{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:52:09Z","timestamp":1790855529107,"version":"4.1.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Alz Res Therapy"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The E4 variant of Apolipoprotein E (APOE) is a primary genetic susceptibility risk factor for late-onset Alzheimer\u2019s disease and has been implicated in cerebrovascular dysfunction. Preclinical mouse models are widely used to study APOE4, but cohesive understanding of APOE\u2019s role is still inconsistent and lacking. The aim of this study was to systematically review and synthesise evidence from preclinical mouse studies assessing APOE4 related effects on blood-brain barrier (BBB) integrity, vascular morphology and cerebral blood flow (CBF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main<\/jats:title>\n                    <jats:p>A systematic search of MEDLINE, Embase, Scopus, and Web of Science was conducted (March-April 2025). Eligible studies included transgenic APOE-targeted replacement or knock-in mice reporting vascular outcomes (cerebral blood flow, blood brain barrier permeability, vascular measures). Risk of bias was assessed using SYRCLE and reporting quality with CAMARADES. Random-effects meta-analyses were conducted (where sufficient data was available), otherwise findings were narratively synthesised. Eighteen studies met inclusion. Outcome measures varied widely, including diverse approaches to CBF measurement (e.g. arterial spin labelling, autoradiography, DSC-MRI), immunohistochemical measures (e.g. collagen-IV, laminin, CD31), and diverse approaches to measurement of BBB leakage (e.g. fibronectin, fibrinogen, gadolinium-based ktrans). Seven studies contributed to meta-analysis: APOE4 mice showed a consistent reduction in CBF associated with APOE4 genotype (SMD = -2.87, 95% CI: -5.14 to -0.604, df = 2.66), and a negative non-significant trend towards reduced vascular morphology expression. Narrative synthesis identified three key mechanistic pathways linking APOE4 to vascular dysfunction: (i) insulin resistance and PI3K\/AKT-mTOR signalling, (ii) Cyclophilin A\u2013NF\u03baB\u2013MMP9 activation, and (iii) occludin\/ECM remodelling. Risk of bias assessment revealed frequent shortcomings in randomisation, blinding, and sample size justification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Preclinical evidence demonstrates that APOE4 drives alterations in vascular functioning primarily through involvement with pathways related to vascular metabolism, ECM remodelling and BBB leakage. However, heterogeneity in the model (e.g. age, sex, techniques), restricts direct comparability across studies. As such, standardisation or clarification of methodological approaches are necessary for rigorous assessment in the future.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13195-026-02018-3","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T12:25:52Z","timestamp":1778156752000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impact of Apolipoprotein E4 on blood-brain barrier integrity in target replacement murine models: a systematic review and meta-analysis"],"prefix":"10.1186","volume":"18","author":[{"given":"Krystal K.","family":"Laing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nela","family":"Fialova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Wardlaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Montagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"2018_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.nbd.2014.08.025","volume":"72","author":"Y Huang","year":"2014","unstructured":"Huang Y, Mahley RW, Apolipoprotein E. Structure and function in lipid metabolism, neurobiology, and Alzheimer\u2019s diseases. Neurobiol Dis. 2014;72:3\u201312.","journal-title":"Neurobiol Dis"},{"issue":"9","key":"2018_CR2","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/iub.1314","volume":"66","author":"MC Phillips","year":"2014","unstructured":"Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life. 2014;66(9):616\u201323.","journal-title":"IUBMB Life"},{"issue":"2","key":"2018_CR3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/s41583-023-00776-9","volume":"25","author":"J Blumenfeld","year":"2024","unstructured":"Blumenfeld J, Yip O, Kim MJ, Huang Y. Cell type-specific roles of APOE4 in Alzheimer disease. Nat Rev Neurosci. 