Blood-brain barrier permeable β-blockers linked to lower risk of Alzheimer's disease in hypertension

Emily Eufaula Beaman, Anders Nissen Bonde, Sara Marie Ulv Larsen, Brice Ozenne, Terhi Johanna Lohela, Maiken Nedergaard, Gunnar Hilmar Gíslason, Gitte Moos Knudsen, Sebastian Camillo Holst*

*Corresponding author for this work


Alzheimer's disease is a neurodegenerative disorder in which the pathological accumulation of amyloid-β and tau begins years before symptom onset. Emerging evidence suggests that β-blockers (β-adrenergic antagonists) increase brain clearance of these metabolites by enhancing CSF flow. Our objective was to determine whether β-blocker treatments that easily cross the blood-brain barrier reduce the risk of Alzheimer's disease compared to less permeable β-blockers. Data from the Danish national registers were used to identify a retrospective cohort of individuals with hypertension, and those treated with β-blockers were included in the analysis. People with indications for β-blocker use other than hypertension (e.g. heart failure) were only retained in a sensitivity analysis. β-blockers were divided into three permeability groups: low, moderate and high. We used multivariable cause-specific Cox regression to model the effect of β-blocker blood-brain 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. In a cohort of 69 081 (median age = 64.4 years, 64.8% female) people treated with β-blockers for hypertension, highly blood-brain barrier-permeable β-blockers were associated with reduced risk of Alzheimer's disease versus low permeability β-blockers (-0.45%, P < 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-brain barrier-permeable patients also detected a decreased Alzheimer's risk (-0.92%, P < 0.001) in the high permeability group compared to the low, as did a 1-year landmark analysis (-0.57%, P < 0.029) in which events within the first year of follow-up were ignored as likely unrelated to treatment. Our results suggest that amongst people taking β-blockers for hypertension, treatment with highly blood-brain barrier permeable β-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs. Our findings support the hypothesis that highly permeable β-blockers protect against Alzheimer's disease by promoting waste brain metabolite clearance.

Original languageEnglish
Issue number3
Pages (from-to)1141-1151
Number of pages11
Publication statusPublished - 1 Mar 2023


  • Alzheimer's disease
  • adrenergic antagonists
  • antihypertensive drugs
  • blood-brain barrier
  • glymphatic clearance
  • Humans
  • Middle Aged
  • Male
  • Adrenergic beta-Antagonists/therapeutic use
  • Alzheimer Disease/drug therapy
  • Female
  • Retrospective Studies
  • Blood-Brain Barrier
  • Hypertension/drug therapy


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