INTRODUCTION
Alpha-1 adrenergic receptor (α1-AR) blockers, also known as alpha blockers, are a commonly prescribed medication class: over 5 million Medicare patients received a prescription for an alpha blocker in 2019 [1]. Alpha blockers are commonly used to treat benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS), hypertension, or a combination of these conditions. In a large observational study, Duan et al. [2] found that a second-generation alpha blocker, tamsulosin, was associated with an increased the risk of dementia in older men with BPH, which raised concerns about the safety of alpha blockers in patients with new or worsening cognitive impairment. Subsequent studies have offered differing conclusions [3,4]. The conflicting results pose a clinical challenge in determining the risks vs benefits for patients with concern for cognitive impairment and LUTS who would have traditionally benefitted from alpha blocker therapy.
For the treatment of BPH/LUTS, alpha blockers work by blocking norepinephrine signaling through α1-ARs in the bladder and prostatic smooth muscle, allowing for relaxation of the smooth muscle in the bladder neck and prostatic urethra [5,6]. The American Urological Association recommended α1-AR antagonist medications as first-line medical therapy for symptoms of obstruction in their 2021 guidelines for treatment of BPH/LUTS considering decades of successful use, reasonable tolerance, and low cost [7].
The role of α1-ARs in memory is important in understanding the theoretical impact of alpha blockers on cognition. Α1-ARs are found in high concentrations within the human hippocampus and prefrontal cortex cognitive domains [8-10] as well as the entorhinal cortex [11,12]. Histopathologic findings like neuritic plaques and neurofibrillary tangles in these areas have been associated with the pathophysiology of Alzheimer disease and other dementias [13]. Mice with α1-AR knock-out mutation show a decrease in cognition, particularly in learning and memory [14,15]; in a different study, mice who received α1-AR agonists had improved cognition [16]. Somewhat paradoxically, α1-AR antagonists improved memory in rats [17] and glycolysis-enhancing α1-AR antagonists (including terazosin) may protect against cognitive symptoms of Parkinson disease in rats [18].
Although preclinical models provide evidence linking α1-ARs and cognitive function, the clinical impact on human cognition is not well understood [19]. Α1-AR agonists (e.g., guanfacine and clonidine) are currently prescribed for children with attention deficit hyperactivity disorder to mitigate cognitive inefficiencies, but outside of this population there is little evidence to suggest a neurocognitive protective effect or benefit for people with dementia [20-23], and until 2018 there had been no concerns about negative cognitive effects of alpha blockers.
Given that α1-AR are commonly used medications, for a very common problem as BPH in older adult men, and the conflicting data surrounding its association with cognitive dysfunction, we performed this systematic review to further examine the association between alpha blockers and cognitive impairment, with a goal of aiding medical decision making regarding the initiation or discontinuation of alpha blockers when a concern for cognitive impairment arises.
MATERIALS AND METHODS
Search Strategy and Selection Criteria
We conducted an initial comprehensive search of several databases on March 7, 2023, limited to the English language and excluding animal studies and conference abstracts. The search was updated on January 22, 2024. The search was designed and conducted by a medical librarian (DG), with the input of other investigators (RK, SP). Databases included Ovid Cochrane Central Register of Controlled Trials (1991+), Ovid Embase (1974+), Ovid MEDLINE (1946+ including epub ahead of print, in-process, and other nonindexed citations), Scopus (1788+), and Web of Science Core Collection (Science Citation Index Expanded 1975+ and Emerging Sources Citation Index 2015+). Search strategies used a combination of keywords and standardized index terms for α1-AR antagonists (including tamsulosin, silodosin, alfuzosin, terazosin, doxazosin, and prazosin) and cognitive impairment/dementia. A list of all search terms used and how they were combined is available in Supplementary Table 1. The study protocol is registered and can be accessed in PROSPERO, CRD42024505751.
Included studies met the following criteria: (1) human participants aged 18 years or older; (2) designed as prospective study, retrospective study, randomized controlled trial (RCT), or case report; (3) published after 1975; (4) English language. Excluded studies met the following criteria: (1) articles that did not measure cognitive outcomes of interest. Reviewers worked independently using the above criteria to screen titles/abstracts (CE, DJ, RW) and full texts (AP, RW) with all disagreements arbitrated by RK or SP. This process was accomplished using Covidence software [24].
Data Collection and Quality Assessment
Data were manually abstracted by AP and RK and independently reviewed for accuracy by SP. Information abstracted included author, year, country, study type, medications studied, data collection time period, sample size, age range and/or median age of sample, cognitive outcome measures, cognitive baseline, cognitive endpoint, change in cognitive status, other side effects, study funding, and study inclusion and exclusion criteria. Studies were divided into 2 groups: RCTs and non-RCTs for reporting. Analysis by medication type was also performed, and the effect of each medication on cognitive outcomes was reported.
RESULTS
Search Results
Four hundred nine abstracts were screened, of which 35 studies were selected for full-text review. Seven studies met inclusion criteria for systematic review, as shown in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram (Fig. 1). Table 1 outlines author, publication year, country, study design, study population, sample size, medications studied, follow-up duration, and cognitive outcomes, and funding.
