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Disrupted angiopoietin\/TIE (ANGPT\/TIE) signalling causes neurovascular instability and BBB leakiness accelerating cognitive decline and disease pathology in mouse models of AD. To explore ANGPT\/TIE signalling in human AD, we measured CSF TIE\u20101 and TIE\u20102 levels by ELISA in two independent clinical dementia cohorts, and serum and CSF Tie\u20101\/\u20102 in paired CSF and serum samples from neurologically normal individuals. ANGPT1, ANGPT2, TIE\u20101 and TIE\u20102 levels were measured by ELISA in crude homogenate (CH) and microvessel\u2010enriched fractions (MVFs) of post\u2010mortem human parietal cortex in relation to biochemical markers of cerebral perfusion (MAG:PLP1) and BBB leakiness (parenchymal fibrinogen) in a control, AD, and vascular dementia (VaD) cohort. CSF soluble TIE\u20102 was elevated in AD biomarker+ve individuals and correlated positively with CSF t\u2010tau and p\u2010tau, and markers of BBB leakiness, neuronal injury, and neuroinflammation. Tissue TIE\u20102 levels were significantly reduced in Braak tangle stage (BS) III\u2010IV, that is, brains with early\u2010intermediate AD pathology, and were lower in MVFs in end\u2010stage AD pathology (BSV\u2010VI) than in controls or VaD. Lower levels of MVF TIE\u20102 correlated with markers of cerebral hypoperfusion and BBB leakiness. Our study reveals a reciprocal relationship between elevated CSF and reduced tissue TIE\u20102 expression that is related to markers of tau pathology, BBB leakiness, and cerebral hypoperfusion, providing novel insights into ANGPT\/TIE signalling in AD.<\/jats:p>","DOI":"10.1111\/bpa.70109","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T01:29:11Z","timestamp":1780882151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dysregulated\n                    <scp>TIE<\/scp>\n                    \u20102 expression is associated with\n                    <scp>blood\u2010brain barrier<\/scp>\n                    leakiness and Alzheimer's disease\u2010related neuropathology"],"prefix":"10.1111","volume":"36","author":[{"given":"Selvi","family":"Ince","sequence":"first","affiliation":[{"name":"Cerebrovascular &amp; Dementia Research Group, Learning and Research Building Bristol Medical School, Translational Health Sciences, University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Van Hulle","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendlyn","family":"Kollmorgen","sequence":"additional","affiliation":[{"name":"Roche Diagnostics GmbH  Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Quijano\u2010Rubio","sequence":"additional","affiliation":[{"name":"Roche Diagnostics International Ltd  Rotkreuz Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carey","family":"Gleason","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara B.","family":"Bendlin","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozioma","family":"Okonkwo","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital  M\u00f6lndal Sweden"},{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital  M\u00f6lndal Sweden"},{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology  London UK"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology Sahlgrenska Academy at University of Gothenburg  M\u00f6lndal Sweden"},{"name":"UK Dementia Research Institute at UCL  London UK"},{"name":"Hong Kong Center for Neurodegenerative Diseases Clear Water Bay  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling C.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Institute University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8683-3625","authenticated-orcid":false,"given":"Seth","family":"Love","sequence":"additional","affiliation":[{"name":"Cerebrovascular &amp; 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