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Leveraging plasma neuron\u2010derived extracellular vesicles (NDEVs), we sought to identify biomarkers of cognitive resilience and their interplay with APOE<\/jats:italic> genotype.<\/jats:p><\/jats:sec>Methods<\/jats:title>In this case\u2010control study nested within the Women's Health Initiative (WHI), we analyzed 1130 plasma samples from 676 women in the WHI Memory Study (WHIMS)\/Long Life Study (LLS), with APOE<\/jats:italic> \u03b54 or \u03b53\/\u03b53 genotypes. At baseline, all participants were cognitively intact and at LLS visit, 13\u201317\u2009years later, were classified as still cognitively intact (resilient) or having become impaired at age >\u200980 or \u2264\u200980\u2009years. We isolated NDEVs using immunoaffinity capture for the neuronal marker L1CAM and quantified AD pathogenic proteins (A\u03b242<\/jats:sub>, total Tau, p181\u2010Tau), insulin signaling (pSer312\u2010IRS\u20101), TNFR1\/NF\u03baB pathway mediators and targets, and mitochondrial Complex V. Linear mixed models assessed group differences, adjusting for NDEV yield, age, and education, with FDR correction.<\/jats:p><\/jats:sec>Results<\/jats:title>No group differences were found for A\u03b242<\/jats:sub>, Tau proteins, or pS312\u2010IRS\u20101. Resilient \u03b54 carriers had higher baseline levels of phosphorylated TNFR1, NF\u03baB, c\u2010Myc, and FADD than \u03b54 carriers who eventually developed impairment at >\u200980 or \u2264\u200980\u2009years. Additionally, resilient \u03b54 carriers had higher baseline Complex V levels than \u03b54 carriers impaired at age >\u200980.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Augmented neuronal TNFR1\/NF\u03baB signaling and Complex V levels may promote cognitive resilience in \u03b54 carrier women. Boosting these mechanisms may have preventive and therapeutic potential against cognitive decline in this high\u2010risk population.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70143","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:31:32Z","timestamp":1752730292000},"page":"2097-2106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cognitive Resilience in Apolipoprotein \u03b54 Carrier Women Predicted by Neuron\u2010Derived Extracellular Vesicles"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1055-0324","authenticated-orcid":false,"given":"Apostolos","family":"Manolopoulos","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program National Institute on Aging Baltimore Maryland 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