Anticholinergic drugs and clinical outcomes in older people with and without dementia- A systematic Review

Anticholinergic drugs and clinical outcomes in older people with and without dementia- A systematic Review | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Anticholinergic drugs and clinical outcomes in older people with and without dementia- A systematic Review View ORCID Profile Delia Bishara , View ORCID Profile Katrina Davis , View ORCID Profile Christoph Mueller , Olubanke Dzahini , Nicola Funnell , Justin Sauer , Daniel Harwood , David Taylor , View ORCID Profile Robert Stewart doi: https://doi.org/10.1101/2025.03.14.25323976 Delia Bishara 1 Mental Health for Older Adults and Dementia Clinical Academic Group, South London and Maudsley NHS Foundation Trust , London 2 King’s College London, Institute of Psychiatry, Psychology and Neuroscience , London 3 Pharmacy Department, South London and Maudsley NHS Foundation Trust , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Delia Bishara For correspondence: delia.bishara{at}slam.nhs.uk Katrina Davis 2 King’s College London, Institute of Psychiatry, Psychology and Neuroscience , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Katrina Davis Christoph Mueller 1 Mental Health for Older Adults and Dementia Clinical Academic Group, South London and Maudsley NHS Foundation Trust , London 2 King’s College London, Institute of Psychiatry, Psychology and Neuroscience , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christoph Mueller Olubanke Dzahini 3 Pharmacy Department, South London and Maudsley NHS Foundation Trust , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nicola Funnell 1 Mental Health for Older Adults and Dementia Clinical Academic Group, South London and Maudsley NHS Foundation Trust , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site Justin Sauer 1 Mental Health for Older Adults and Dementia Clinical Academic Group, South London and Maudsley NHS Foundation Trust , London 2 King’s College London, Institute of Psychiatry, Psychology and Neuroscience , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Harwood 1 Mental Health for Older Adults and Dementia Clinical Academic Group, South London and Maudsley NHS Foundation Trust , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Taylor 2 King’s College London, Institute of Psychiatry, Psychology and Neuroscience , London 3 Pharmacy Department, South London and Maudsley NHS Foundation Trust , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert Stewart 1 Mental Health for Older Adults and Dementia Clinical Academic Group, South London and Maudsley NHS Foundation Trust , London 2 King’s College London, Institute of Psychiatry, Psychology and Neuroscience , London Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Robert Stewart Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Background Anticholinergic medications are widely used, however their use in older people has been linked to cognitive decline, dementia and increased mortality. This systematic review examines the literature investigating relationships between anticholinergic burden and risk of dementia, cognitive impairment, and outcomes in dementia. Methods Cochrane database and PubMed searches using the terms “anticholinergic” and “dementia” or “cognition” were performed up to May 2023. Outcomes included: (i) dementia diagnosis, (ii) cognitive outcomes in people without dementia (iii) cognitive outcomes, hospitalisation and death in people with dementia. Inclusion and exclusion criteria were defined, and papers were evaluated for inclusion by two researchers independently. Papers examining these relationships specifically for urinary drugs and antidepressants were also analysed separately. Results Sixty observational studies met our criteria across the three outcomes of interest. Anticholinergic burden was found to be consistently associated with increased risk of dementia however the relationships with cognitive outcomes were less clear. In people with dementia, there were consistent associations between the anticholinergic burden and mortality (hazard ratio (HR) range: 1.04-1.23) or hospitalisation (HR range: 1.13-4.54) but not for cognitive outcomes. Urological drugs with high anticholinergic burden were associated with a ≥50% increased mortality risk in people with dementia. Conclusion Anticholinergic burden has been consistently associated with increased dementia incidence. Furthermore, in people with existing dementia, anticholinergic burden is associated with increased mortality and hospitalisation. Associations with cognitive outcomes in people without/with dementia remains uncertain. Clinicians should be advised to exercise caution with anticholinergic medication use in older people. Introduction Anticholinergic medications are widely used to treat many medical conditions, however they have been linked to cognitive decline 1 , dementia and higher