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

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

*Corresponding author for this work

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Abstract

Alzheimer’s disease is a neurodegenerative disorder where pathological accumulation of amyloid-β and tau begin years before symptom onset. Emerging evidence suggests that β-blockers (β-adrenergic antagonists) increase brain clearance of these metabolites by enhancing cerebrospinal fluid flow. Our objective was to determine whether β-blockers 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. Persons 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 modeled 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 βBs for hypertension, highly BBB-permeable βBs were associated with reduced risk of Alzheimer’s disease versus low permeability βBs (−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 BBB-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
JournalBrain
Volume146
Issue number3
Pages (from-to)1141–1151
Number of pages11
ISSN0006-8950
DOIs
Publication statusPublished - 2023

Keywords

  • Faculty of Health and Medical Sciences
  • Alzheimer's disease and dementia
  • β-adrenergic signaling
  • Hypertension
  • Adrenergic alpha-2 Receptor Antagonists
  • Blood brain barrier

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