer's pathology. The research highlights the potential of iPSCs in modeling Alzheimer's disease and understanding its mechanisms, including the role of APP processing in tau phosphorylation and GSK-3β activation. The findings suggest that sporadic Alzheimer's disease may be influenced by genetic factors and that iPSCs can help identify genetic variants contributing to the disease. The study also emphasizes the importance of studying neuronal phenotypes in iPSC-derived neurons to better understand Alzheimer's disease progression and potential therapeutic targets.