An overactive bladder (OAB), one of several clinical presentations of lower urinary tract syndrome [1], [2], has been reported in 10–15% of the population with symptoms of urinary urgency, according to the International Continence Society [3]. The primary treatment options consist of behavioural therapy and medical management [4], [5]. The most widely used medications for an OAB are anticholinergics and beta-3 agonists [4], [6]. Studies have suggested that both anticholinergics and beta-3 agonists demonstrate equivalent efficacy and are recommended equally as the first treatment options for an OAB by the American Urology Association (AUA) and European Association of Urology [7], [8].

Several studies have reported an association between anticholinergic medications (when all drug classes are combined) and the risk of new-onset dementia [6], [7], [8], while other studies have reported contradictory results [9], [10]. The effects of dementia induced by anticholinergics differ according to the level of anticholinergic activity, receptor sensitivity, central nervous system (CNS) penetration, and drug class [11], [12], [13], and the drugs used for an OAB exhibit strong anticholinergic activity [14]. Five observational studies have shown an association between anticholinergics and an increased risk of dementia [11], [12], [15], [16], [17]. However, none of these studies specifically examined the effects of the different anticholinergics, each of which has distinct pharmacological specificities [18]. Recently, the AUA emphasised the need for further research on the long-term cognitive side effects of anticholinergics overall and for each drug separately when used to treat an OAB [4]. Malcher et al [19] and Matta et al [13] reported differential effects of individual anticholinergics with respect to the incidence of dementia.

Beta-3 agonists, which involve mechanisms that differ from those of anticholinergics, reportedly reverse memory deficits in a mouse model [20], and a recent population-based cohort study in Canada found that the use of anticholinergic medications by patients with an OAB was associated with an increased risk of new-onset dementia compared with users of beta-3 agonists [17]. However, the Canadian study did not address the effects of the use of a beta-3 agonist alone on the incidence of dementia. Although beta-3 agonists are not known to have any cognitive effects [21], the follow-up period was too short to determine the cognitive effects of beta-3 agonists.

As a combination treatment of a beta-3 agonist and an anticholinergic is reportedly more effective in improving multiple OAB symptoms than either a beta-3 agonist alone or an anticholinergic [22], [23], [24], [25], [26], [27], AUA guidelines recommend pharmacotherapy with beta-3 agonists or anticholinergics (or both) after and in conjunction with behavioural treatments [4], [7]. Moreover, increasing the anticholinergic dosing for patients with previous suboptimal responses to anticholinergic drugs alone only leads to a greater risk of anticholinergic-related adverse events [23]. However, any association between combination therapy consisting of beta-3 agonists plus anticholinergics and dementia has yet to be evaluated.

Our study comprehensively analysed the relationship between beta-3 agonists and/or anticholinergics used to treat an OAB and the risk of new-onset dementia for overall anticholinergics, both together and for each drug separately.