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Previous studies, using iPSC-derived neurons and\/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons, including the favored production of longer over shorter \u03b2-amyloid (A\u03b2) peptides, endo-lysosomal abnormalities, and increased vulnerability phenotypes in response to toxic insults. Importantly, mechanistic studies define inefficient \u03b3-secretase and impaired endo-lysosomes as the upstream events of increased neuronal susceptibility. This discovery of the unique population of neurons with disease phenotypes would open a new avenue to develop novel therapeutics targeting neuronal vulnerability.<\/jats:p>","DOI":"10.1038\/s41419-025-07934-0","type":"journal-article","created":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T14:51:38Z","timestamp":1754751098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A unique subpopulation of wild-type neurons recapitulating familial Alzheimer\u2019s disease phenotypes"],"prefix":"10.1038","volume":"16","author":[{"given":"Midori","family":"Yokomizo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1532-6613","authenticated-orcid":false,"given":"Michael","family":"Sadek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei C. 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