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Inheritance of the apolipoprotein E-e4 (\n                  <jats:italic>APOE4)<\/jats:italic>\n                  allele of the\n                  <jats:italic>APOE<\/jats:italic>\n                  gene on chromosome 19 remains the greatest genetic risk factor for AD in the typical population, yet its role in DS-associated AD (DS-AD) neuropathogenesis in people with DS is unclear. We generated human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, and cerebral organoids (COs) using cells from people with DS and from euploid individuals. Aged DS COs were smaller than aged euploid COs and showed robust amyloid-\u03b2 neuropathology that was positively correlated with the levels of apoE expression. We then captured extracellular vesicles (EVs) from the conditioned media of COs and observed a decrease in the levels of secreted AD-related proteins, including amyloid, contained within the EVs and in the media from which the EVs were isolated. We also identified distinct neuronal and astrocytic gene expression signatures in DS COs relative to euploid COs, including a set of genes known to interact with both\n                  <jats:italic>APOE<\/jats:italic>\n                  and\n                  <jats:italic>APP<\/jats:italic>\n                  at the gene and\/or protein levels. Lastly, we determined that, despite differences in the expression levels of the specific genes involved, several common pathways were upregulated in T21 hiPSC-derived neurons, astrocytes, and COs, including apoptosis, the endolysosome, and structural stabilization pathways. Taken together, our findings provide novel insights into molecular mechanisms that may contribute to DS-AD and indicate that apoE plays an important role in the disease process.\n                <\/jats:p>","DOI":"10.64898\/2026.07.01.735908","type":"posted-content","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:35:18Z","timestamp":1783431318000},"source":"Crossref","is-referenced-by-count":2,"title":["Trisomy 21 cerebral organoids exhibit Alzheimer\u2019s disease amyloid and apolipoprotein E co-pathologies"],"prefix":"10.64898","author":[{"given":"Breanna R.","family":"Dooling","sequence":"first","affiliation":[{"name":"Department of Neurology and the University of Colorado Alzheimer\u2019s and Cognition Center, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Vielle","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Department of Anesthesiology, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban M.","family":"Lucero","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Rydland","sequence":"additional","affiliation":[{"name":"Department of Neurology and the University of Colorado Alzheimer\u2019s and Cognition Center, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Quang","sequence":"additional","affiliation":[{"name":"Department of Neurology and the University of Colorado Alzheimer\u2019s and Cognition Center, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Summers","sequence":"additional","affiliation":[{"name":"Department of Neurology and the University of Colorado Alzheimer\u2019s and Cognition Center, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector","family":"Esquer","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Coughlan","sequence":"additional","affiliation":[{"name":"Department of Neurology and the University of Colorado Alzheimer\u2019s and Cognition Center, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Galbraith","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Department of Pharmacology, University of Colorado Anschutz, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin M.","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO, USA"},{"name":"Department of 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