2024;25(2):91\u2013110.","journal-title":"Nat Rev Neurosci"},{"issue":"16","key":"2018_CR4","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","volume":"278","author":"LA Farrer","year":"1997","unstructured":"Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis. JAMA. 1997;278(16):1349\u201356.","journal-title":"JAMA"},{"issue":"5123","key":"2018_CR5","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","volume":"261","author":"EH Corder","year":"1993","unstructured":"Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer\u2019s Disease in Late Onset Families. Science. 1993;261(5123):921\u20133.","journal-title":"Science"},{"issue":"7399","key":"2018_CR6","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/nature11087","volume":"485","author":"RD Bell","year":"2012","unstructured":"Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485(7399):512\u20136.","journal-title":"Nature"},{"issue":"1","key":"2018_CR7","doi-asserted-by":"publisher","first-page":"3816","DOI":"10.1038\/s41467-018-06301-2","volume":"9","author":"K Koizumi","year":"2018","unstructured":"Koizumi K, Hattori Y, Ahn SJ, Buendia I, Ciacciarelli A, Uekawa K, et al. Apo\u03b54 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat Commun. 2018;9(1):3816.","journal-title":"Nat Commun"},{"issue":"9","key":"2018_CR8","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.3390\/ijms20092161","volume":"20","author":"GL Suidan","year":"2019","unstructured":"Suidan GL, Ramaswamy G. Targeting Apolipoprotein E for Alzheimer\u2019s Disease: An Industry Perspective. Int J Mol Sci. 2019;20(9):2161.","journal-title":"Int J Mol Sci"},{"issue":"2","key":"2018_CR9","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","volume":"9","author":"CC Liu","year":"2013","unstructured":"Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106\u201318.","journal-title":"Nat Rev Neurol"},{"issue":"5","key":"2018_CR10","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/gim.2015.117","volume":"18","author":"C Van Cauwenberghe","year":"2016","unstructured":"Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016;18(5):421\u201330.","journal-title":"Genet Med"},{"issue":"3","key":"2018_CR11","doi-asserted-by":"publisher","first-page":"222","DOI":"10.3390\/genes10030222","volume":"10","author":"P Abondio","year":"2019","unstructured":"Abondio P, Sazzini M, Garagnani P, Boattini A, Monti D, Franceschi C, et al. The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity. Genes. 2019;10(3):222.","journal-title":"Genes"},{"issue":"2","key":"2018_CR12","doi-asserted-by":"publisher","first-page":"NS20180203","DOI":"10.1042\/NS20180203","volume":"3","author":"HC Hunsberger","year":"2019","unstructured":"Hunsberger HC, Pinky PD, Smith W, Suppiramaniam V, Reed MN. The role of APOE4 in Alzheimer\u2019s disease: strategies for future therapeutic interventions. Neuronal Signal. 2019;3(2):NS20180203.","journal-title":"Neuronal Signal"},{"issue":"1","key":"2018_CR13","doi-asserted-by":"publisher","first-page":"778","DOI":"10.3390\/ijms24010778","volume":"24","author":"M Pires","year":"2023","unstructured":"Pires M, Rego AC. Apoe4 and Alzheimer\u2019s Disease Pathogenesis\u2014Mitochondrial Deregulation and Targeted Therapeutic Strategies. Int J Mol Sci. 2023;24(1):778.","journal-title":"Int J Mol Sci"},{"key":"2018_CR14","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13024-020-00391-7","volume":"15","author":"T Guo","year":"2020","unstructured":"Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer\u2019s disease. Mol Neurodegener. 2020;15:40.","journal-title":"Mol Neurodegener"},{"key":"2018_CR15","doi-asserted-by":"publisher","unstructured":"Foley KE, Wilcock DM. Three major effects of APOE\u03b54 on A\u03b2 immunotherapy induced ARIA. Front Aging Neurosci. 