Overactive bladder (OAB) is a common condition in both the general population and in those with cognitive dysfunction. It is defined as urinary urgency, usually with frequency and urgency, and may or may not include urgency incontinence. These symptoms are significant as they can lead to falls and fractures, skin breakdown, institutionalization and impair quality of life. There is a large body of research suggesting that OAB anticholinergic medications may lead to cognitive dysfunction, and an increased risk of dementia; however there is a need for more studies in those with pre-existing cognitive dysfunction, and studies with longer follow-up periods.(1) In addition, the APOE-e4 allele is a genetic risk factor for Alzheimer’s, and may lead to increased sensitivity to anticholinergic-mediated cognitive decline(2); to our knowledge it hasn’t been evaluated in the context of OAB anticholinergics. Our objective was to use routinely collected data from the National Alzheimer’s Coordinating Centers (NACC) to see if the use of OAB anticholinergics was associated with an increased risk of cognitive decline, and to examine if APOE-e4 carrier status interacts with any observed cognitive decline with OAB anticholinergic use.

This is a retrospective, propensity-score matched cohort study using prospective collected data from the NACC. The NACC started collecting prospective data from approximately 40 specialized Alzheimer’s research centers in the United Sates in 2005. Participants may volunteer to be included in the NACC dataset, or they may be offered enrollment by participating clinicians. We identified all participants who were enrolled between September 1 2005 and January 1 2020. We excluded people if: they did not have at least one follow-up visit, their medication list was not available, they were already on an OAB anticholinergic medication at enrollment, they had a cognitive condition other than normal cognition, mild cognitive impairment, or dementia, they were missing genetic testing results for APOE-e4 allele status, or if there was >4 years between their first and second visit.

Our primary exposure was defined as new reported use of an OAB anticholinergic medication (oxybutynin, tolterodine, solifenacin, trospium, darifenacin or fesoterodine) at a subsequent NACC visit. Medication use was determined by having the patient bring all medication bottles to the appointment, and these were reviewed by study staff. We considered APOE-e3/e4 or APOE-e4/e4 status as being positive for the APOE-e4 allele. Our co-primary outcomes were the clinical dementia rating (CDR, 0=no dementia, 4=severe cognitive impairment) and the mini-mental state examination (MMSE, which measures orientation, attention, memory, language and visual-spatial skills and is scored from 0-30; a lower score represents increased cognitive impairment).  Secondary outcomes included the Boston naming test, Wechsler Adult Intelligence Scale-revised (WAIS-R), and the trail making test part B. Outcomes were compared between the baseline visit and the next follow-up visit.

We created a propensity score using 38 variables available in the NACC dataset that were relevant to cognition such as age, gender, language, years of education, marital status, vision and hearing impairment, and the prevalent use of several medications. Patients who were newly taking an OAB anticholinergic medication were matched 1:1 with participants who were not newly taking an OAB anticholinergic medication using the propensity score, data era (pre/post 2015), total number of NACC visits, and based on their cognitive status (normal, mild cognitive impairment, or dementia). Comparisons between primary and secondary outcomes were carried out using t-tests; a conditional logistic regression model (odds ratio, OR) was used to determine if OAB anticholinergic medication exposure predicted a clinically important cognitive decline based on our primary endpoints (≥1 point increase on the CDR, or a ≥3 point decrease on the MMSE). Means and standard deviation (SD) are reported. Statistical analysis was carried out using SAS 9.4, and a two-sided p<0.05 was considered significant. This analysis was exempt from ethics review.

Our initial cohort consisted of 44,713 people, and after exclusions we were left with 18,835 people. We were able to successfully match 782 of the possible 792 participants who newly started an OAB anticholinergic to 782 participants who did not start an OAB anticholinergic. After matching, all measured baseline characteristics were similar (selected ones are shown in table 1). Among the new OAB anticholinergic users, the most common OAB anticholinergic medications were oxybutynin (299/782, 38%), tolterodine (178/782, 23%), and solifenacin (163/782, 21%).

The mean time between the primary visit and follow-up visit was 445 (SD 153) days. There was no significant difference in the change in the primary or secondary outcomes between the unexposed and exposed participants (table 2). The proportion of participants who had a clinically significant change in the CDR score and MMSE score was similar among unexposed and exposed participants (8.1% versus 10.1%, and 20.7% versus 21.9% respectively). In the conditional logistic regression model, there was no significant increased risk of important cognitive decline among OAB anticholinergic users (MMSE decrease ≥3 points, OR 1.06, 95%CI 0.79-1.43, p=0.70 and CDR increase ≥1 point, OR 1.38, 95%CI 0.93-2.05, p=0.11). There was no significant interaction between APOE-e4 carriers and clinically important cognitive decline measured with either the CDR (p=0.38) or MMSE (p=0.95). Results were similar within each cognitive group (normal, mild cognitive impairment, dementia). There was an increased risk of a clinically important change in CDR among users of oxybutynin or tolterodine (OR 1.65, 95%CI 0.98-2.77) that was close to statistical significance (p=0.06); this was not seen in users of the other anticholinergics (OR 1.05, 95%CI 0.56-1.97, p-0.87).

We did not find that the prevalent use of OAB anticholinergic medications was associated with a clinically important change in overall cognitive status, or with a change in three tests of cognitive function. Additionally, APOE-e4 allele carrier status did not have a significant interaction with OAB anticholinergic medication and cognitive decline. This study provides a level of reassurance that the risk of significant cognitive dysfunction in a population with baseline cognitive dysfunction is not impacted by OAB anticholinergic medications, particularly when looking at newer OAB anticholinergic medications (solifenacin, trospium, darifenacin or fesoterodine).  The previous literature on longer-term effects (6-12 months) of OAB anticholinergic medications on cognition has been conflicting (with studies both suggesting or refuting a significant effect on cognition), limited by methodologic flaws, and generally not conducted in those with variable levels of baseline cognitive function.(1) 

Strengths of our study include the use of valid and sensitive measures of cognitive function, the use of a change threshold to define clinically important cognitive decline (which considers the minimally important differences of the CDR and MMSE), and the creation of matched groups using a propensity score. Limitations of our research include the lack of data on the duration of use of the OAB anticholinergic medications, and the fact that some people may have used OAB anticholinergic medications in between visits and discontinued them before there follow-up (and therefore counted as a non-user).

In a population with mixed normal and cognitive impairment, we did not find that there was a significant difference in the proportion of people that developed cognitive impairment when comparing new anticholinergic OAB medication users to propensity score-matched nonusers.

Welk B, Richardson K, Panicker JN. The cognitive effect of anticholinergics for patients with overactive bladder. Nat Rev Urol. 2021;1–15.
Pomara N, Willoughby LM, Wesnes K, Sidtis JJ. Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-?4 Allele in the Elderly: A Controlled Pilot Study. Neuropsychopharmacol. 2004;29(2):403–9.

Continence 2S2 (2022) 100270
DOI: 10.1016/j.cont.2022.100270