TY - JOUR

T1 - Blood–brain barrier permeable β-blockers linked to lower risk of Alzheimer’s disease in hypertension

AU - Beaman, Emily

AU - Bonde, Anders Nissen

AU - Larsen, Sara Marie Ulv

AU - Ozenne, Brice Maxime Hugues

AU - Lohela, Terhi Johanna

AU - Nedergaard, Maiken

AU - Gislason, Gunnar Hilmar

AU - Knudsen, Gitte Moos

AU - Holst, Sebastian Camillo

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Faculty of Health and Medical Sciences

KW - Alzheimer's disease and dementia

KW - β-adrenergic signaling

KW - Hypertension

KW - Adrenergic alpha-2 Receptor Antagonists

KW - Blood brain barrier

U2 - 10.1093/brain/awac076

DO - 10.1093/brain/awac076

M3 - Journal article

C2 - 35196379

VL - 146

SP - 1141

EP - 1151

JO - Brain

JF - Brain

SN - 0006-8950

IS - 3

ER -