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

Abstract

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.

Keywords: Alzheimer's disease; adrenergic antagonists; antihypertensive drugs; blood–brain barrier; glymphatic clearance.

Figure 1

BBB permeable βBs may reduce the risk of Alzheimer’s disease. Proposed model: βBs increase CSF-dependent brain clearance of soluble neurotoxic proteins, including amyloid-β and tau, which are prominent in Alzheimer's disease pathology.^, CSF enters via the periarterial space, facilitated by aquaporin 4 (AQP4) water channels on surrounding astrocytic endfeet and driven by cardio-respiratory pulsations. As CSF is propelled into the parenchyma it mixes with solute-laden interstitial fluid. Convective bulk flow carries both towards the perivenous spaces, where fluid drains into meningeal or cervical lymphatic vessels (efflux along cranial and spinal nerves not illustrated here). βBs that cross the BBB (pink) may reduce Alzheimer's risk compared to those that do not cross (blue) by binding to astrocytes and decreasing their cell volume, thereby lowering resistance to bulk flow and promoting convection of waste products from the brain's interstitium to the periphery.

Figure 2

Flow chart describing cohort selection. A total of 1 275 458 individuals took at least two different antihypertensive drug classes between 1995 and 2017. For 454 508 (35.6%) of them, βBs were one of the drug classes. Following exclusion criteria, we included 69 081 people in the primary cohort, from which people with indications for βBs other than hypertension were excluded. Individuals were further divided into groups based on the BBB permeability of the βB prescribed at baseline, with atenolol and bisoprolol considered low; metoprolol moderate; and carvedilol and propranolol high BBB permeability. Altogether, 23.9% of people were grouped as taking low BBB permeability βBs, 62.3% as moderate, and 13.7% as high.

Figure 3

Standardized absolute risk over time. Standardized absolute risk over 10 years for the primary cohort, where subjects with indications other than hypertension for treatment with β-adrenergic antagonists were excluded. 95% CIs are shaded. Models were corrected and P-values adjusted for multiple comparisons as described in the ‘Materials and methods’ section. (A) Absolute risk of Alzheimer's with death as a competing risk, showing significantly reduced risk for those taking high BBB permeability βBs (pink) compared to low BBB permeability βBs (blue) from 1.5 years onward. (B) Absolute risk of death with Alzheimer's disease as a competing risk. (C) Absolute risk of any dementia (including Alzheimer's, unspecified dementia and other causes) with death as a competing risk. n.s. = not significant.