mortality 2 , 3 . Drugs for urinary frequency and antidepressants have also been linked with a higher risk of dementia 2 , 3 . Our objective was to review associations between anticholinergic agents in older people and associations with cognition, dementia risk, and dementia clinical outcomes. Methods Cochrane database and PubMed searches were executed on 4February 2020 using the keywords “anticholinergic” and “dementia” or “cognition”. The search was limited to English language, “human” subjects and to publications within the last 10 years. Three top-up searches were made to bring date of inclusion to articles indexed before May 2023. Abstracts were examined to identify original research and reviews comparing groups of older people (>50 years) with or without dementia with different anticholinergic drug load. We identified three related groups for participants and outcomes: Group 1. Risk of dementia, Group 2. Cognitive outcomes in people without dementia, and Group 3. Outcomes in people with dementia. Our inclusion criteria are described below. Inclusion criteria for papers examining the associations between anticholinergic agents and: – (Group 1) dementia – (Group 2) cognitive outcomes – (Group 3) outcomes in dementia: mortality, hospitalisation or cognitive outcomes: – Population - Recruitment from any setting. Group 1 and 2: Older adults >50 years without cognitive impairment. Group 3: Older adults >50 years with dementia. – Index prognostic factor- Groups with difference in anticholinergic burden (using validated scale). – Comparative prognostic factors (covariates of interest)- Studies must report, and preferably control for, baseline age, gender, comorbidities (e.g., using Charlson Comorbidity Index) and severity of dementia (where relevant) by Mini Mental State Examination (MMSE) or other cognitive measure. – Outcomes- Group 1: Diagnosis of dementia. Group 2: Outcome from standardised cognitive assessments (e.g., MMSE). Group 3: Outcome from standardised cognitive assessments, hospitalisation, mortality. – Study: Any design. Minimum size, 10 participants. Studies comprising of 10 subjects or fewer were excluded as were studies including some subjects younger than 50 years old. Where systematic reviews were available, these took precedence over original research. The PRISMA flow chart (see Figure 1 ) describes the selection process. DB and KD examined the abstracts and full papers independently to determine whether they met inclusion criteria with discussion and resolution of any disagreement. The search was updated three times to include new papers using identical selection criteria. Download figure Open in new tab Figure 1 Prisma flow diagram of the study selection process Where required, we contacted authors for additional information. Exclusions were primarily due to the wrong or unreported population, no outcome of interest or lack of covariate reporting. Several otherwise eligible studies were excluded because a recognised anticholinergic burden scale had not been used. An exception was made for within-class comparisons of antidepressants and drugs used in urinary conditions, which we retained and analysed separately. The rational for this was that an anticholinergic burden scale was not deemed necessary where individual drugs were directly compared against others within the same class. We carried out back-referencing of reviews and papers, and forward-referencing using Google Scholar, to ascertain any missed studies meeting inclusion criteria. Study quality was assessed using the Newcastle-Ottawa Scale, separately rated by DM and KD resulting in an agreed consensus score. “Selection” has four items on the definition of cohort and exposure. “Comparability” has two items regarding control of major confounders (age, sex and comorbidities), and “Outcome” has three items regarding the definition and ascertainment of outcome, including whether exposure and observation were long enough to see the plausible effect. There is no agreed definition as to how to combine these scores; we present the sum for reference. Analysis Endnote was used to organise references. MS Excel was used to collect and organise extracted information. The Cochrane Foundation Review Manager (RevMan version 5.4) was used to draw plots. We planned to carry out meta-analysis if there was a group of more than two studies that had compatible exposure and outcome measures for combining. Results Sixty papers met inclusion criteria for at least one outcome of interest. Twenty-four investigated cognitive outcomes in people without dementia, 23 the risk of incident dementia, and 13 outcomes in dementia. Thirteen reviews in groups 1 and 2 were identified and summarised. Only one review of outcomes in dementia (group 3) was identified. Due to the limited evidence in this area, this review focussed mainly on dementia outcomes; however study data for dementia risk and cognitive outcomes