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

Alzheimer's disease is a neurodegenerative disorder in which the pathological accumulation of amyloid-beta and tau begins years before symptom onset. Emerging evidence suggests that beta-blockers (beta-adrenergic antagonists) increase brain clearance of these metabolites by enhancing CSF flow. Our objective was to determine whether beta-blocker treatments that easily cross the blood-brain barrier reduce the risk of Alzheimer's disease compared to less permeable beta-blockers. Data from the Danish national registers were used to identify a retrospective cohort of individuals with hypertension, and those treated with beta-blockers were included in the analysis. People with indications for beta-blocker use other than hypertension (e.g. heart failure) were only retained in a sensitivity analysis. beta-blockers were divided into three permeability groups: low, moderate and high. We used multivariable cause-specific Cox regression to model the effect of beta-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 beta-blockers for hypertension, highly blood-brain barrier-permeable beta-blockers were associated with reduced risk of Alzheimer's disease versus low permeability beta-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 beta-blockers for hypertension, treatment with highly blood-brain barrier permeable beta-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs. Our findings support the hypothesis that highly permeable beta-blockers protect against Alzheimer's disease by promoting waste brain metabolite clearance. Beaman et al. report that among people taking beta-blockers for hypertension, treatment with highly blood-brain barrier permeable beta-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs, possibly by promoting brain waste clearance via the glymphatic system.