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Emerging evidence suggests that \u03b2-blockers (\u03b2-adrenergic antagonists) increase brain clearance of these metabolites by enhancing CSF flow. Our objective was to determine whether \u03b2-blocker treatments that easily cross the blood\u2013brain barrier reduce the risk of Alzheimer's disease compared to less permeable \u03b2-blockers.<\/jats:p>\n                  <jats:p>Data from the Danish national registers were used to identify a retrospective cohort of individuals with hypertension, and those treated with \u03b2-blockers were included in the analysis. People with indications for \u03b2-blocker use other than hypertension (e.g. heart failure) were only retained in a sensitivity analysis. \u03b2-blockers were divided into three permeability groups: low, moderate and high. We used multivariable cause-specific Cox regression to model the effect of \u03b2-blocker blood\u2013brain barrier permeability on time to dementia outcomes, adjusting for baseline comorbidities, demographics and socioeconomic variables. Death was modelled as a competing risk. The 10-year standardized absolute risk was estimated as the averaged person-specific risks per treatment.<\/jats:p>\n                  <jats:p>In a cohort of 69 081 (median age = 64.4 years, 64.8% female) people treated with \u03b2-blockers for hypertension, highly blood\u2013brain barrier-permeable \u03b2-blockers were associated with reduced risk of Alzheimer's disease versus low permeability \u03b2-blockers (\u22120.45%, P &amp;lt; 0.036). This effect was specific to Alzheimer's diagnoses and did not extend to dementia in general. Propensity score analysis matching high and low blood\u2013brain barrier-permeable patients also detected a decreased Alzheimer's risk (\u22120.92%, P &amp;lt; 0.001) in the high permeability group compared to the low, as did a 1-year landmark analysis (\u22120.57%, P &amp;lt; 0.029) in which events within the first year of follow-up were ignored as likely unrelated to treatment.<\/jats:p>\n                  <jats:p>Our results suggest that amongst people taking \u03b2-blockers for hypertension, treatment with highly blood\u2013brain barrier permeable \u03b2-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs. Our findings support the hypothesis that highly permeable \u03b2-blockers protect against Alzheimer's disease by promoting waste brain metabolite clearance.<\/jats:p>","DOI":"10.1093\/brain\/awac076","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T15:25:34Z","timestamp":1645457134000},"page":"1141-1151","source":"Crossref","is-referenced-by-count":86,"title":["Blood\u2013brain barrier permeable \u03b2-blockers linked to lower risk of Alzheimer\u2019s disease in hypertension"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9457-562X","authenticated-orcid":false,"given":"Emily Eufaula","family":"Beaman","sequence":"first","affiliation":[{"name":"Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet , 2100 Copenhagen \u00d8 , Denmark"},{"name":"Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , 2200 Copenhagen N , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders Nissen","family":"Bonde","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte , 2900 Hellerup , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Marie Ulv","family":"Larsen","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet , 2100 Copenhagen \u00d8 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Ozenne","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet , 2100 Copenhagen \u00d8 , Denmark"},{"name":"Department of Public Health, Section of Biostatistics, University of Copenhagen , 1353 Copenhagen K , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terhi Johanna","family":"Lohela","sequence":"additional","affiliation":[{"name":"Center for Translational Neuromedicine, Faculty of Health and Medical Sciences (SUND), University of Copenhagen , 2200 Copenhagen N , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiken","family":"Nedergaard","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , 2200 Copenhagen N , Denmark"},{"name":"Center for Translational Neuromedicine, Faculty of Health and Medical Sciences (SUND), University of Copenhagen , 2200 Copenhagen N , Denmark"},{"name":"Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center , Rochester, NY 14642 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar Hilmar","family":"G\u00edslason","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte , 2900 Hellerup , Denmark"},{"name":"Department of Cardiovascular Epidemiology and Research, The Danish Heart Foundation , 1120 Copenhagen K , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gitte Moos","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet , 2100 Copenhagen \u00d8 , Denmark"},{"name":"Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , 2200 Copenhagen N , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3657-4535","authenticated-orcid":false,"given":"Sebastian Camillo","family":"Holst","sequence":"additional","affiliation":[{"name":"Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet , 2100 Copenhagen \u00d8 , 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