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.

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-β or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated α-synuclein, which is seen in, e.g., Parkinson's Disease. Access to a large animal model with α-synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here established a pig model with cerebral injections of α-synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimer's disease (AD) or dementia with Lewy body (DLB) into the pig's brain using minimally invasive surgery and validated against saline injections. In the absence of a suitable α-synuclein radioligand, we validated the model with an unselective amyloid-β tracer [11C]PIB, which has a high affinity for β-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier function was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in α-synuclein-preformed-fibrils-injected regions compared to the saline-injected regions. The [11C]PIB uptake was the same in the occipital cortex, cerebellum, DLB-homogenate, and saline-injected regions. With its large brains and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.

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