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Amyloid\u2010\u03b2 (A\u03b2) aggregation, vascular damage and altered immune response interact at the blood\u2013brain barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta\u2010analyses, published in English language from 01\/2000 to 07\/2021, using the keywords Alzheimer*, amyloid\u2010\u03b2 or \u03b2\u2010amyloid or abeta and BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes\/macrophages characterise BBB damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD\u2010specific brain regions. The toxic effects of A\u03b2 and apolipoprotein E (ApoE) are likely to induce a non\u2010cerebral\u2010amyloid\u2010angiopathy\u2010related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, proinflammatory signalling and cerebral amyloid angiopathy enhance BBB damage. Novel therapeutic approaches for AD, including magnetic resonance\u2010guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of A\u03b2 along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE\u2010modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of proinflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of A\u03b2 deposition as a primary versus a secondary event in the complex pathogenesis of AD.<\/jats:p>","DOI":"10.1111\/nan.12782","type":"journal-article","created":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T19:40:17Z","timestamp":1637869217000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":188,"title":["Dysfunction of the blood\u2013brain barrier in Alzheimer's disease: Evidence from human studies"],"prefix":"10.1111","volume":"48","author":[{"given":"Carolin","family":"Kurz","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Hospital LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Walker","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Campus for Ageing and Vitality Newcastle 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