2024 May 2;16. Available from: https:\/\/www.frontiersin.org\/journals\/aging-neuroscience\/articles\/https:\/\/doi.org\/10.3389\/fnagi.2024.1412006\/full. Cited 11 Feb 2025.","DOI":"10.3389\/fnagi.2024.1412006\/full"},{"issue":"11","key":"2018_CR16","doi-asserted-by":"publisher","first-page":"4414","DOI":"10.1093\/brain\/awad188","volume":"146","author":"H Hampel","year":"2023","unstructured":"Hampel H, Elhage A, Cho M, Apostolova LG, Nicoll JAR, Atri A. Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain. 2023;146(11):4414\u201324.","journal-title":"Brain"},{"issue":"1","key":"2018_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000334607","volume":"38","author":"A Ward","year":"2012","unstructured":"Ward A, Crean S, Mercaldi CJ, Collins JM, Boyd D, Cook MN, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4\/4) among patients diagnosed with Alzheimer\u2019s disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):1\u201317.","journal-title":"Neuroepidemiology"},{"key":"2018_CR18","doi-asserted-by":"publisher","first-page":"104811","DOI":"10.1016\/j.nbd.2020.104811","volume":"139","author":"CT Lewandowski","year":"2020","unstructured":"Lewandowski CT, Weng JM, LaDu MJ. Alzheimer\u2019ss Disease Pathology in ApoE Transgenic Mouse Models: The Who, What, When, Where, Why, and How. Neurobiol Dis. 2020;139:104811.","journal-title":"Neurobiol Dis"},{"issue":"7806","key":"2018_CR19","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41586-020-2247-3","volume":"581","author":"A Montagne","year":"2020","unstructured":"Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020;581(7806):71\u20136.","journal-title":"Nature"},{"issue":"6","key":"2018_CR20","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1038\/s43587-021-00073-z","volume":"1","author":"A Montagne","year":"2021","unstructured":"Montagne A, Nikolakopoulou AM, Huuskonen MT, Sagare AP, Lawson EJ, Lazic D, et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer\u2019s mice via cyclophilin A independently of amyloid-\u03b2. Nat Aging. 2021;1(6):506\u201320.","journal-title":"Nat Aging"},{"key":"2018_CR21","first-page":"100131","volume":"3","author":"A Kapoor","year":"2022","unstructured":"Kapoor A, Nation DA. Platelet-derived growth factor-BB and white matter hyperintensity burden in APOE4 carriers. Cereb Circ - Cogn Behav. 2022;3:100131.","journal-title":"Cereb Circ - Cogn Behav"},{"issue":"6","key":"2018_CR22","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1038\/s41591-020-0886-4","volume":"26","author":"JW Blanchard","year":"2020","unstructured":"Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L, Frank A, et al. Reconstruction of the Human Blood-Brain Barrier in vitro reveals a Pathogenic Mechanism of APOE4 in Pericytes. Nat Med. 2020;26(6):952\u201363.","journal-title":"Nat Med"},{"key":"2018_CR23","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","volume":"372","author":"MJ Page","year":"2021","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.","journal-title":"BMJ"},{"key":"2018_CR24","doi-asserted-by":"crossref","unstructured":"Bahor Z, Liao J, Currie G, Ayder C, Macleod M, McCann SK et al. Development and uptake of an online systematic review platform: the early years of the CAMARADES Systematic Review Facility (SyRF). BMJ Open Sci. 2021 Mar 31;5(1). Available from: http:\/\/access.portico.org\/stable?au=phzmqrt8kdx. Cited 1 Jun 2025.","DOI":"10.1136\/bmjos-2020-100103"},{"key":"2018_CR25","unstructured":"Rhea EM, Hansen K, Pemberton S, Torres ERS, Holden S, Raber J et al. Effects of apolipoprotein E isoform, sex, and diet on insulin BBB pharmacokinetics in mice. Sci Rep. 2021;11(1). Available from: https:\/\/www.scopus.com\/inward\/record.uri?eid=2-s2.0-85115398840&doi=10.1038%2fs41598-021-98061-1&partnerID=40&md5=367fc7cda7da7aeafa7603dd86c6cc43."