can be found in the supplementary material. Anticholinergic burden and risk of dementia Twenty-three studies were included, comprising over 3 million patients across the US, Europe, Australia and Asia ( Supplementary Table 1 ). All were observational, including longitudinal database studies, conventional cohort and case-control studies. A significant association between anticholinergic drug use and dementia risk was observed in most studies. Systematic reviews confirmed these findings. One systematic review and meta-analysis concluded that anticholinergic use for ≥ 3 months increased the risk of dementia on average by an estimated 46% 5 , a dose-dependent relationship concluded by another 6 . Both reviews highlighted antidepressants, antiparkinsonian and urological drugs as associated with higher risk. View this table: View inline View popup Supplementary Table 1 Papers examining the association between anticholinergic drugs and risk of dementia Anticholinergic burden and cognitive outcomes Twenty-four studies of nearly 150,000 patients investigated the effects of anticholinergic agents on cognitive outcomes ( Supplementary Table 2 ). Studies were mostly conducted in the USA, Europe, and Australia with one in Canada and one in Taiwan; they included observational research, both cross-sectional and longitudinal. Fifteen reported a significant association between anticholinergic burden and cognitive outcomes, despite different study design, anticholinergic burden scales, populations, and cognitive measures. Of the remainder, four reported mixed results and five studies found no significant association. Three systematic reviews 7 – 9 concluded an association between anticholinergic medication and significant decline in cognition, although this was not observed for all studies. View this table: View inline View popup Supplementary Table 2 Papers examining the association between anticholinergic drugs and risk of cognitive outcomes Anticholinergic burden and mortality, hospitalisation or cognitive outcomes in people with dementia Thirteen studies from our review met inclusion criteria ( Table 1 ). Further details of quality assessments are shown in Table 2 . No paper scored full points on the quality scale, but many dropped only one mark, for selecting only people with dementia who were on medication or attending a specialist clinic, thereby reducing generalisability. View this table: View inline View popup Table 1 Papers examining the association between anticholinergic burden and cognitive decline, hospitalisation or mortality in people with dementia. View this table: View inline View popup Table 2 Summary of study outcomes for papers (included in meta-analysis) examining the association between anticholinergic burden and cognitive decline, hospitalisation or mortality in people with dementia. Anticholinergic burden and mortality in dementia Table 1 describes seven studies 4 , 10 – 15 with mortality as an outcome, all of which were longitudinal cohort studies, five of which included over 10,000 participants. Six of the seven studies found a significant effect on mortality, with only one 15 showing no association; however, this included patients with both Mild Cognitive Impairment and dementia. Combining data from different studies was hampered by differences in anticholinergic burden scale used and the anticholinergic burden scores that were compared, except for two studies 14 , 16 . The forest plot ( Figure 2a ) illustrates a consistent significant excess risk of death associated with a higher anticholinergic burden of effect size ranging between HR of 1.04 to 1.23. Moreover, three 11 – 13 of seven studies showed a dose-response relationship. Three 11 , 12 , 17 rated highly on the NOS (concerns were about representativeness only), while two had other quality concerns 10 , 4 . Considering noteworthy secondary findings, elevated mortality was associated with urological and respiratory anticholinergic drugs, but not with antidepressants 4 . Also the association between ACB and mortality was consistent across dementia sub-types 13 . Only one relevant review was identified 18 which also concluded an association between anticholinergic medication and all-cause mortality. Download figure Open in new tab Figure 2a) Forest plot of hazard ratios for mortality Anticholinergic burden and hospitalisation in dementia Of four studies 11 , 12 , 19 , 20 examining the association between anticholinergic burden and hospitalisation in people with dementia ( Table 1 ), three 11 , 12 , 19 found a higher risk and one 20 found no association. In NOS assessment, quality concerns for three 11 , 12 , 20 were for representativeness only, while one 19 had some other quality concerns. Again, a meta-analysis could not be carried out as each study used a different exposure scale. The forest plot ( Figure 2b ) illustrates a higher anticholinergic burden associated with significantly more