{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:23:13Z","timestamp":1789154593771,"version":"build-2803163510"},"posted":{"date-parts":[[2025,9,9]]},"group-title":"Neuroscience","reference-count":174,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["80ARC022CA004"],"award-info":[{"award-number":["80ARC022CA004"]}],"id":[{"id":"https:\/\/ror.org\/027ka1x80","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG089533"],"award-info":[{"award-number":["R01AG089533"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UH3NS115064"],"award-info":[{"award-number":["UH3NS115064"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG063819"],"award-info":[{"award-number":["R01AG063819"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 AG064020"],"award-info":[{"award-number":["R01 AG064020"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32GM146636"],"award-info":[{"award-number":["T32GM146636"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54AG090669"],"award-info":[{"award-number":["U54AG090669"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/05ewr7t48","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cerebrovascular disease is a major but poorly understood feature of Alzheimer\u2019s disease (AD). The strongest genetic AD risk factor, APOE4, is associated with cerebrovascular degeneration, including vascular amyloid deposition and fibrosis. To uncover how APOE4 promotes cerebrovascular pathology, we assembled a single-cell transcriptomic atlas of human brain vasculature. In APOE4 carriers, pericyte abundance was significantly reduced and accompanied by the emergence of a myofibroblast-like cell population co-expressing contraction and extracellular matrix genes. Immunostaining confirmed non-vascular myofibroblasts in APOE4 human and mouse brains. We show that APOE4 pericytes transition into myofibroblasts that secrete fibronectin, which promotes vascular amyloid accumulation. Computational and experimental analyses identified elevated TGF-\u03b2 signaling as the driver of this pericyte-to-myofibroblast transition. Inhibition of TGF-\u03b2 restored pericyte coverage and reduced vascular fibrosis and amyloid to APOE3 levels, revealing a targetable mechanism linking APOE4 to cerebrovascular pathology in AD.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>Cerebrovascular disease is a prominent but poorly understood component of Alzheimer\u2019s disease (AD). The strongest genetic risk factor for AD, APOE4, is associated with multiple cerebrovascular pathologies, including vascular amyloid accumulation and fibrosis. APOE4 also renders the cerebrovasculature fragile to the point where the only disease-modifying AD therapeutic, anti-amyloid monoclonal antibodies, are warned against use in APOE4 carriers due to a high risk of hemorrhage and edema. To determine how APOE4 impacts cerebrovascular cells and pathogenesis, we assembled a high-resolution single-cell transcriptomics atlas of human cerebrovasculature from APOE4 carriers and non-carriers. In APOE4 individuals, we found that the number of microvascular pericytes was significantly reduced. Notably, loss of pericytes in APOE4 carriers was accompanied by the emergence of a unique population of mural cells characterized by high expression of contraction and extracellular matrix (ECM) genes, hallmarks of myofibroblasts. Immunostaining revealed the presence of myofibroblasts surrounding the microvasculature in APOE4 human hippocampi that were absent in age-matched APOE3\/3 controls, even in cases of AD. Myofibroblast presence coincided with a significant increase in fibronectin and amyloid surrounding the vasculature. Myofibroblasts were also present around the microvasculature of aged APOE4\/4 but not APOE3\/3 mice, suggesting myofibroblast appearance is a direct effect of the APOE4 genotype and not a technical artifact of processing human tissue. To determine the mechanisms and functional implications of APOE4-mediated myofibroblast, we leveraged a vascularized human brain tissue (miBrain) derived from induced pluripotent stem cells. Similar to the post-mortem human brain, APOE4\/4 miBrains showed significantly reduced microvascular pericyte coverage, coinciding with the emergence of myofibroblasts co-expressing ECM and contractile genes. Lineage tracing and genetic mixing experiments confirmed that the myofibroblasts emerge from APOE4 pericytes and secrete fibronectin-rich ECM. Knocking down fibronectin in APOE4 mural cells significantly reduced vascular amyloid accumulation. To determine how myofibroblast-like cells arise in the APOE4 brain, we performed computational analysis (NicheNet) on our post-mortem human single-cell transcriptomics cerebrovascular atlas. This predicted that TGF-\u03b2 is the top causal driver of the pericyte-to-myofibroblast transition. Consistent with this prediction, we found that TGF-\u03b2 ligands in astrocytes and receptors in mural cells are significantly upregulated compared to APOE3 controls. Chemical inhibition of TGF-\u03b2 signaling in APOE4 miBrains and APOE4-TR mice significantly reduced myofibroblast presence, while concurrently increasing pericyte microvascular coverage and ultimately lowering vascular fibrosis and amyloid accumulation to APOE3 levels. Using a comprehensive three-pronged approach incorporating analysis of human post-mortem brain, APOE humanized mice, and human iPSC-derived vascularized brain tissue, we demonstrate that APOE4 causes increased TGF-\u03b2 signaling, promoting a pericyte-to-myofibroblast transition that leads to vascular fibrosis and amyloid deposition. This provides critical insight into the mechanisms underlying APOE4 cerebrovascular dysfunction, highlighting new diagnostic and therapeutic strategies for a major AD risk population.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.04.674192","type":"posted-content","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:30:12Z","timestamp":1757431812000},"source":"Crossref","is-referenced-by-count":2,"title":["APOE4 promotes cerebrovascular fibrosis and amyloid deposition via a pericyte-to-myofibroblast transition"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1737-707X","authenticated-orcid":false,"given":"Braxton R.","family":"Schuldt","sequence":"first","affiliation":[{"name":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"},{"name":"Institute for Regenerative Medicine, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Haworth-Staines","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"},{"name":"Ronald M. 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