},{"issue":"9","key":"2018_CR26","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1194\/jlr.R076315","volume":"58","author":"LM Tai","year":"2017","unstructured":"Tai LM, Balu D, Avila-Munoz E, Abdullah L, Thomas R, Collins N, et al. EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimer\u0149s disease [S]. J Lipid Res. 2017;58(9):1733\u201355.","journal-title":"J Lipid Res"},{"issue":"1\u20132","key":"2018_CR27","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.jns.2009.03.002","volume":"283","author":"JC Shenk","year":"2009","unstructured":"Shenk JC, Liu J, Fischbach K, Xu K, Puchowicz M, Obrenovich ME, et al. The effect of acetyl-L-carnitine and R-\u03b1-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer\u2019s disease. J Neurol Sci. 2009;283(1\u20132):199\u2013206.","journal-title":"J Neurol Sci"},{"issue":"5","key":"2018_CR28","first-page":"1841","volume":"219","author":"D Jansen","year":"2014","unstructured":"Jansen D, Zerbi V, Janssen CIF, van Rooij D, Zinnhardt B, Dederen PJ, et al. Impact of a multi-nutrient diet on cognition, brain metabolism, hemodynamics, and plasticity in apoE4 carrier and apoE knockout mice. Brain Struct Funct. 2014;219(5):1841\u201368.","journal-title":"Brain Struct Funct"},{"issue":"42","key":"2018_CR29","doi-asserted-by":"publisher","first-page":"13963","DOI":"10.1523\/JNEUROSCI.0684-14.2014","volume":"34","author":"V Zerbi","year":"2014","unstructured":"Zerbi V, Wiesmann M, Emmerzaal TL, Jansen D, Van Beek M, Mutsaers MPC, et al. Resting-state functional connectivity changes in aging apoE4 and apoE-KO mice. J Neurosci Off J Soc Neurosci. 2014;34(42):13963\u201375.","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"2018_CR30","unstructured":"Rohatgi A. WebPlotDigitizer. automeris.io; 2025. Available from: https:\/\/automeris.io. Cited 17 Jan 2025."},{"issue":"20","key":"2018_CR31","doi-asserted-by":"publisher","first-page":"17536","DOI":"10.1074\/jbc.M111.225532","volume":"286","author":"K Nishitsuji","year":"2011","unstructured":"Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem. 2011;286(20):17536\u201342.","journal-title":"J Biol Chem"},{"issue":"1","key":"2018_CR32","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/jcbfm.2014.172","volume":"35","author":"W Alata","year":"2015","unstructured":"Alata W, Ye Y, St-Amour I, Vandal M, Calon F. Human apolipoprotein E \u025b4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J Cereb Blood Flow Metab. 2015;35(1):86\u201394. https:\/\/doi.org\/10.1038\/jcbfm.2014.172.","journal-title":"J Cereb Blood Flow Metab"},{"key":"2018_CR33","unstructured":"Thomas R, Morris AWJ, Tai LM. Epidermal growth factor prevents APOE4-induced cognitive and cerebrovascular deficits in female mice. Heliyon. 2017;3(6). Available from: https:\/\/www.scopus.com\/inward\/record.uri?eid=2-s2.0-85020180648&doi=10.1016%2fj.heliyon.2017.e00319&partnerID=40&md5=9e788ede5036ea91221ed97b94b08774."},{"issue":"1","key":"2018_CR34","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1177\/0271678X15621575","volume":"37","author":"AL Lin","year":"2017","unstructured":"Lin AL, Jahrling JB, Zhang W, DeRosa N, Bakshi V, Romero P, et al. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer\u2019s disease. J Cereb Blood Flow Metab. 2017;37(1):217\u201326.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"4","key":"2018_CR35","doi-asserted-by":"publisher","first-page":"175909141771920","DOI":"10.1177\/1759091417719201","volume":"9","author":"FM Marottoli","year":"2017","unstructured":"Marottoli FM, Katsumata Y, Koster KP, Thomas R, Fardo DW, Tai LM. Peripheral Inflammation, Apolipoprotein E4, and Amyloid-\u03b2 Interact to Induce Cognitive and Cerebrovascular Dysfunction. ASN Neuro. 2017;9(4):1759091417719201.","journal-title":"ASN Neuro"},{"issue":"5","key":"2018_CR36","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1177\/0271678X17746186","volume":"39","author":"LA Johnson","year":"2019","unstructured":"Johnson LA, Torres ER, Weber Boutros S, Patel E, Akinyeke T, Alkayed NJ, et al. Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response. J Cereb Blood Flow Metab. 2019;39(5):770\u201381.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"1","key":"2018_CR37","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1161\/ATVBAHA.119.313169","volume":"40","author":"Y Yamazaki","year":"2020","unstructured":"Yamazaki Y, Shinohara M, Yamazaki A, Ren Y, Asmann YW, Kanekiyo T, et al. ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by Modulating Basement Membrane Components. Arter Thromb Vasc Biol. 2020;40(1):128\u201344.","journal-title":"Arter Thromb Vasc Biol"},{"key":"2018_CR38","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.neurobiolaging.2020.06.018","volume":"95","author":"C Ringland","year":"2020","unstructured":"Ringland C, Schweig JE, Paris D, Shackleton B, Lynch CE, Eisenbaum M, et al. Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer\u2019s disease. Neurobiol Aging. 2020;95:56\u201368.","journal-title":"Neurobiol Aging"},{"key":"2018_CR39","doi-asserted-by":"publisher","first-page":"104834","DOI":"10.1016\/j.nbd.2020.104834","volume":"139","author":"AL Lin","year":"2020","unstructured":"Lin AL, Parikh I, Yanckello LM, White RS, Hartz AMS, Taylor CE, et al. APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer\u2019s disease. Neurobiol Dis. 2020;139:104834.","journal-title":"Neurobiol Dis"},{"key":"2018_CR40","doi-asserted-by":"crossref","unstructured":"Barisano G, Kisler K, Wilkinson B, Nikolakopoulou AM, Sagare AP, Wang Y et al. A \u2018multi-omics\u2019 analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice. J Exp Med. 2022;219(11).","DOI":"10.1084\/jem.20221137"},{"issue":"10","key":"2018_CR41","doi-asserted-by":"publisher","first-page":"3582","DOI":"10.1093\/brain\/awab478","volume":"145","author":"RJ Jackson","year":"2022","unstructured":"Jackson RJ, Meltzer JC, Nguyen H, Commins C, Bennett RE, Hudry E, et al. APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain. 2022;145(10):3582\u201393.","journal-title":"Brain"},{"issue":"8","key":"2018_CR42","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1080\/1028415X.2021.1889452","volume":"25","author":"LM Yanckello","year":"2022","unstructured":"Yanckello LM, Hoffman JD, Chang YH, Lin P, Nehra G, Chlipala G, et al. Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis. Nutr Neurosci. 2022;25(8):1669\u201379.","journal-title":"Nutr Neurosci"},{"issue":"7","key":"2018_CR43","doi-asserted-by":"publisher","first-page":"4951","DOI":"10.1002\/alz.13842","volume":"20","author":"KD Onos","year":"2024","unstructured":"Onos KD, Lin PB, Pandey RS, Persohn SA, Burton CP, Miner EW, et al. Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction. Alzheimers Dement. 2024;20(7):4951\u201369.","journal-title":"Alzheimers Dement"},{"key":"2018_CR44","doi-asserted-by":"publisher","unstructured":"Bhattarai P, Yilmaz E, Cakir E\u00d6, Korkmaz HY, Lee AJ, Ma Y et al. APOE-\u03b54-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer\u2019s disease. bioRxiv; 2025. p. 2025.01.24.634732. Available from: https:\/\/www.biorxiv.org\/content\/https:\/\/doi.org\/10.1101\/2025.01.24.634732v1. Cited 28 Jul 2025.","DOI":"10.1101\/2025.01.24.634732v1"},{"issue":"29","key":"2018_CR45","doi-asserted-by":"publisher","first-page":"17972","DOI":"10.1074\/jbc.272.29.17972","volume":"272","author":"PM Sullivan","year":"1997","unstructured":"Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, et al. Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis *. J Biol Chem. 1997;272(29):17972\u201380.","journal-title":"J Biol Chem"},{"issue":"5","key":"2018_CR46","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1161\/01.STR.0000125719.25853.20","volume":"35","author":"MR Macleod","year":"2004","unstructured":"Macleod MR, O\u2019Collins T, Howells DW, Donnan GA. Pooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias. Stroke. 2004;35(5):1203\u20138.","journal-title":"Stroke"},{"issue":"1","key":"2018_CR47","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/1471-2288-14-43","volume":"14","author":"CR Hooijmans","year":"2014","unstructured":"Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE\u2019s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14(1):43.","journal-title":"BMC Med Res Methodol"},{"key":"2018_CR48","doi-asserted-by":"publisher","first-page":"6846721","DOI":"10.1155\/2016\/6846721","volume":"2016","author":"M Wiesmann","year":"2016","unstructured":"Wiesmann M, Zerbi V, Jansen D, Haast R, L\u00fctjohann D, Broersen LM, et al. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice. Neural Plast. 