{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:00:29Z","timestamp":1790834429357,"version":"4.1.0"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder influenced by both causal mutations and genetic modifiers. The rare APOE3 Christchurch (APOE3ch) variant has been associated with delayed disease onset in a familial Alzheimer\u2019s disease case, suggesting a potential protective role. However, the mechanisms underlying this protection, particularly across different genetic backgrounds, remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated isogenic human induced pluripotent stem cell (hiPSC)\u2013derived neural cultures harboring either PSEN1 E280A or amyloid precursor protein duplication (APPdp) mutations, with and without the APOE3ch variant, using prime editing. Neural differentiation, amyloid-beta production, amyloid precursor protein processing, tau phosphorylation and transcriptomic profiles were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>APOE3ch did not affect neural differentiation or apolipoprotein E secretion. However, it exhibited mutation-dependent effects on Alzheimer\u2019s disease phenotypes. In amyloid precursor protein duplication cultures, APOE3ch significantly reduced amyloid-beta production and shifted processing toward non-amyloidogenic pathways, accompanied by decreased phosphorylated tau. In contrast, in PSEN1 E280A cultures, APOE3ch had minimal impact on amyloid-beta levels but increased non-amyloidogenic processing and altered total tau without affecting phosphorylation. Transcriptomic analysis revealed both shared and mutation-specific effects, with consistent modulation of pathways related to synaptic function, including Wnt and cadherin signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that APOE3ch acts as a context-dependent modifier of Alzheimer\u2019s disease pathology, with protective effects varying by genetic background. The variant consistently influences pathways associated with synaptic resilience while differentially modulating amyloid and tau pathology. This work provides mechanistic insight into APOE3ch-mediated protection and highlights the importance of genetic context in developing targeted therapeutic strategies for Alzheimer\u2019s disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1856154","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:53Z","timestamp":1790833313000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch"],"prefix":"10.3389","volume":"18","author":[{"given":"Carlye","family":"Frisch","sequence":"first","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Baker","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayathri","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert E.","family":"Mintah","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Leyasi","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]},{"name":"School for Engineering of Matter, Transport, and Energy, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Pedroza","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Galyon","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Brafman","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University","place":["Tempe, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8233","DOI":"10.1038\/s41598-020-65038-5","article-title":"CDH6 and HAGH protein levels in plasma associate with Alzheimer\u2019s disease in APOE epsilon4 carriers.","volume":"10","author":"Ahmad","year":"2020","journal-title":"Sci. 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