Patients handed a prescription for oxybutynin or a similar overactive bladder pill have spent years hearing that the drug class might be tied to dementia. A University Hospitals Cleveland team reported on Nov. 6 that across 830,393 adults newly treated between 2012 and 2025, dementia rates were similar for older anticholinergic drugs and the newer beta-3 agonists. The authors still say the result needs reproducing before any guideline changes.
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The finding cuts against a worry that dates back at least a decade.
An older warning built on cumulative anticholinergic use
In 2015, Shelly Gray of the University of Washington and colleagues reported in JAMA Internal Medicine that among 3,434 adults aged 65 and older, higher cumulative anticholinergic use was associated with a higher risk of dementia, with 797 dementia cases in the cohort. Gray herself cautioned that older adults should not stop anticholinergic medications their health care provider recommends. The new work asks whether that signal survives in a much larger, more recent population, and whether it applies to the bladder drugs specifically.
That earlier cohort came from the Adult Changes in Thought study at Group Health in Seattle, followed from 1994 through September 2012, and 637 of the 797 dementia cases were Alzheimer disease. That analysis measured strong anticholinergics as a group rather than bladder drugs alone, a gap the Cleveland team set out to close with a population treated specifically for overactive bladder.
Clinical guidance has leaned on that concern. A 2023 narrative review in Advances in Therapy by Roger Dmochowski, Diane Newman and colleagues, which was funded by the maker of vibegron, noted that anticholinergics have long been the mainstay of overactive bladder treatment and that insurers often require them first, even though the AGS Beers Criteria advise avoiding them where possible in older adults. A urology society committee report suggested trying beta-3 agonists, which lack anticholinergic properties, before anticholinergics.
830,393 patients in the Epic Cosmos database
Led by urogynecologist David Sheyn, the group at University Hospitals Cleveland Medical Center’s Urology Institute drew on the Epic Cosmos national electronic health record database. The university’s release describes adults aged 40 to 90 who started treatment for overactive bladder, split between anticholinergic medications and beta-3 agonists. The paper, Drug Therapies and Incidence of Dementia Among Adults With Overactive Bladder, appeared in JAMA Network Open.
Of those 830,393 patients, 65,134, or 7.8%, were later recorded as having dementia, according to the full paper. The anticholinergics were sorted by their reputation for cognitive effects. The higher-risk group was oxybutynin, tolterodine and solifenacin, the lower-risk group was darifenacin, trospium and fesoterodine, and the beta-3 agonists were mirabegron and vibegron. Dementia incidence was 7.5% with beta-3 agonists, 9.3% with lower-risk anticholinergics and 7.8% with higher-risk anticholinergics. Median follow-up ran from 1,046 days for beta-3 agonists to 1,568 days for the higher-risk anticholinergics.
Hazard ratios that pointed the wrong way for the old fear
After weighting to balance the groups, higher-risk anticholinergics compared with beta-3 agonists had a hazard ratio of 0.90, with a confidence interval of 0.87 to 0.93. Lower-risk anticholinergics against beta-3 agonists came in at 0.97, not statistically significant. A hazard ratio under 1 means slightly fewer dementia diagnoses in the anticholinergic group, the reverse of what the old fear predicts. The authors saw no graded exposure-response in any class, and they suggest earlier reports may reflect study design and residual confounding rather than a drug effect.
The individual drugs told a similar story. In exploratory comparisons against beta-3 agonists, oxybutynin had a hazard ratio of 0.92 and tolterodine 0.93. Higher-risk anticholinergics also compared favorably with lower-risk ones, at 0.93 with an interval of 0.90 to 0.96, so the drugs long assumed to be worst for memory did not show up worse in these records. The paper’s own conclusion is that beta-3 agonists were not associated with lower dementia incidence than anticholinergics.
Sheyn offered a different reading of the whole pattern. If some overactive bladder cases are early symptoms of dementia, he said, the bladder condition itself could serve as an early marker, and neurologic mechanisms behind urinary incontinence may be an early sign of neurodegeneration. He added that anticholinergics can cause short-term cognitive and memory side effects in some people that resolve once the drug is stopped, and that beta-3 agonists remain the preferred choice when possible.
No untreated comparison group and a low bar for confounding
The design has real limits. Nobody in the study went without medication, so it compares drug classes and cannot show that these pills carry no dementia risk. Exposure was taken from prescription orders rather than dispensing records, dementia was identified from diagnosis codes or dementia drugs and may miss mild disease, and the paper reports low E-values of 1.29 and 1.20, meaning fairly modest unmeasured confounding could account for the differences. Earlier studies linking anticholinergics to dementia mostly followed patients for five years or less.
What remains unsettled is whether a head-to-head comparison between two drug classes can ever clear either one. Sheyn’s team says reproduction comes first, and the authors wrote that the findings will require reproduction before clinical guidelines change. The groups were followed for different lengths of time, which the weighting is meant to balance. The weighted 10-year dementia risks the paper reports, 20.0% with beta-3 agonists, 19.0% with lower-risk anticholinergics and 18.1% with higher-risk ones, are the figures a replication would need to match.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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