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

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.

Migraine Pharmacological Treatment and Cognitive Impairment: Risks and Benefits

“…On one hand, cognitively impaired subjects taking CNS-active beta-blockers exhibited a consistent trend to worsen memory retrieval and MMSE scores when compared to untreated patients [ 116 ]. On the other hand, highly BBB-permeable compounds (e.g., propranolol or carvedilol) decreased the risk of developing AD compared to low permeable compounds (e.g., atenolol, sotalol, or bisoprolol) according to a large nation-wide retrospective cohort from Denmark [ 117 ]. The effect was significant after a minimum of 1.5 years of treatment and was attributed to improved clearance of AD-related neurotoxic molecules [ 117 ].…”

“…On the other hand, highly BBB-permeable compounds (e.g., propranolol or carvedilol) decreased the risk of developing AD compared to low permeable compounds (e.g., atenolol, sotalol, or bisoprolol) according to a large nation-wide retrospective cohort from Denmark [ 117 ]. The effect was significant after a minimum of 1.5 years of treatment and was attributed to improved clearance of AD-related neurotoxic molecules [ 117 ]. Since each compound has unique biochemical properties, a separate evaluation of each anti-migraine beta-blocker is still warranted.…”

Beta-blockers in elderly patients: neuroprotective effect or risk of cognitive decline?

“…Beaman и соавт. полагают, что бета-адреноблокаторы, проникая через гематоэнцефалический барьер и блокируя адренергические рецепторы, влияют на снижение сосудистого сопротивления и увеличение интерстициального пространства, что способствует усилению потока спинномозговой жидкости и выведению бета-амилоида из ткани мозга по периваскулярным путям [11].…”

“…Метопролол является бета-адреноблокатором с умеренной проницаемостью, а карведилол и пропранолол -с высокой. Прием препаратов с высокой проницаемостью через гематоэнцефалический барьер ассоциирован со снижением риска развития болезни Альцгеймера на 45 % в отличие от приема бета-адреноблокаторов с низкой проницаемостью (р < 0,036) [11].…”

Biomedical Discovery through the integrative Biomedical Knowledge Hub (iBKH)

“…There has been evidence suggesting that ߚ-blockers increase brain clearance of these metabolites by enhancing cerebrospinal fluid flow. Recent studies have demonstrated that the use of ߚblockers is associated with reduced risk of AD onset(Beaman et al, 2022) and functional decline in AD(Rosenberg et al, 2008). Phenoxybenzamine is an ߙ-blocker, which has been reported to have neuroprotective activity(Rau et al, 2014).…”