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Early interventions that can improve these functions may help delay or slow AD progression. In this study, we repurposed rapamycin (sirolimus), an FDA-approved medication with anti-aging properties, to target APOE4 associated multisystem dysfunction. We conducted a single arm trial of low dose rapamycin (1\u2009mg\/day for 4\u2009weeks) in cognitively normal adults aged 45 to 65\u2009years, prior to detectable AD pathology, stratified by APOE genotype. The primary outcome was cerebral blood flow (CBF), while secondary outcomes included plasma metabolomics, inflammatory cytokines, AD biomarkers, and gut microbiome composition. Twenty-three participants completed the study, including 9 APOE4 carriers and 14 non-carriers. Rapamycin significantly increased CBF in APOE4 carriers, with increases exceeding 15% across multiple brain regions, and improved metabolic and inflammatory profiles with minimal adverse effects. In contrast, non-carriers showed no significant change in CBF and exhibited distinct physiological responses, highlighting genotype dependent effects. These findings suggest that rapamycin may mitigate early cerebrovascular and systemic dysfunction in APOE4 carriers and support a precision medicine approach in which therapeutic response is influenced by genotype.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    ClinicalTrials.gov (NCT05386914). Title: Short Term ApoE-dependent Cerebral Blood Flow Response to Sirolimus in Cognitively Normal Adults (Part I).\n                  <\/jats:p>","DOI":"10.1177\/0271678x261490342","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:28:27Z","timestamp":1789104507000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Rapamycin increases cerebral blood flow and modulates metabolic, inflammatory, and microbiome profiles in healthy middle-aged APOE4 carriers: A pilot single-arm trial"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0892-2803","authenticated-orcid":false,"given":"Chetan","family":"Aware","sequence":"first","affiliation":[{"name":"Department of Radiology, University of Missouri, Columbia, MO, USA"},{"name":"NextGen Precision Health, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8249-6319","authenticated-orcid":false,"given":"Caitlin Maria","family":"Neher","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carter","family":"Woods","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Missouri, Columbia, MO, USA"},{"name":"NextGen Precision Health, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleksandr","family":"Khegai","sequence":"additional","affiliation":[{"name":"Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA"},{"name":"BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4574-1761","authenticated-orcid":false,"given":"Alok Kumar","family":"Dwivedi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Biostatistics, and Medical Epidemiology, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2724-7797","authenticated-orcid":false,"given":"Maalavika","family":"Govindarajan","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Missouri, Columbia, MO, USA"},{"name":"NextGen Precision Health, University of Missouri, Columbia, MO, USA"},{"name":"Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8234-4481","authenticated-orcid":false,"given":"Kira","family":"Ivanich","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Missouri, Columbia, MO, USA"},{"name":"NextGen Precision Health, University of Missouri, Columbia, MO, USA"},{"name":"Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Kurt","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0298-0634","authenticated-orcid":false,"given":"David","family":"Beversdorf","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Missouri, Columbia, MO, USA"},{"name":"Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, USA"},{"name":"Department of Neurology, University of Missouri, Columbia, MO, USA"},{"name":"Department of Psychological Sciences, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlin","family":"Cheng","sequence":"additional","affiliation":[{"name":"NextGen Precision Health, University of Missouri, Columbia, MO, USA"},{"name":"Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA"},{"name":"Institute for Data Science &amp; 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