{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:05:37Z","timestamp":1785207937610,"version":"3.55.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Suzhou Municipal Bureau on Science and Technology","award":["SYW2025166"],"award-info":[{"award-number":["SYW2025166"]}]},{"name":"Suzhou Municipal Health Commission Science and Education Strengthening Health Project","award":["MSXM2024059"],"award-info":[{"award-number":["MSXM2024059"]}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Apolipoprotein E (APOE) epsilon4 (\u03b54) is a major genetic risk factor for late-onset Alzheimer\u2019s disease (AD), with women exhibiting heightened vulnerability to APOE \u03b54-associated cognitive impairment. Despite recognition of this sexual dimorphism, the underlying biological mechanisms remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data from the Mayo Clinic cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f277 temporal cortex samples) to identify sex- and APOE \u03b54-linked co-expression modules. 315 hub genes were identified within the most relevant gene modules derived from female AD patients with APOE \u03b54. The expression patterns of representative hub genes were then validated in female APOE \u03b54 carriers. Causal genes were prioritized via Summary-data-based Mendelian Randomization (SMR), and diagnostic biomarkers were identified using machine learning. Single-cell RNA-seq elucidated cell-type-specific gene expression, and Connectivity Map (CMap) screening nominated candidate therapeutics validated in a tauopathy mouse model (AAV-hTau-injected APP\/PS1 mice).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four co-expression modules (\n                      <jats:italic>tan<\/jats:italic>\n                      ,\n                      <jats:italic>blue2<\/jats:italic>\n                      ,\n                      <jats:italic>grey60<\/jats:italic>\n                      ,\n                      <jats:italic>antiquewhite4<\/jats:italic>\n                      ) specifically correlated with female AD patients with APOE \u03b54-positive and were enriched for vascular endothelial development and extracellular matrix pathways. Ten hub genes were implicated in the pathogenesis of female-specific APOE \u03b54 AD.\n                      <jats:italic>LAMC1<\/jats:italic>\n                      ,\n                      <jats:italic>RBMS2<\/jats:italic>\n                      ,\n                      <jats:italic>TMOD3<\/jats:italic>\n                      , and\n                      <jats:italic>LRP10<\/jats:italic>\n                      were suggested as key drivers of AD progression associated with endothelial dysfunction. Single-cell analysis confirmed endothelial-specific upregulation of these genes in female APOE \u03b54 AD brains. Drug repositioning nominated the vasodilator vincamine, which downregulated\n                      <jats:italic>Lrp10<\/jats:italic>\n                      ,\n                      <jats:italic>Lamc1<\/jats:italic>\n                      in cortex tissue, and effectively inhibited the tau protein propagation from the medial entorhinal cortex (MEC) to the hippocampus in female AD mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>we reveal a female-specific APOE \u03b54-driven molecular network linking endothelial dysfunction to tau pathology. These hub genes provide potential biomarkers, while vincamine represents a targeted prevention and therapeutic candidate for high-risk APOE \u03b54-positive women.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2025.1683204","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T06:27:21Z","timestamp":1764656841000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["APOE \u03b54 allele drives female-specific Alzheimer\u2019s disease progression via vascular dysfunction and tau spreading"],"prefix":"10.3389","volume":"19","author":[{"given":"Shuai","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1002\/ana.24135","article-title":"Sex modifies the APOE-related risk of developing Alzheimer disease","volume":"75","author":"Altmann","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1001\/jamaneurol.2023.3599","article-title":"APOE genotype and Alzheimer disease risk across age, sex, and population ancestry","volume":"80","author":"Belloy","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1161\/STROKEAHA.122.036946","article-title":"Neuroinflammation, stroke, blood-brain barrier dysfunction, and imaging modalities","volume":"53","author":"Candelario-Jalil","year":"2022","journal-title":"Stroke"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.cmet.2021.02.007","article-title":"The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity","volume":"33","author":"Chen","year":"2021","journal-title":"Cell Metab."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/bs.apcsb.2024.08.004","article-title":"The cross-talk between ApoE and tau protein in Alzheimer's disease","volume":"146","author":"Chinnathambi","year":"2025","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1001\/jamaneurol.2025.0013","article-title":"Sex differences in longitudinal tau-PET in preclinical Alzheimer disease: a Meta-analysis","volume":"82","author":"Coughlan","year":"2025","journal-title":"JAMA Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"8254","DOI":"10.1523\/JNEUROSCI.0305-12.2012","article-title":"Gender modulates the APOE epsilon4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels","volume":"32","author":"Damoiseaux","year":"2012","journal-title":"J. Neurosci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1001\/jamaneurol.2021.2806","article-title":"Sex-specific Association of