Nonlinear dose–response relationship between cumulative anticholinergic use and the risk of dementia in adults with overactive bladder: a systematic review and dose–response meta-analysis
Jae Heon Kim, Yong Nam Gwon, Sung Ryul Shim, Taeho Greg Rhee, Benjamin I ChungAbstract
Background and objective
Whilst anticholinergics (ACH) are standard treatments for overactive bladder (OAB), cumulative exposure is linked to an increased risk of dementia. Most evidence assumes a linear dose–response relationship, which may fail to capture complex biological dynamics. We aimed to characterise the functional form (linear vs. non-linear) of this association and identify clinically meaningful inflection points of risk escalation.
Methods
A systematic literature search was conducted through 10 December 2025, in PubMed, Cochrane and Embase. Following PRISMA guidelines, we included comparative observational cohorts evaluating cumulative ACH exposure and incident dementia in OAB patients without baseline cognitive impairment. Pairwise meta-analysis and dose–response meta-analyses (DRMA) using one-stage and two-stage random-effects models with restricted cubic splines were performed to assess non-linearity.
Key findings and limitations
Thirteen studies encompassing 7 891 574 participants were included. ACH use was associated with significantly increased dementia risk (HR: 1.52; 95% CI: 1.29–1.80). DRMA identified a significant non-linear, inverted U-shaped relationship. Risk escalated sharply during the initial 3 years: HRs at 90 days, 1 year, and 3 years were 1.11, 1.42 and 1.61, respectively. Peak risk occurred at ~874 cumulative defined daily dose (HR: 1.63 [95% CI, 1.32–2.00]), with apparent attenuation thereafter likely reflecting survivor bias and the depletion-of-susceptibles phenomenon rather than biological protection. Limitations include the observational nature of the data and heterogeneity in dementia ascertainment.
Conclusions and clinical implications
Dementia risk in OAB patients follows a non-linear trajectory, with a critical vulnerability window during the first 3 years of cumulative ACH exposure. Clinical management should prioritise non-anticholinergic alternatives (e.g. mirabegron) or implement structured cognitive surveillance during this early treatment phase.