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Type 2 diabetes (T2DM) is one of the most important modifiable AD risk factors, so we hypothesize that T2DM could substantially exacerbate A\u03b2 neurotoxicity and reproduce typical AD pathology. Human islet amyloid polypeptide (hIAPP) was used to mimic T2DM and was co\u2010oligomerized with A\u03b21\u201042 peptide, and delivered to the central of human iPSC\u2010derived mature COs through intermittently repeated microinjections, so as to simulate the chronic exposure to A\u03b2 within the brain. The A\u03b242\u2010hIAPP co\u2010oligomers induced a pathological phenotype more closely resembling the pathological features of advanced AD, notably, neuronal density showed significant reduction, with 3.2 times more neuronal death. Dynamic metabolomic analysis revealed the metabolic pathways and differential metabolites that may be correlated to the primary mechanism underlying the enhanced neurotoxic effects and accelerated AD pathology. Furthermore, this study developed a sAD CO model more resembling the pathological features of advanced AD, which potentially provides a valuable platform for AD pathogenesis research and novel drug screening.<\/jats:p>","DOI":"10.1002\/advs.202516837","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T04:43:21Z","timestamp":1769143401000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Islet Amyloid Polypeptide Modelled to Simulate Diabetes Co\u2010Oligomerized with \u03b2\u2010Amyloid 1\u201042 Reproducing the Pathological Cascade of Alzheimer's Disease in Human Cerebral Organoids"],"prefix":"10.1002","volume":"13","author":[{"given":"Jin","family":"Yan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering School of Biomedical Engineering Hainan University  Sanya China"},{"name":"Collaborative Innovation Center of One Health Hainan University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimeng","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering School of Biomedical Engineering Hainan University  Sanya China"},{"name":"Collaborative Innovation Center of One Health Hainan University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyu","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering School of Biomedical Engineering Hainan University  Sanya China"},{"name":"Collaborative Innovation Center of One Health Hainan University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering School of Biomedical Engineering Hainan University  Sanya China"},{"name":"Collaborative Innovation Center of One Health Hainan University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering School of Biomedical Engineering Hainan University  Sanya China"},{"name":"Collaborative Innovation Center of One Health Hainan University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wei","sequence":"additional","affiliation":[{"name":"iRegene Therapeutics Co. 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