the X Chromosome with Cognitive Change and tau Pathology in aging and Alzheimer disease","volume":"78","author":"Davis","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/s41582-018-0032-9","article-title":"Sex differences in Alzheimer disease - the gateway to precision medicine","volume":"14","author":"Ferretti","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1001\/jamaneurol.2020.0528","article-title":"Positron emission tomography imaging with [18F]flortaucipir and postmortem assessment of Alzheimer disease Neuropathologic changes","volume":"77","author":"Fleisher","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41593-024-01801-5","article-title":"Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease","volume":"28","author":"Fowler","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e22220","DOI":"10.1096\/fj.202101011R","article-title":"Erythroid differentiation in mouse erythroleukemia cells depends on Tmod3-mediated regulation of actin filament assembly into the erythroblast membrane skeleton","volume":"36","author":"Ghosh","year":"2022","journal-title":"FASEB J."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/S1474-4422(20)30440-3","article-title":"New insights into atypical Alzheimer's disease in the era of biomarkers","volume":"20","author":"Graff-Radford","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/pl00007425","article-title":"Practical measures to simplify the Braak tangle staging method for routine pathological screening","volume":"99","author":"Harding","year":"2000","journal-title":"Acta Neuropathol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.neuroimage.2014.04.081","article-title":"Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults","volume":"98","author":"Heise","year":"2014","journal-title":"NeuroImage"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1016\/j.jalz.2018.08.004","article-title":"The clinical practice of risk reduction for Alzheimer's disease: a precision medicine approach","volume":"14","author":"Isaacson","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/s41586-019-1769-z","article-title":"NLRP3 inflammasome activation drives tau pathology","volume":"575","author":"Ising","year":"2019","journal-title":"Nature"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1177\/13872877251360321","article-title":"From APOE to cellular changes: unraveling the multidimensional mechanisms of blood-brain barrier damage in Alzheimer's disease","volume":"107","author":"Jiang","year":"2025","journal-title":"J Alzheimer's Dis"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.chroma.2005.01.043","article-title":"Measurement and pharmacokinetics of vincamine in rat blood and brain using microdialysis","volume":"1088","author":"Juan","year":"2005","journal-title":"J. Chromatogr. A"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"4260","DOI":"10.1016\/j.cell.2023.08.021","article-title":"Alzheimer's disease: from immunotherapy to immunoprevention","volume":"186","author":"Jucker","year":"2023","journal-title":"Cell"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2651","DOI":"10.1016\/j.immuni.2024.09.014","article-title":"Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding beta-amyloidosis","volume":"57","author":"Kaji","year":"2024","journal-title":"Immunity"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/s41586-021-04330-4","article-title":"Androgens increase excitatory neurogenic potential in human brain organoids","volume":"602","author":"Kelava","year":"2022","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.2174\/1570159X18666200528142429","article-title":"Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer's disease","volume":"18","author":"Khan","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.jalz.2012.09.012","article-title":"The Finnish geriatric intervention study to prevent cognitive impairment and disability (FINGER): study design and progress","volume":"9","author":"Kivipelto","year":"2013","journal-title":"Alzheimers Dement."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"4411","DOI":"10.3390\/ijms20184411","article-title":"Vascular endothelial cell biology: an update","volume":"20","author":"Kruger-Genge","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"6336","DOI":"10.3390\/ijms21176336","article-title":"ApoE Lipidation as a therapeutic target in Alzheimer's disease","volume":"21","author":"Lanfranco","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.yjmcc.2009.09.018","article-title":"Extracellular matrix alterations in hypertensive vascular remodeling","volume":"48","author":"Lemarie","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s00401-018-1815-1","article-title":"Functional morphology of the blood-brain barrier in health and disease","volume":"135","author":"Liebner","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","article-title":"Single-cell transcriptomic analysis of Alzheimer's disease","volume":"570","author":"Mathys","year":"2019","journal-title":"Nature"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1161\/01.cir.81.6.1874","article-title":"Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells","volume":"81","author":"Miyauchi","year":"1990","journal-title":"Circulation"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3352","DOI":"10.1002\/alz.13770","article-title":"Minimal clinically important difference in Alzheimer's disease: rapid review","volume":"20","author":"Muir","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref33","first-page":"166","article-title":"Escherichia coli alkaline phosphatase","volume":"31","author":"Nakata","year":"1986","journal-title":"Tanpakushitsu Kakusan