{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:29:23Z","timestamp":1791919763045,"version":"4.3.4"},"reference-count":75,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 162431"],"award-info":[{"award-number":["PJT 162431"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 159781"],"award-info":[{"award-number":["PJT 159781"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>About two\u2010thirds of Alzheimer's Disease (AD) patients are women, who exhibit more severe pathology and cognitive decline than men. Whether biological sex causally modulates the relationship between cholinergic signaling and amyloid pathology remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We quantified amyloid beta (A\u03b2) in male and female App\u2010mutant mice with either decreased or increased cholinergic tone and examined the impact of ovariectomy and estradiol replacement in this relationship. We also investigated longitudinal changes in basal forebrain (cholinergic function) and A\u03b2 in elderly individuals.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We show a causal relationship between cholinergic tone and amyloid pathology in males and ovariectomized female mice, which is decoupled in ovary\u2010intact and ovariectomized females receiving estradiol. In elderly humans, cholinergic loss exacerbates A\u03b2.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Our findings emphasize the importance of reflecting human menopause in mouse models. They also support a role for therapies targeting estradiol and cholinergic signaling to reduce A\u03b2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Cholinergic tone regulates amyloid beta (A\u03b2) pathology in males and ovariectomized female mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Estradiol uncouples the relationship between cholinergic tone and A\u03b2.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In elderly humans, cholinergic loss correlates with increased A\u03b2 in both sexes.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13481","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T07:01:11Z","timestamp":1697526071000},"page":"995-1012","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Sex\u2010dependent cholinergic effects on amyloid pathology: A translational study"],"prefix":"10.1002","volume":"20","author":[{"given":"Liliana","family":"German\u2010Castelan","sequence":"first","affiliation":[{"name":"Robarts Research Institute Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"},{"name":"Neuroscience program Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley R. 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