hospitalisation with HRs ranging from 1.13 to 4.54. The review by Wang 18 also noted longer hospital length of stay in three studies. Download figure Open in new tab Figure 2b) Forest plot of hazard ratios for hospitalisation Anticholinergic burden and cognitive outcomes in dementia Of the 13 studies of dementia cohorts, 5 examined cognitive outcomes in dementia and none found an association with anticholinergic burden ( Table 1 ). Bishara 2020 11 found that anticholinergic burden was associated with impaired cognitive function around the dementia diagnosis, rather than differences in subsequent cognitive decline; Dyer 2020 21 found that anticholinergic burden was not associated with greater progression on the ADAS-Cog/CDR-sb over time, although a higher burden predicted greater dementia severity which persisted after robust covariate adjustment. Fox 2011 22 found no differences in MMSE or other cognitive functioning at either 6 or 18 months, after adjusting for covariates, between those with and without high anticholinergic load. Similarly, Lampela 2013 23 found no association between anticholinergic scores and MMSE in people with dementia, and Sanders 2017 24 also found no associations in multivariate models for total drug burden, anticholinergic burden, or sedative burden with physical or cognitive function. The review by Wang 18 concluded inconsistent results due to varying study characteristics and quality. Only two cited studies found an association between use of anticholinergic medications and reduced cognitive performance; however, these did not meet our inclusion criteria due to crude assessment of cognition and no adjustment for confounders. Bladder anticholinergic drug studies Risk of dementia and cognitive outcomes Fifteen studies investigating specific anticholinergic medications for bladder disorders in relation to dementia or cognitive outcomes are included in Supplementary Table 3 . These varied in design including small randomised controlled trials (RCTs) such as Geller 2017 25 (n=59), cohort studies such as Moga 2017 26 (n=7,735) and large case-control studies using electronic health records such as Richardson 2018 (n=40,770 cases, 283,933 controls) 3 . All studies investigating risk of dementia in those taking any bladder drug (vs none) found a significant relationship; those examining scores on cognitive scales were more inconsistent in their findings. View this table: View inline View popup Supplementary Table 3 Papers examining the association between bladder anticholinergic drugs and risk of dementia or cognitive decline Barthold 2020 27 compared agents with selective antimuscarinic action at the M 3 receptor, (solifenacin and darifenacin) with non-selective agents (oxybutynin, tolterodine, trospium, fesoterodine), but found no difference in dementia risk. Malcher 2022 28 found that OAB anticholinergic use was associated with an increased risk of dementia with a cumulative dose response and when comparing drugs, they found a particularly marked increased risk of dementia for oxybutynin and solifenacin, but no increased risk for trospium. In contrast, Matta 2021 29 found that receipt of solifenacin (OR 1.34), darifenacin (OR 1.49), tolterodine (OR 1.21), and fesoterodine (OR 1.39) were associated with increased odds of incident dementia compared with receipt of mirabegron. However, no effect was seen with oxybutynin or trospium. Our search identified 13 reviews estimating the risks associated with anticholinergic agents used for Overactive Bladder (OAB). Most reviews were not systematic. One systematic review by Triantafylidis 2018 30 investigated combined cholinesterase inhibitors with bladder anticholinergic drugs and found mixed results for cognitive and functional outcomes, another by Paquette 2011 31 investigated reporting bias associated with adverse central nervous system events in clinical drug trials of younger and older adults with overactive bladder; however, study heterogeneity, dosing inconsistency, and reporting bias limited interpretation of the findings from the meta-analyses. Rangganata 2020 32 conducted a systematic review and meta-analysis of reported effects on cognitive function in older people, finding that oxybutynin had the strongest association with MMSE decline, with weaker but statistically significant associations for darifenacin and tolterodine. Mortality and hospitalisation in people with dementia Four studies examining these relationships from the UK, US, and Northern Ireland (see Table 3 ) were included. McMichael 2021 33 reported an association between urological drugs and increased mortality in people with dementia, but did not compare different bladder agents. Kachru 2020 34 compared M 3 selective (solifenacin, darifenacin) and the remaining non-selective bladder antimuscarinic agents and found a 50% higher risk of 180-day mortality associated with non-selective drugs, consistent across multiple