The bladder drugs feared for dementia risk did no worse than their newer rivals in 830,000 patients

Overactive bladder, a sudden, hard-to-delay urge to urinate, is common: the paper cites figures of up to a third of adults and more than 40% of people over 60. It is usually treated with pills of two kinds. The older kind are anticholinergics: they block acetylcholine, a chemical messenger that makes the bladder muscle contract, but which the brain also uses for memory and attention. The newer kind, beta-3 agonists (mirabegron and vibegron), relax the bladder through a different signal.

Several large studies have linked long-term use of anticholinergic drugs to a higher risk of dementia, and professional guidelines now advise caution with them. Many doctors have therefore moved older patients to the beta-3 agonists. This study asks whether that move is backed by the data.

What they did

A team at University Hospitals Cleveland Medical Center used Epic Cosmos, a database that pools anonymized electronic health records from more than 2,000 hospitals and 40,000 clinics. They found 830,393 adults aged 40 to 90 who were diagnosed with overactive bladder between 2012 and 2025 and started a bladder medicine within a year, and who had no dementia at that point.

People were grouped by the first drug they were prescribed:

• "High-risk" anticholinergics (oxybutynin, tolterodine, solifenacin), which get into the brain more easily: 572,489 people.
• "Low-risk" anticholinergics (darifenacin, trospium, fesoterodine), which cross into the brain less: 49,592 people.
• Beta-3 agonists: 208,312 people.

A statistical weighting made the groups similar in age and other personal details, illnesses, the total anticholinergic load of their other medicines, and how often they saw a doctor. Dementia was counted from diagnosis codes or prescriptions of dementia drugs, over up to 10 years. The team also looked at whether staying on a drug longer went with more dementia.

What they found

• No advantage for the newer drugs. 65,134 people (7.8%) developed dementia. After weighting, the estimated 10-year dementia risk was 20.0% with beta-3 agonists, 19.0% with the low-risk anticholinergics and 18.1% with the high-risk anticholinergics.
• If anything, the reverse. People who started a high-risk anticholinergic had a slightly lower rate of dementia than those starting a beta-3 agonist (about 10% lower). The low-risk anticholinergics did not differ clearly from the beta-3 agonists.
• No dose–response. Taking an anticholinergic for longer (up to the first 400 days) was not linked to more dementia; for the high-risk drugs the trend even pointed slightly downwards.
• Mixed subgroups. Results differed somewhat by age and sex (for example, women under 65 on the low-risk anticholinergics had a higher rate than those on beta-3 agonists), but no subgroup showed the pattern expected if the drugs were harming the brain.

What to keep in mind

• Observational. Patients were not assigned a drug at random. The authors think the slightly lower rate with the old drugs is itself probably a bias: following the guidelines, doctors may give the newer drugs to older patients or those they already worry about. A statistical check (the "E-value") showed that a modest unmeasured factor could explain the differences in either direction.
• Prescriptions, not pills taken. The data show what was ordered, not what was picked up or swallowed. Doses were often missing, so the team used duration as a stand-in.
• Dementia from records. Diagnosis codes can miss mild or early dementia, and events outside the hospitals in the network were not captured. Things like genes (such as APOE4) and frailty were not available.
• A possible common cause. The authors point out that bladder urgency can itself be an early sign of the brain changes that later lead to dementia, such as damage to small blood vessels, which could make any bladder medicine look linked to dementia.
• Shorter look-back. Some earlier studies looked at drug use 13 to 16 years before diagnosis; this study's exposure window was much shorter.

Why it matters

Bladder problems and dementia are both common in later life, and fear of one treatment has shaped how millions of older people are treated. This very large study did not find that switching to the newer drug class lowers dementia risk, and it found no sign that longer use of the older drugs adds to it. The authors conclude that differences reported before may come from study design and confounding rather than from the drugs. It does not prove the older drugs are safe for the brain, and anticholinergics have other known side effects; decisions about these prescription medicines belong with a doctor.