{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:47:01Z","timestamp":1773251221063,"version":"3.50.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"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. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The apolipoprotein E (APOE) gene represents the strongest genetic determinant of sporadic Alzheimer\u2019s disease (AD), yet its interaction with sex-specific endocrine factors remains poorly understood. Lifetime estrogen exposure, estimated through reproductive lifespan, may modulate neurodegenerative risk, but findings are inconsistent. Previous studies have examined reproductive factors and APOE interactions in relation to cognitive outcomes, but dose-dependent effects across all APOE alleles (\u03b52, \u03b53, \u03b54) in clinically diagnosed AD patients remain underexplored. This study investigates the joint effects of reproductive lifespan, age at natural menopause (ANM), and APOE genotype on AD risk in females.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 396 female participants (103 with AD, 293 cognitively healthy controls) were retrospectively analyzed. Demographic, clinical, and reproductive data were extracted from medical records. APOE genotyping was performed by sequencing rs429358 and rs7412 polymorphisms. Logistic regression models tested associations between ANM, reproductive lifespan, and AD diagnosis, adjusting for education, body mass index (BMI), smoking, diabetes, hypertension, and number of children. Moderation analyses assessed the interaction between reproductive variables and APOE \u03b52, \u03b53, and \u03b54 alleles, and were followed by simple slope analyses to clarify the direction of significant effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      AD females exhibited later ANM (50.3 \u00b1 4.4 vs. 48.3 \u00b1 6.2\u00a0years;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.004) and longer reproductive lifespan (37.4 \u00b1 4.4 vs. 35.4 \u00b1 6.0\u00a0years;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.005) than controls. Both ANM and reproductive lifespan independently predicted higher AD risk (adjusted OR = 1.07, 95% CI = 1.02\u20131.12,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01). These effects were amplified by APOE \u03b54 and attenuated by \u03b53, while \u03b52 showed no influence. Simple slope analyses confirmed an allele-specific gradient, with the association between later menopause and AD risk steepest in \u03b54 carriers and absent in high \u03b53 carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This work provides novel evidence that extended ovarian function is associated with increased AD vulnerability in females, particularly among APOE \u03b54 carriers. These findings highlight a dose-dependent, genotype-specific interaction between reproductive aging and neurodegeneration, suggesting APOE as a molecular bridge linking estrogenic exposure and AD risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1733593","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T22:10:25Z","timestamp":1773180625000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Age at natural menopause, reproductive lifespan and Alzheimer\u2019s disease in females: is APOE \u03b54 the missing link?"],"prefix":"10.3389","volume":"17","author":[{"given":"Francesco","family":"Bruno","sequence":"first","affiliation":[{"name":"Department of Human and Social Sciences, Universitas Mercatorum","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Spadafora","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation (IRIB), Italian National Research Council (CNR)","place":["Cosenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Abondio","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Qualtieri","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation (IRIB), Italian National Research Council (CNR)","place":["Cosenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ersilia","family":"Paparazzo","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria","place":["Arcavacata di Rende, Italy"]},{"name":"Unit of Geriatric Medicine, Italian National Research Center on Aging - 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