sensitivity analyses. Similarly, Bishara 2021 35 found that bladder drugs with a high central anticholinergic burden (tolterodine, oxybutynin) were associated with a 55% increased mortality risk compared to drugs with a low or zero score (darifenacin, fesoterodine, trospium, mirabegron, solifenacin). View this table: View inline View popup Download powerpoint Table 3 Papers examining the association between bladder anticholinergics and mortality or hospitalisation in people with dementia Kachru 2021 36 found no increased risk of hospitalisation in patients receiving non-selective M 3 medications compared to selective agents and Bishara 35 found no excess hospitalisation in patients prescribed bladder anticholinergics with high central anticholinergic burden. Antidepressant investigations Risk of dementia and cognitive outcomes Supplementary Table 4 displays seven studies that specifically investigated anticholinergic antidepressants: mainly large cohort or population-based database studies. All four studies examining risk of dementia found an association between anticholinergic antidepressants and increased risk 2 , 3 , 37 , 38 . However, the three 39 – 41 investigating cognition (whether in a specific population 40 or in people with dementia 39 ) found no association. No reviews were identified from our search. View this table: View inline View popup Supplementary Table 4 Papers examining the association between antidepressants with high anticholinergic burden and risk of dementia or cognitive decline View this table: View inline View popup Mortality or hospitalisation in dementia Studies investigating the relationship between anticholinergic burden of antidepressants and outcomes in dementia are shown in Table 4 . McMichael 2021 33 found that antidepressant drugs were not significantly associated with mortality rates in people with dementia but did not compare the risk between different antidepressants or by anticholinergic burden. Mate 2022 40 found no association with increased hospitalisation. Bishara 2021 39 found a reduced risk of mortality in people receiving antidepressants with high central anticholinergic burden compared to those with no or low burden. No significant associations were detected between antidepressant’s central anticholinergic burden and hospitalisation (or cognitive decline). View this table: View inline View popup Download powerpoint Table 4 Papers examining the association between antidepressants with high anticholinergic burden and risk of mortality or hospitalisation in people with dementia. Discussion Our review found consistent associations between certain classes of drugs with anticholinergic action (antidepressants and urological drugs) as well as anticholinergic burden and future dementia incidence 2 , 3 underscoring the importance of anticholinergic drugs as a potential modifiable risk factor for dementia prevention 6 . Evidence for an effect on cognitive outcomes in community populations was considerably less consistent. Regarding studies investigating outcomes in people with dementia, it appears that whilst significant associations have been reported between anticholinergic burden and both mortality and hospitalisation, no papers examined found an association between anticholinergic burden and longitudinal cognitive trajectories. An association between anticholinergic burden and cognitive outcomes has not been conclusively shown for people with or without dementia. This review, as well as others 8 , 9 highlight the complexities of assessing the long-term cognitive effects of anticholinergic drugs: measurement issues, reporting issues and confounding by indication. For instance, inconsistencies between studies may reflect the limited accuracy and consistency in the measurements used, or the way the results are reported. Even when using the same measure, different studies may report cognitive decline (change in cognitive function over time), cognitive impairment (cognitive function below a given level at a given time), transition to mild cognitive impairment (MCI), cognitive or neuropsychological performance etc. Furthermore, the measures themselves have limitations. MMSE scores are known to be limited by “floor effects” in those with more severe dementia and “ceiling effects” when used in individuals with a high educational background 42 . Also, recording of serial MMSE scores from clinical records can also be unreliable, which is an important limitation to the evaluations of cognitive function in studies. Cognitive decline measured by a change or cut-off based on cognitive tests, may have questionable clinical relevance as the tests may be insufficiently sensitive to detect cognitive decline among older adults 8 . In conclusion, a causal link between anticholinergic agents and cognitive decline cannot yet be inferred from these observational studies with considerable risk of bias, although the consistent finding of