There are a few studies that report cognitive impairment as a complication of treatment with beta- blockers. We aimed to evaluate the longitudinal association between use of betablockers, as a class, and incident risk of all-cause dementia, vascular dementia, Alzheimer and mixed dementia in the prospective population-based Malmö Preventive Project. We included 18,063 individuals (mean age 68.2, males 63.4%) followed up for 84,506 person-years. Dementia cases were retrieved from the Swedish National Patient Register and validated by review of medical records and neuroimaging data. We performed propensity score matching analysis, resulting in 3,720 matched pairs of beta-blocker users and non-users at baseline, and multivariable Cox proportional-hazards regression. Overall, 122 study participants (1.6%) were diagnosed with dementia during the follow-up. Beta-blocker therapy was independently associated with increased risk of developing vascular dementia, regardless of confounding factors (HR: 1.72, 95%CI 1.01-3.78; p=0.048). Conversely, treatment with beta-blockers was not associated with increased risk of all-cause, Alzheimer and mixed dementia (HR:1.15; 95%CI 0.80-1.66; p=0.44; HR:0.85; 95%CI 0.48–۱٫۵۴; P=0.59 and HR:1.35; 95%CI 0.56– ۳٫۲۷; p=0.50, respectively). We observed that use of beta-blockers, as a class, is associated with increased longitudinal risk of vascular dementia in the general elderly population, regardless of cardiovascular risk factors, prevalent or incident history of atrial fibrillation, stroke, coronary events and heart failure. Further studies are needed to confirm our findings in the general population and to explore the mechanisms underlying the relationship between use of beta- blockers and increased risk of vascular dementia.

Introduction

Dementia is a general term for neurodegeneration marked by the development of multiple cognitive deficits such as the ability to memorize, learn, perceive and process information 1 . Since the number of people affected by dementia is expected to increase rapidly 2 , the research to find different pathological mechanisms for prevention has been intensified 3 . Previous studies have revealed a possible relationship between blood pressure (BP) changes and the risk of developing dementia 4, 5. A decline in blood pressure between middle-and advanced age, and lower BP in advanced age have been disclosed as independent risk factors of incident dementia 6 . A theory has been proposed that blood pressure reduction causes a decline in cerebral perfusion, which has previously been emphasized as an important factor in the pathology in vascular dementia7 . Hence, antihypertensive treatment (AHT) which is commonly used among elderly individuals has been suggested to be implicated in dementia risk as the blood pressure lowering effect may reduce the cerebral perfusion 8 . A systematic review including fifteen randomized clinical trials studying the impact of different AHTs on cognition in older individuals without dementia reported an improvement in episodic memory in patients treated with angiotensin receptor blockers versus placebo or other types of antihypertensive drugs 9 . However, the knowledge is sparse on the adverse effects of AHT including potential harms such as orthostasis, fatigue, and depression, which can negatively impact daily functioning and quality of life 10.