2016;2016:6846721.","journal-title":"Neural Plast"},{"key":"2018_CR49","unstructured":"CAMARADES Systematic Review Wiki. Meta-Analysis. Available from: https:\/\/camarades.de\/wiki-content\/10-metaanalysis.html. Cited 26 Aug 2025."},{"issue":"1","key":"2018_CR50","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/jcbfm.2015.44","volume":"36","author":"MR Halliday","year":"2016","unstructured":"Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, et al. Accelerated pericyte degeneration and blood\u2013brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer\u2019s disease. J Cereb Blood Flow Metab. 2016;36(1):216.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"4","key":"2018_CR51","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1007\/s12017-014-8318-6","volume":"16","author":"C Bachmeier","year":"2014","unstructured":"Bachmeier C, Shackleton B, Ojo J, Paris D, Mullan M, Crawford F. Apolipoprotein E Isoform-Specific Effects on Lipoprotein Receptor Processing. NeuroMol Med. 2014;16(4):686\u201396.","journal-title":"NeuroMol Med"},{"key":"2018_CR52","doi-asserted-by":"crossref","unstructured":"Oue H, Yamazaki Y, Qiao W, Yuanxin C, Ren Y, Kurti A et al. LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4. JCI Insight. 2023 Apr 10;8(7). Available from: https:\/\/insight.jci.org\/articles\/view\/163822. Cited 31 Jul 2024.","DOI":"10.1172\/jci.insight.163822"},{"key":"2018_CR53","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.neurobiolaging.2023.02.013","volume":"127","author":"H Na","year":"2023","unstructured":"Na H, Yang JB, Zhang Z, Gan Q, Tian H, Rajab IM, et al. Peripheral apolipoprotein E proteins and their binding to LRP1 antagonize Alzheimer\u2019s disease pathogenesis in the brain during peripheral chronic inflammation. Neurobiol Aging. 2023;127:54\u201369.","journal-title":"Neurobiol Aging"},{"issue":"11","key":"2018_CR54","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1177\/0271678X231172842","volume":"43","author":"O Bonnar","year":"2023","unstructured":"Bonnar O, Shaw K, Anderle S, Grijseels DM, Clarke D, Bell L, et al. APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice. J Cereb Blood Flow Metab. 2023;43(11):1826\u201341.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"1","key":"2018_CR55","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/s42003-025-07585-z","volume":"8","author":"S Anderle","year":"2025","unstructured":"Anderle S, Bonnar O, Henderson J, Shaw K, Chagas AM, McMullan L, et al. APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice. Commun Biol. 2025;8(1):144.","journal-title":"Commun Biol"},{"key":"2018_CR56","unstructured":"Rhea EM, Torres ERS, Raber J, Banks WA. Insulin BBB pharmacokinetics in young apoE male and female transgenic mice. PLoS ONE. 2020;15(1). Available from: https:\/\/www.scopus.com\/inward\/record.uri?eid=2-s2.0-85078745276&doi=10.1371%2fjournal.pone.0228455&partnerID=40&md5=a33e8c83538370a3279425e62da5608b"},{"issue":"1","key":"2018_CR57","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1073\/pnas.0802741106","volume":"106","author":"T Suzuki","year":"2009","unstructured":"Suzuki T, Elias BC, Seth A, Shen L, Turner JR, Giorgianni F, et al. PKC\u03b7 regulates occludin phosphorylation and epithelial tight junction integrity. Proc Natl Acad Sci. 2009;106(1):61\u20136.","journal-title":"Proc Natl Acad Sci"},{"key":"2018_CR58","unstructured":"Laing K, BioRender. 2025. Evidence-mapping schematic of studies included in the narrative synthesis. Available from: https:\/\/BioRender.com\/b0tt4qm. Cited 2 Nov 2025."},{"issue":"23","key":"2018_CR59","doi-asserted-by":"publisher","first-page":"20572","DOI":"10.1074\/jbc.M100900200","volume":"276","author":"SJ Kridel","year":"2001","unstructured":"Kridel SJ, Chen E, Kotra LP, Howard EW, Mobashery S, Smith JW. Substrate Hydrolysis by Matrix Metalloproteinase-9*. J Biol Chem. 2001;276(23):20572\u20138.","journal-title":"J Biol Chem"},{"key":"2018_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/bs.pmbts.2017.02.005","volume":"147","author":"N Cui","year":"2017","unstructured":"Cui N, Hu M, Khalil RA. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog Mol Biol Transl Sci. 2017;147:1\u201373.","journal-title":"Prog Mol Biol Transl Sci"},{"key":"2018_CR61","doi-asserted-by":"publisher","unstructured":"Kant S, Feng J. Protein kinase C and endothelial dysfunction in select vascular diseases. Front Cardiovasc Med. 2025 Aug 25;12. Available from: https:\/\/www.frontiersin.org\/journals\/cardiovascular-medicine\/articles\/https:\/\/doi.org\/10.3389\/fcvm.2025.1618343\/full. Cited 15 Feb 2026.","DOI":"10.3389\/fcvm.2025.1618343\/full"},{"issue":"14","key":"2018_CR62","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1038\/emboj.2008.119","volume":"27","author":"T Ikenoue","year":"2008","unstructured":"Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 2008;27(14):1919\u201331.","journal-title":"EMBO J"},{"issue":"56","key":"2018_CR63","doi-asserted-by":"publisher","first-page":"9062","DOI":"10.1038\/sj.onc.1208093","volume":"23","author":"SE Aeder","year":"2004","unstructured":"Aeder SE, Martin PM, Soh JW, Hussaini IM. PKC-\u03b7 mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene. 2004;23(56):9062\u20139.","journal-title":"Oncogene"},{"issue":"12","key":"2018_CR64","doi-asserted-by":"publisher","first-page":"e964","DOI":"10.1038\/cddis.2013.506","volume":"4","author":"MV Blagosklonny","year":"2013","unstructured":"Blagosklonny MV. TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis. 2013;4(12):e964\u2013964.","journal-title":"Cell Death Dis"},{"issue":"8","key":"2018_CR65","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.3390\/biomedicines12081802","volume":"12","author":"SM Stanciu","year":"2024","unstructured":"Stanciu SM, Jinga M, Miricescu D, Stefani C, Nica RI, Stanescu-Spinu II, et al. mTOR Dysregulation, Insulin Resistance, and Hypertension. Biomedicines. 2024;12(8):1802.","journal-title":"Biomedicines"},{"key":"2018_CR66","doi-asserted-by":"publisher","unstructured":"Sarfstein R, Werner H. The INSR\/IGF1R Receptor Family. In: Wheeler DL, Yarden Y, editors. Receptor Tyrosine Kinases: Family and Subfamilies. Cham: Springer International Publishing; 2015. pp. 297\u2013320. Available from: https:\/\/doi.org\/10.1007\/978-3-319-11888-8_7. Cited 15 Feb 2026.","DOI":"10.1007\/978-3-319-11888-8_7"},{"issue":"1","key":"2018_CR67","doi-asserted-by":"publisher","first-page":"810981","DOI":"10.4061\/2011\/810981","volume":"2011","author":"LM Tai","year":"2011","unstructured":"Tai LM, Youmans KL, Jungbauer L, Yu C, LaDu MJ. Introducing Human APOE into A\u03b2 Transgenic Mouse Models. Int J Alzheimer\u2019s Dis. 2011;2011(1):810981.","journal-title":"Int J Alzheimer\u2019s Dis"},{"issue":"50","key":"2018_CR68","doi-asserted-by":"publisher","first-page":"41774","DOI":"10.1074\/jbc.M112.407957","volume":"287","author":"KL Youmans","year":"2012","unstructured":"Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, et al. APOE4-specific Changes in A\u03b2 Accumulation in a New Transgenic Mouse Model of Alzheimer Disease *. J Biol Chem. 2012;287(50):41774\u201386.","journal-title":"J Biol Chem"},{"key":"2018_CR69","doi-asserted-by":"publisher","unstructured":"Yamazaki Y, Liu CC, Yamazaki A, Shue F, Martens YA, Chen Y, et al. Vascular ApoE4 Impairs Behavior by Modulating Gliovascular Function. Neuron. 2021;109(3):438\u201347.e6. https:\/\/doi.org\/10.1016\/j.neuron.2020.11.019.","DOI":"10.1016\/j.neuron.2020.11.019"}],"container-title":["Alzheimer's Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13195-026-02018-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13195-026-02018-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13195-026-02018-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:02:51Z","timestamp":1779368571000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13195-026-02018-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":69,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2018"],"URL":"https:\/\/doi.org\/10.1186\/s13195-026-02018-3","relation":{},"ISSN":["1758-9193"],"issn-type":[{"value":"1758-9193","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"2 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not Applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not Applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"119"}}