association with incident dementia may be enough for some clinicians to act on. This review also examined papers investigating bladder drugs specifically and found again a consistent association between the use of anticholinergic agents used in OAB and the risk of dementia; however, the association with cognitive decline is also less clear. In addition to the reasons already discussed, this could also be because newer agents less likely to penetrate the BBB and to act centrally were used in most studies. Supporting this, in studies investigating dementia outcomes, two studies compared bladder agents and found that non-selective agents or centrally acting drugs (oxybutynin, tolterodine) were associated with a 50% 34 and 55% 35 increased mortality risk than the more selective agents or those with lower central activity. However, there was no association within this group with high central anticholinergic burden and hospitalisation. This may be due to the non-differential effects of the muscarinic receptors on falls/fractures and all-cause hospitalisation 36 . Another reason might be that muscarinic selectivity is not binary, meaning the drugs categorised as selective to M 3 receptors still have some activity with the M 1 receptors, albeit weaker than the non-selective drugs, and that this activity may still be strong enough to be harmful 27 . With regards to the papers exploring the relationships with antidepressants, whilst anticholinergic antidepressants were associated with increased risk of dementia in some studies, they were also not associated with cognitive decline, although this could reflect the treatment of depression resulting in improved cognition, even when anticholinergic agents are used 43 . In addition, antidepressant drugs with high anticholinergic burden were not significantly associated with increased mortality rates in people with dementia 4 ; if anything, risks were reduced 39 . Furthermore, no significant associations were detected between antidepressant’s central anticholinergic burden and hospitalisation (or cognitive decline) 39 , 40 . While further data are required, it appears that these counter-intuitive findings may reflect factors underlying the prescriber choice of antidepressants rather than the agents themselves 39 . Strengths and limitations Strengths of this review include the wider inclusion of studies investigating anticholinergic medication and dementia outcomes alongside those investigating dementia risk, meaning that the evidence from both fields can be considered in combination to build up a better understanding of the overall risks involved. It is even more necessary to triangulate results with observational data. Limitations include our use of only PubMed and Cochrane databases, although front and back referencing was carried out and references from all papers and reviews were scanned carefully so as not to miss any relevant studies. Equally, while we assessed paper quality when looking at the effect of anticholinergic medication on people with dementia, we did not extend this to other aspects of the review where there was sufficient existing review evidence. Issues of quality with the evidence base are of note. The methods for collecting medication use, whilst more reliable with the use of electronic pharmacy dispensing data, may still not accurately reflect actual or continued use. Second, multiple risk scales are available for estimating anticholinergic burden of drugs and therefore studies cannot easily be compared nor combined. It is unclear why there is a consistent association between anticholinergic burden and dementia risk however a similar relationship was not found with cognitive impairment/decline either in people with or without dementia. Higher dementia incidence may be occurring through a reduced ability to compensate in the early stages of neurodegeneration. Anticholinergic drugs could potentially bring forward the onset of dementia, by compromising brain function at borderline impairment, rather than directly influencing the underlying disease processes. This may therefore not manifest as detectable cognitive deficits. Moreover, mortality and hospitalisation outcomes in dementia might possibly reflect non-cognitive adverse consequences of anticholinergic actions. Urinary drugs with high anticholinergic burden including oxybutynin and tolterodine should be avoided in people with dementia due to the associated increased mortality risk identified in studies. Furthermore, whilst anticholinergic antidepressants are associated with increased risk of dementia, they were not found to increase mortality in dementia. Antidepressant studies are likely to be most subject to confounding by indication, which may explain these results; clinicians may avoid the more anticholinergic ones in people who are frail, have various comorbidities and who are already at higher risk of mortality whereas risks with urinary