{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:46:42Z","timestamp":1787312802660,"version":"build-2736575974"},"posted":{"date-parts":[[2025,9,26]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,17]]},"abstract":"<title>Abstract<\/title>\n                <p>Apolipoprotein E4 (ApoE4) genotype, hypertension, and biological sex are critical risk factors for Alzheimer\u2019s disease and related dementias. Yet, their combined impact on early cerebrovascular dysfunction, brain inflammation, and memory impairment remains poorly understood. We developed a translational mouse model incorporating human ApoE4, hypertension via angiotensin II infusion, and induced accelerated ovarian failure (AOF) to mimic perimenopause in females to investigate these interactions. Hypertensive ApoE4 mice of both sexes exhibited impaired spatial working memory, decreased cerebral blood flow, increased neuroinflammation, and decreased blood brain barrier integrity, recapitulating key early clinical features observed in human populations with these risk factors. Brain blood flow reduction was associated with an increased incidence of capillary stalling, with notable sex differences in the extent and cellular composition of stalls: in males, stalling was strongly elevated and mostly due to red blood cell arrest, while stalling was modestly elevated in peri-AOF females with most stalls including leukocytes. Treatment with prasugrel, a P2Y12 receptor inhibitor, improved memory performance in both sexes but was correlated with different physiological effects \u2013 restored cerebral blood flow in males and reduced microglia motility and inflammation in peri-AOF females. Platelet depletion mimicked prasugrel\u2019s blood flow and cognitive benefits in males, while microglia depletion selectively rescued memory in females. Our work emphasizes the necessity of including translationally relevant female mouse models in neurodegenerative disease studies, and our findings highlight the importance of risk profile-specific interventions and demonstrate that early vascular dysfunction may be a key, sex-dependent driver of cognitive decline.<\/p>","DOI":"10.21203\/rs.3.rs-7643285\/v1","type":"posted-content","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T10:25:58Z","timestamp":1758882358000},"source":"Crossref","is-referenced-by-count":1,"title":["Memory deficits in hypertensive ApoE4 mice reversed by P2Y12 inhibition via different mechanisms in males and perimenopausal females"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-7903","authenticated-orcid":false,"given":"Lianne","family":"Trigiani","sequence":"first","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Chernavsky","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Kim","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuri","family":"Hong","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Le","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Bahninameh","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4040-7239","authenticated-orcid":false,"given":"Keri","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Cornell University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonah","family":"Bernard","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Huang","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4558-7402","authenticated-orcid":false,"given":"Daniel","family":"Rivera","sequence":"additional","affiliation":[{"name":"Cornell University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Allan-Rahill","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lamont","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-7000","authenticated-orcid":false,"given":"Roberta","family":"Marongiu","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9797-073X","authenticated-orcid":false,"given":"Costantino","family":"Iadecola","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4342-9416","authenticated-orcid":false,"given":"Nozomi","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Cornell University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-9596","authenticated-orcid":false,"given":"Chris","family":"Schaffer","sequence":"additional","affiliation":[{"name":"Cornell University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7643285\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7643285\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T14:47:04Z","timestamp":1781621224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7643285\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-7643285\/v1","relation":{},"subject":[],"published":{"date-parts":[[2025,9,26]]},"subtype":"preprint"}}