{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:24:10Z","timestamp":1768523050996,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,29]]},"group-title":"Physiology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,27]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Postmenopausal females who carry an\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    allele are at higher risk of late-onset Alzheimer\u2019s Disease compared to age-matched\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype and estrogen on cerebrovascular endothelial and mitochondrial function.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Young female homozygous\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    and\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    mice (n=19-20\/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17\u03b2-estradiol, or left intact.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17\u03b2-estradiol. However, in\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    mice, there was no effect of OVX or 17\u03b2-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17\u03b2-estradiol treatment in\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    mice, but there was no impact of OVX or 17\u03b2-estradiol in the\n                    <jats:italic>APOE\u03b54 mice.<\/jats:italic>\n                    In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    mice compared with\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    mice. 17\u03b2-estradiol led to higher mitochondrial complex I respiration in\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    but not\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17\u03b2-estradiol treatment was associated with lower cerebral artery stiffness in\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    but not\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Overall, these results indicate that the\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17\u03b2-estradiol enhances cerebrovascular endothelial and mitochondrial function in\n                    <jats:italic>APOE\u03b53<\/jats:italic>\n                    mice but not in\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    mice. The results suggest that 17\u03b2-estradiol supplementation has more cerebrovascular benefit for\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    non-carriers.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Novelty &amp; Significance<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What is known?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>\n                          Females have twice the risk of Alzheimer\u2019s disease compared with males, and the\n                          <jats:italic>APOE4<\/jats:italic>\n                          genetic variant is associated with a greater risk for Alzheimer\u2019s disease compared with the\n                          <jats:italic>APOE3<\/jats:italic>\n                          variant.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The risk for Alzheimer\u2019s disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          There are highly inconsistent results among past studies examining the interaction of\n                          <jats:italic>APOE<\/jats:italic>\n                          genotype and estrogens on cognitive function and other brain outcomes.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What new information does this article contribute?<\/jats:title>\n                    <jats:p>\n                      Vascular outcomes were not measured in previous studies examining the interaction between\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype and estrogens. As such, we aimed to determine the impact of\n                      <jats:italic>APOE4<\/jats:italic>\n                      genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in\n                      <jats:italic>APOE3<\/jats:italic>\n                      mice following ovariectomy. In contrast,\n                      <jats:italic>APOE4<\/jats:italic>\n                      mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.23.666474","type":"posted-content","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T14:55:10Z","timestamp":1753800910000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>APOE4<\/i>\n                  genotype negates the benefits of 17\u03b2-estradiol on cerebrovascular endothelial and mitochondrial function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-8499","authenticated-orcid":false,"given":"Mackenzie N","family":"Kehmeier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Famiano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0375-9712","authenticated-orcid":false,"given":"Abigail E","family":"Cullen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Leonhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Skylyn","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeleine","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1177-9040","authenticated-orcid":false,"given":"Carrie E","family":"McCurdy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-6724","authenticated-orcid":false,"given":"Daniel","family":"Tyrrell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3489-4730","authenticated-orcid":false,"given":"Nabil J","family":"Alkayed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1612-4545","authenticated-orcid":false,"given":"Ashley E","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025073114550916000_2025.07.23.666474v1.1","first-page":"1349","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease","volume":"278","year":"1997","journal-title":"A meta-analysis. 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