drugs may be less widely known. Further studies that can dissect the level at which anticholinergic agents act would be useful and could help better inform guides for safe usage in the future. Conclusion Consistent associations were therefore found between anticholinergic burden and future dementia incidence. In people with dementia, anticholinergic burden was associated with increased mortality and hospitalisation. Associations with cognitive outcomes in people without/with dementia remains uncertain. Current evidence remains derived from observation studies and will need reconsideration as improved methodology is developed. However, it remains reasonable for clinicians to exercise caution with anticholinergic medication and carefully weigh up risks and benefits when making prescribing decisions. Data Availability All data produced in the present work are contained in the manuscript Funding No funding was received for this project. DB, KD, CM and RS are part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. RS is also part-funded by i) the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King’s College Hospital NHS Foundation Trust; ii) UKRI – Medical Research Council through the DATAMIND HDR UK Mental Health Data Hub (MRC reference: MR/W014386); iii) the UK Prevention Research Partnership (Violence, Health and Society; MR-VO49879/1), an initiative funded by UK Research and Innovation Councils, the Department of Health and Social Care (England) and the UK devolved administrations, and leading health research charities. Disclosure statement RS has received research support in the last 3 years from Janssen, GSK and Takeda. DT receives research funding from Janssen Pharmaceuticals and Lundbeck speaking honoraria from Janssen, Lundbeck, Sunovion, and Recordati but no sources of funding were received for the preparation of this article. References 1. ↵ Campbell NL , Boustani MA , Lane KA , et al. Use of anticholinergics and the risk of cognitive impairment in an African American population . Neurology 2010 ; 75 ( 2 ): 152 – 59 . doi: 10.1212/WNL.0b013e3181e7f2ab OpenUrl CrossRef PubMed 2. ↵ Coupland CAC , Hill T , Dening T , et al. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study . JAMA Internal Medicine 2019 ; 179 ( 8 ): 1084 – 93 . doi: 10.1001/jamainternmed.2019.0677 %J JAMA Internal Medicine OpenUrl CrossRef PubMed 3. ↵ Richardson K , Fox C , Maidment I , et al. Anticholinergic drugs and risk of dementia: case-control study . 2018 ; 361 : k1315 . doi: 10.1136/bmj.k1315 %J BMJ OpenUrl Abstract / FREE Full Text 4. ↵ McMichael AJ , Zafeiridi E , Ryan M , et al. Anticholinergic drug use and risk of mortality for people with dementia in Northern Ireland . Aging & Mental Health 2021 ; 25 ( 8 ): 1475 – 82 . doi: 10.1080/13607863.2020.1830028 OpenUrl CrossRef PubMed 5. ↵ Dmochowski RR , Thai S , Iglay K , et al. Increased risk of incident dementia following use of anticholinergic agents: A systematic literature review and meta-analysis . Neurourol Urodyn 2021 ; 40 ( 1 ): 28 – 37 . doi: 10.1002/nau.24536 [published Online First: 2020/10/25] OpenUrl CrossRef PubMed 6. ↵ Zheng YB , Shi L , Zhu XM , et al. Anticholinergic drugs and the risk of dementia: A systematic review and meta-analysis . Neuroscience and biobehavioral reviews 2021 ; 127 : 296 – 306 . doi: 10.1016/j.neubiorev.2021.04.031 [published Online First: 2021/05/03] OpenUrl CrossRef PubMed 7. ↵ Fox C , Smith T , Maidment I , et al. Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review . Age Ageing 2014 ; 43 ( 5 ): 604 – 15 . doi: 10.1093/ageing/afu096 [published Online First: 20140719] OpenUrl CrossRef PubMed 8. ↵ Andre L , Gallini A , Montastruc F , et al. Association between anticholinergic (atropinic) drug exposure and cognitive function in longitudinal studies among individuals over 50 years old: a systematic review . Eur J Clin Pharmacol 2019 ; 75 ( 12 ): 1631 – 44 . doi: 10.1007/s00228-019-02744-8 [published Online First: 2019/08/31] OpenUrl CrossRef 9. ↵ Pieper NT , Grossi CM , Chan WY , et al. Anticholinergic drugs and incident dementia, mild cognitive impairment and cognitive decline: a meta-analysis . Age Ageing 2020 ; 49 ( 6 ): 939 – 47 . doi: 10.1093/ageing/afaa090 [published Online First: 2020/07/01] OpenUrl CrossRef PubMed 10. ↵ Ah Y-M , Suh Y , Jun K , et al. Effect of anticholinergic burden on treatment modification, delirium and mortality in newly diagnosed dementia patients starting a cholinesterase inhibitor: A population-based study . Basic & Clinical Pharmacology & Toxicology 2019 ; 124 ( 6 ): 741 – 48 . doi: 10.1111/bcpt.13184 OpenUrl CrossRef PubMed 11. ↵ Bishara D , Perera G , Harwood D , et al. The anticholinergic effect on cognition (AEC) scale— Associations with mortality, hospitalisation and cognitive decline following dementia diagnosis . International Journal of Geriatric Psychiatry 2020 ; 35 ( 9 ): 1069 – 77 . doi: 10.1002/gps.5330 OpenUrl CrossRef