Koso"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/S1474-4422(22)00168-5","article-title":"Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials","volume":"21","author":"Ossenkoppele","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.ajpath.2023.09.012","article-title":"The role of endothelial cells in atherosclerosis: insights from genetic association studies","volume":"194","author":"Pepin","year":"2024","journal-title":"Am. J. Pathol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13024-022-00574-4","article-title":"ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies","volume":"17","author":"Raulin","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/s0140-6736(20)32205-4","article-title":"Alzheimer's disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"225","DOI":"10.14283\/jpad.2018.34","article-title":"Female sex and Alzheimer's risk: the menopause connection","volume":"5","author":"Scheyer","year":"2018","journal-title":"J. Prev Alzheimers Dis."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e2460","DOI":"10.1212\/WNL.0000000000207905","article-title":"Validation study of the MDS criteria for the diagnosis of multiple system atrophy in the Mayo Clinic brain Bank","volume":"101","author":"Sekiya","year":"2023","journal-title":"Neurology"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/S1474-4422(20)30412-9","article-title":"APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches","volume":"20","author":"Serrano-Pozo","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/978-3-319-77932-4_27","article-title":"Sex-specific physiology and cardiovascular disease","volume":"1065","author":"Shufelt","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1093\/humupd\/dmr027","article-title":"Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis","volume":"17","author":"Su","year":"2011","journal-title":"Hum. Reprod. Update"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A next generation connectivity map: L1000 platform and the first 1,000,000 profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s10194-024-01828-w","article-title":"Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine","volume":"25","author":"Sun","year":"2024","journal-title":"J. Headache Pain"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s43587-022-00204-0","article-title":"Biomarker modeling of Alzheimer's disease using PET-based Braak staging","volume":"2","author":"Therriault","year":"2022","journal-title":"Nat Aging"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/cvr\/cvy023","article-title":"Vascular smooth muscle contraction in hypertension","volume":"114","author":"Touyz","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"e14412","DOI":"10.1002\/alz.14412","article-title":"Longitudinal synaptic loss versus tau Braak staging in amnestic mild cognitive impairment","volume":"21","author":"Vanderlinden","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"104784","DOI":"10.1016\/j.nbd.2020.104784","article-title":"APOE-amyloid interaction: therapeutic targets","volume":"138","author":"Wisniewski","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"21969","DOI":"10.1038\/s41598-024-67283-4","article-title":"Comparative study of ten machine learning algorithms for short-term forecasting in gas warning systems","volume":"14","author":"Wu","year":"2024","journal-title":"Sci. Rep."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"114776","DOI":"10.1016\/j.expneurol.2024.114776","article-title":"LAMC1 attenuates neuronal apoptosis via FAK\/PI3K\/AKT signaling pathway after subarachnoid hemorrhage","volume":"376","author":"Wu","year":"2024","journal-title":"Exp. Neurol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1007\/s12640-018-9895-1","article-title":"Clearance of amyloid Beta and tau in Alzheimer's disease: from mechanisms to therapy","volume":"34","author":"Xin","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/s41586-022-04463-0","article-title":"FSH blockade improves cognition in mice with Alzheimer's disease","volume":"603","author":"Xiong","year":"2022","journal-title":"Nature"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s12916-023-02878-8","article-title":"Oxidative stress gene expression, DNA methylation, and gut microbiota interaction trigger Crohn's disease: a multi-omics Mendelian randomization study","volume":"21","author":"Xu","year":"2023","journal-title":"BMC Med."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"4145","DOI":"10.1113\/jphysiol.2012.232306","article-title":"Deciphering actin cytoskeletal function in the contractile vascular smooth muscle cell","volume":"590","author":"Yamin","year":"2012","journal-title":"J. Physiol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"2812","DOI":"10.3390\/molecules29122812","article-title":"Role of tau protein in neurodegenerative diseases and development of its targeted drugs: a literature review","volume":"29","author":"Yang","year":"2024","journal-title":"Molecules"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13024-022-00562-8","article-title":"Trem2 deletion enhances tau dispersion and pathology through microglia exosomes","volume":"17","author":"Zhu","year":"2022","journal-title":"Mol. Neurodegener."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1683204\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T06:27:22Z","timestamp":1764656842000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1683204\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":57,"alternative-id":["10.3389\/fnins.2025.1683204"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1683204","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,2]]},"article-number":"1683204"}}