Study Characteristics
Design, year, and country
Studies consisted of 3 RCTs and 4 non-RCTs (3 cohort studies and 1 nested case-control study). One study was published in 2009 [27], the rest were published from 2018–2022. Two RCTs were conducted in Russia [28,29] and 1 in the United States [27]. Of the non-RCTs, 1 was conducted in Finland [30], 1 in the United States [2], and 2 in South Korea [3,4]. Two additional studies initially appeared to meet inclusion criteria, however 1 study by Coindreau-Frías et al. [31] listed the medications studied as “anti-prostatic hypertrophy agents” without description of what medication classes this included. RK and SP contacted the authors but were unable to ascertain which medications were included in this class. The second study by Norgaard et al. [27] included 5-alpha reductase inhibitors and α1-AR antagonists such that the effect of a1-AR antagonist effect could not be determined. Therefore, both studies were excluded.
Participants
Participants were mostly men, except for one RCT analyzing the role of prazosin for dementia-related behaviors that included 9 women out of 22 total participants [28]. For the RCTs, the mean age of participants varied from 62.8 years to 80.6 years. For the non-RCTs, the mean age of participants varied from 71.6–77.03 years. Most participants had a diagnosis of BPH.
The RCTs comprised 679 total participants, including 472 participants who received an alpha blocker. Of those, 461 received tamsulosin, the remaining 11 received prazosin. There were 207 controls. RCTs were conducted over a short duration of 8 or 12 weeks. The non-RCTs comprised 759,627 total participants, including 425,967 participants who were exposed to alpha blockers. Of those, 318,356 received tamsulosin. The median follow-up period for the 3 cohort studies ranged from 19.8 months [2] to 56.4 months [3].
Medications
Studies included 5 of 6 alpha blockers listed in the search criteria, including tamsulosin, doxazosin, terazosin, alfuzosin, and prazosin. Silodosin was not mentioned in any of the included studies. Two RCTs included tamsulosin, separately and in conjunction with an antimuscarinic medication [29,30]; the remaining RCT studied prazosin [28]. All non-RCTs included tamsulosin [2-4,32], and 3 of them included other alpha blockers [2,3,32].
Cognitive outcomes
In the RCT studies, cognitive outcomes included Mini-Mental State Examination (MMSE) and CVLT (California Verbal Learning Test) in 2 studies. Other cognitive outcome tools included: COWAT (Controlled Oral Word Association Test), WAIS (Wechsler Adult Intelligence Scale), WMS (Wechsler Memory Scale), logical memory test, CTT (Color Trails Test), Neuropsychiatric Inventory (NPI), WCST (Wisconsin Card Sorting Test), CGIC (Clinical Global Impression of Change), and Brief Psychiatric Rating Scale (BPRS). In the non-RCT studies, 3 [2,3,32] included new diagnosis of dementia or Alzheimer disease as cognitive outcomes and one study [4] included change in MMSE in patients with mild to moderate Alzheimer disease. Outcome measure heterogeneity limited further meta-analysis.
Association of Alpha Blockers to Cognitive Outcomes
Tamsulosin
Tamsulosin was not associated with changes in cognition in 2 RCTs [29,30] of 8- and 12-week duration. In 1 of these studies, patients served as their own controls [29]; this trial was intended to examine the effect of anticholinergic medications and all groups received tamsulosin. Tamsulosin was associated with an increased risk of dementia, with hazard ratio (HR) 1.17 (95% confidence interval [CI], 1.17–1.21) in a retrospective cohort study of men (median age, 73–74) with BPH (dose-responsive relationship; median follow-up duration, 19.8 months) [2] and increased odds of Alzheimer disease (odds ratio, 1.23; 95% CI, 1.19–1.27) in a case-control study of older men (median age, 78.7 years at time of dementia diagnosis, no dose-responsive relationship, relationship diminished when adjusted for confounders and mediators) [32]. However, it was associated with a decreased risk of dementia (HR, 0.71; 95% CI, 0.64–0.78) in another cohort study of men (median age, 76–77) with BPH (median follow-up duration, 56 months) [3]. In patients with mild to moderate Alzheimer disease, it was not associated with a greater decline in MMSE scores over >1,000 days [4].
Prazosin
In a small RCT (11 participants per group) studying patients with dementia-related behaviors, prazosin was associated with improvements in NPI and BPRS at 8 weeks in the intervention group compared to the control group [28].
Alfuzosin
In one case-control study, alfuzosin was associated with an increased odds for Alzheimer disease with odds ratio 1.23 (95% CI, 1.17–1.30) [29]. In contrast, 2 retrospective cohort studies found alfuzosin was not associated with an increased risk of dementia [2], or was associated with a decreased risk of dementia compared to no-medication use (HR, 0.68; 95% CI, 0.61–0.77) [3].
Quality Assessment
The quality assessment of the included studies is reported in Fig. 2, with overall quality being modest across the studies. The detailed quality assessments for each study are included in Supplementary Table 2 (Cochrane risk of bias for RCTs and MINORS criteria for non-RCT studies).
