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The NIA Interventions Testing Program identified the weak estrogen 17\u03b1-estradiol (17\u03b1E2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17\u03b1E2 healthspan benefits were modulated by human apolipoprotein E (\n                  <jats:italic>APOE<\/jats:italic>\n                  ) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated\n                  <jats:italic>APOE4<\/jats:italic>\n                  allele compared to\n                  <jats:italic>APOE3<\/jats:italic>\n                  , the risk neutral and most common\n                  <jats:italic>APOE<\/jats:italic>\n                  allele. Here, we tested whether\n                  <jats:italic>APOE<\/jats:italic>\n                  -dependent, AD-relevant benefits of 17\u03b1E2 observed in males extend to females. Specifically, we treated 12-month-old\n                  <jats:italic>APOE3<\/jats:italic>\n                  and\n                  <jats:italic>APOE4<\/jats:italic>\n                  targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17\u03b1E2. We find that relative to\n                  <jats:italic>APOE3<\/jats:italic>\n                  ,\n                  <jats:italic>APOE4<\/jats:italic>\n                  genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17\u03b1E2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in\n                  <jats:italic>APOE4<\/jats:italic>\n                  females. In the CNS, we observed mixed effects of\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype on behavioral performance and indices of brain aging, with\n                  <jats:italic>APOE4<\/jats:italic>\n                  females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble \u03b2-amyloid, but no\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17\u03b1E2 did not significantly improve neural outcomes in\n                  <jats:italic>APOE3<\/jats:italic>\n                  or\n                  <jats:italic>APOE4<\/jats:italic>\n                  females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against\n                  <jats:italic>APOE4<\/jats:italic>\n                  phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.\n                <\/jats:p>","DOI":"10.64898\/2026.08.06.743074","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:50:21Z","timestamp":1786117821000},"source":"Crossref","is-referenced-by-count":0,"title":["17\u03b1-Estradiol Confers Limited Protection Against\n                  <i>APOE4<\/i>\n                  Phenotypes in Middle-Aged Female Mice"],"prefix":"10.64898","author":[{"given":"Cassandra J.","family":"McGill","sequence":"first","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Department 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