{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:03:35Z","timestamp":1785323015435,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,28]]},"group-title":"Physiology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Alzheimer's Association","award":["ALZDISCOVERY-1049110"],"award-info":[{"award-number":["ALZDISCOVERY-1049110"]}]},{"name":"NIH","award":["R01AG064016"],"award-info":[{"award-number":["R01AG064016"]}]},{"name":"John L. Luvaas Family Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,28]]},"abstract":"<jats:p>Apolipoprotein E4 (E4) increases the risk of Alzheimer's disease (AD) by up to 12-fold. However, understanding of the mechanisms underlying this increased risk has been limited by a lack of preclinical models that accurately reflect the effects of E4 in the presence of humanized non-mutant amyloid-\u03b2 precursor protein (hA\u03b2PP). Therefore, we studied novel humanized APOE and hA\u03b2PP mice to investigate the contributions of the E4 genotype to cognitive, inflammatory, and vascular dysfunction, specifically comparing male and female E3\/hA\u03b2PP and E4\/hA\u03b2PP mice. E4\/hA\u03b2PP mice exhibited impaired nest-building behavior and novel object recognition compared with E3\/hA\u03b2PP mice. Microglial content was higher in E4\/hA\u03b2PP mice, whereas astrocyte content was not different across groups. E4\/hA\u03b2PP mice had greater carotid and cerebral artery stiffness, and higher collagen I content in cerebral arteries than E3\/hA\u03b2PP mice. Under static pressure, cerebral artery endothelium-dependent and endothelium-independent vasodilation were similar across genotypes. However, high pulse pressure selectively impaired cerebral artery endothelial function in E4\/hA\u03b2PP mice, with the greatest impairment observed in females. The E4\/hA\u03b2PP mice also exhibited higher cortical expression of Nox2 and Sod1 and elevated cerebral artery Il1b expression. As such, E4\/hA\u03b2PP mice exhibit convergent cognitive, inflammatory, and vascular abnormalities that recapitulate several features of AD. Elevated pulse pressure revealed an E4-dependent vulnerability of the cerebral vasculature, suggesting that vascular stress may be an important contributor to disease risk. Together, our findings support the use of the APOExhA\u03b2PP model to investigate the mechanisms by which E4 promotes vascular dysfunction, neuroinflammation, and cognitive impairment in AD.<\/jats:p>","DOI":"10.64898\/2026.07.28.740806","type":"posted-content","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:30:14Z","timestamp":1785321014000},"source":"Crossref","is-referenced-by-count":0,"title":["A humanized A\u03b2 mouse model reveals E4-dependent cognitive impairments, microglial activation, and cerebrovascular dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3782-2211","authenticated-orcid":false,"given":"Skylyn J","family":"Ferguson","sequence":"first","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Pelayo","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siena","family":"Stueland","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kennedy","family":"Krajack","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiara","family":"Gardley","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Herbert","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Tafoya","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5897-8994","authenticated-orcid":false,"given":"Alexandra","family":"Famiano","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0375-9712","authenticated-orcid":false,"given":"Abigail E","family":"Cullen","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8358-9062","authenticated-orcid":false,"given":"Naly","family":"Setthavongsack","sequence":"additional","affiliation":[{"name":"Oregon Health and Sciences University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-9846","authenticated-orcid":false,"given":"Randall L","family":"Woltjer","sequence":"additional","affiliation":[{"name":"Oregon Health and Sciences University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1612-4545","authenticated-orcid":false,"given":"Ashley E.","family":"Walker","sequence":"additional","affiliation":[{"name":"University of Oregon;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.28.740806","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:30:14Z","timestamp":1785321014000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.28.740806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.07.28.740806","relation":{},"subject":[],"published":{"date-parts":[[2026,7,28]]},"subtype":"preprint"}}