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Nonetheless, some <jats:italic>APOE4<\/jats:italic> carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial\u2010derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the <jats:italic>APOE4<\/jats:italic> allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and <jats:italic>APOE4<\/jats:italic>. Utilizing an <jats:italic>APOE4<\/jats:italic>\u2010centric mouse model of amyloidosis (APP\/PS1\/<jats:italic>APOE4<\/jats:italic>), we observed that humanin P3S significantly attenuated brain amyloid\u2010beta accumulation compared to the wild\u2010type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in\u00a0vitro studies corroborated humanin P3S's efficacy in promoting amyloid\u2010beta clearance. Notably, in the temporal cortex of <jats:italic>APOE4<\/jats:italic> carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in <jats:italic>APOE4<\/jats:italic>\u2010linked amyloidosis, underscoring its significance in longevity and cognitive health among <jats:italic>APOE4<\/jats:italic> carriers.<\/jats:p>","DOI":"10.1111\/acel.14153","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T06:12:34Z","timestamp":1711174354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Humanin variant <scp>P3S<\/scp> is associated with longevity in <i>APOE4<\/i> carriers and resists <i>APOE4<\/i>\u2010induced brain pathology"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7461-7973","authenticated-orcid":false,"given":"Brendan","family":"Miller","sequence":"first","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su\u2010Jeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Cao","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemal H.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los 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