DISCUSSION
This study systematically reviews existing literature on the cognitive impact of α1-AR antagonists, or alpha blockers. It is the first systematic review analyzing this topic to date. Only 7 studies were identified, reflecting the relative paucity of information on this topic. The primary population studied was older adult men with BPH, and the most common outcomes measured were changes in cognitive outcome measures, or new dementia or Alzheimer disease diagnosis. Our review found no clear association between alpha blockers and an increased risk of cognitive impairment or dementia. We were unable to perform a meta-analysis due to the small number and outcome measure heterogeneity across studies.
Of the alpha blockers studied, tamsulosin has generated the most concern about the nature of its cognitive effects. It is certainly the most prescribed, having a reputation for causing the fewest side effects particularly hypotension, and has ten to 38 times the selectivity for the alpha 1A adrenergic receptor subtype versus 1B subtype compared to other common alpha blockers [33]. This is of relevance as the alpha 1A subtype is postulated to play a role in cognitive function [33]. However, our systematic review does not support a strong association between tamsulosin and dementia. The study that first associated tamsulosin with an increased risk of dementia [2] has been thoughtfully critiqued by Andrade [34].
While clear evidence of an association between alpha blocker use and cognitive impairment is lacking, there is also limited evidence to support the biological plausibility of a causal relationship. Whether alpha blockers, particularly tamsulosin, can traverse the blood brain barrier to activate α1-ARs in the brain is incompletely understood. Preclinical studies have provided conflicting findings [35-39] and there are no published clinical studies investigating this question. As a complicating factor, dementia is associated with blood brain barrier dysfunction [40,41].
Cognitive impairment or dementia is a geriatric syndrome and has multiple contributing factors. A possible confounder of the relationship between alpha blockers and dementia is BPH/LUTS. Urinary retention is a known risk factor for delirium [42] and people with dementia have a higher incidence of urinary incontinence, typically due to urge urinary incontinence [43,44]. Nocturia may contribute to sleep disorders, which have a bidirectional relationship with dementia [45,46]. In a large Danish cohort study analyzing the impact of sleep disruption and Alzheimer disease risk in patients with BPH, Norgaard et al. [27] found that men with BPH were at increased risk of dementia (cumulative risk, 1.15; 95% CI, 1.11– 1.20) compared to age-matched counterparts. The majority (75.6%) of BPH diagnoses were based on a prescription for alpha blockers or 5-alpha reductase inhibitors. Alzheimer disease risk did not change if BPH was diagnosed via diagnosis code or medication prescription.
Indeed, BPH—and medications for BPH—may be associated with increased overall morbidity, including dementia. In 1 observational study, individuals with BPH had higher rates of comorbidities including heart disease, diabetes, renal failure and prostate cancer compared to individuals without BPH [27]. The high comorbid burden in this study could imply that poor health status increased the risk for cognitive impairment. The relationship between comorbid conditions and risk of dementia in patients with BPH is also demonstrated by the work of Tae et al. [3]. In this study, the unadjusted no-medication BPH group had more comorbidities than the medication groups and had a higher risk of dementia. One possible limitation in this topic could be the publication bias associated with negative outcome studies, or early study termination due to potential medication side effects, though our systematic review did not exclude any published studies that met our inclusion criteria. The overall limitation of this systematic review is due to the lack of robust RCT studies, and no prospective open label studies that exist. Of the 3 RCT studies we included in this review, 1 of them studied the role of prazosin which is not routinely used for BPH management though is in the class of α1-AR antagonists. Despite the limited use of prazosin for BPH management we included this study in our review as it did meet our study inclusion criteria given the α1-AR medication category and cognition outcomes measured. The study timeline in all the existing RCT studies ranges from 8–12 weeks which is relatively short to measure the effect on cognitive impairment. The etiology for cognitive dysfunction is multifactorial that are not well considered in the existing RCT studies.
In the future, prospective studies would be helpful in improving our understanding of the relationship between alpha blockers and cognition. Dementia is an umbrella term that encompasses Alzheimer dementia, vascular dementia, Lewy body dementia, frontotemporal dementia, and others, and examining associations between alpha blockers and specific dementias may be important. Additionally, studies specifically examining the relationship between BPH/LUTS, and cognitive impairment would be useful. Given the advancement and wide availability of different urological procedures including transurethral resection of the prostate and other robotic prostate surgeries, future studies should include these populations. In general, longer follow-up periods may be needed, as diseases such as Alzheimer dementia are believed to take years to develop, and it would be reasonable to suspect that agents that have a mild to moderate effect of increasing risk may require years of exposure to see their full effect.
In conclusion, some physicians have modified their practice by avoiding alpha blockers in elderly patients in response to the data presented by Duan et al. [2]. Our systematic review did not reveal a convincing causative association between α1-AR antagonists, or alpha blockers, including tamsulosin, and cognitive dysfunction. Based on our review findings, it will be appropriate to start and continue α1-AR antagonists without a concern for cognitive dysfunction. There is not enough evidence to support discontinuing or avoiding prescription of alpha blockers in patients with benign prostatic hypertrophy or LUTS. Future studies, preferably prospective studies with longer duration of follow-up, are required.
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