PubMed 12. ↵ Gnjidic D , Hilmer SN , Hartikainen S , et al. Impact of High Risk Drug Use on Hospitalization and Mortality in Older People with and without Alzheimer’s Disease: A National Population Cohort Study . PloS one 2014 ; 9 ( 1 ): e83224 . doi: 10.1371/journal.pone.0083224 OpenUrl CrossRef PubMed 13. ↵ Tan E , Eriksdotter M , García-Ptacek S , et al. Anticholinergic Burden and Risk of Stroke and Death in People with Different Types of Dementia . Journal of Alzheimer’s Disease 2018 ; 65 : 1 – 8 . doi: 10.3233/JAD-180353 OpenUrl CrossRef 14. ↵ Cross AJ , George J , Woodward MC , et al. Potentially Inappropriate Medication, Anticholinergic Burden, and Mortality in People Attending Memory Clinics . Journal of Alzheimer’s disease : JAD 2017 ; 60 ( 2 ): 349 – 58 . doi: 10.3233/jad-170265 [published Online First: 2017/09/05] OpenUrl CrossRef PubMed 15. ↵ Buckley E , Jonsson A , Flood Z , et al. Potentially inappropriate medication use and mortality in patients with cognitive impairment . Eur J Clin Pharmacol 2022 ; 78 ( 12 ): 2013 – 20 . doi: 10.1007/s00228-022-03410-2 [published Online First: 20221103] OpenUrl CrossRef PubMed 16. ↵ Tan ECK , Eriksdotter M , Garcia-Ptacek S , et al. Anticholinergic Burden and Risk of Stroke and Death in People with Different Types of Dementia . Journal of Alzheimer’s disease : JAD 2018 ; 65 ( 2 ): 589 – 96 . doi: 10.3233/jad-180353 [published Online First: 2018/07/30] OpenUrl CrossRef PubMed 17. ↵ Tan ECK , Eriksdotter M , Garcia-Ptacek S , et al. Anticholinergic Burden and Risk of Stroke and Death in People with Different Types of Dementia . Journal of Alzheimer’s Disease 2018 ; 65 : 589 – 96 . doi: 10.3233/JAD-180353 OpenUrl CrossRef PubMed 18. ↵ Wang K , Alan J , Page AT , et al. Anticholinergics and clinical outcomes amongst people with pre-existing dementia: A systematic review . Maturitas 2021 ; 151 : 1 – 14 . doi: 10.1016/j.maturitas.2021.06.004 [published Online First: 20210620] OpenUrl CrossRef PubMed 19. ↵ Watanabe S , Fukatsu T , Kanemoto K . Risk of hospitalization associated with anticholinergic medication for patients with dementia . Psychogeriatrics 2018 ; 18 ( 1 ): 57 – 63 . doi: 10.1111/psyg.12291 OpenUrl CrossRef PubMed 20. ↵ Liang C-K , Chou M-Y , Hsu Y-H , et al. The association of potentially inappropriate medications, polypharmacy and anticholinergic burden with readmission and emergency room revisit after discharge: A hospital-based retrospective cohort study . British Journal of Clinical Pharmacology 2023 ; 89 ( 1 ): 187 – 200 . doi: 10.1111/bcp.15457 OpenUrl CrossRef PubMed 21. ↵ Dyer AH , Murphy C , Segurado R , et al. Is Ongoing Anticholinergic Burden Associated With Greater Cognitive Decline and Dementia Severity in Mild to Moderate Alzheimer’s Disease? The journals of gerontology Series A, Biological sciences and medical sciences 2020 ; 75 ( 5 ): 987 – 94 . doi: 10.1093/gerona/glz244 [published Online First: 2019/10/16] OpenUrl CrossRef PubMed 22. ↵ Fox C , Livingston G , Maidment ID , et al. The impact of anticholinergic burden in Alzheimer’s Dementia-the Laser-AD study . Age and Ageing 2011 ; 40 ( 6 ): 730 – 35 . doi: 10.1093/ageing/afr102 %J Age and Ageing OpenUrl CrossRef PubMed Web of Science 23. ↵ Lampela P , Lavikainen P , Garcia-Horsman JA , et al. Anticholinergic Drug Use, Serum Anticholinergic Activity, and Adverse Drug Events Among Older People: A Population-Based Study . Drugs & aging 2013 ; 30 ( 5 ): 321 – 30 . doi: 10.1007/s40266-013-0063-2 OpenUrl CrossRef PubMed Web of Science 24. ↵ Sanders LMJ , Hortobágyi T , van Staveren G , et al. Relationship between drug burden and physical and cognitive functions in a sample of nursing home patients with dementia . Eur J Clin Pharmacol 2017 ; 73 ( 12 ): 1633 – 42 . doi: 10.1007/s00228-017-2319-y [published Online First: 2017/09/19] OpenUrl CrossRef PubMed 25. ↵ Geller EJ , Dumond JB , Bowling JM , et al. Effect of Trospium Chloride on Cognitive Function in Women Aged 50 and Older: A Randomized Trial . Female pelvic medicine & reconstructive surgery 2017 ; 23 ( 2 ): 118 – 23 . doi: 10.1097/spv.0000000000000374 [published Online First: 2017/01/10] OpenUrl CrossRef PubMed 26. ↵ Moga DC , Abner EL , Wu Q , et al. Bladder antimuscarinics and cognitive decline in elderly patients . Alzheimers Dement (N Y) 2017 ; 3 ( 1 ): 139 – 48 . doi: 10.1016/j.trci.2017.01.003 OpenUrl CrossRef PubMed 27. ↵ Barthold D , Marcum ZA , Gray SL , et al. Alzheimer’s disease and related dementias risk: Comparing users of non-selective and M3-selective bladder antimuscarinic drugs . Pharmacoepidemiology and Drug Safety 2020 ; 29 ( 12 ): 1650 – 58 . doi: 10.1002/pds.5098 OpenUrl CrossRef PubMed 28. ↵ Malcher MF , Droupy S , Berr C , et al. Dementia Associated with Anticholinergic Drugs Used for Overactive Bladder: A Nested Case-Control Study Using the French National Medical-Administrative Database . Journal of Urology 2022 ; 208 ( 4 ): 863 – 71 . doi : doi: 10.1097/JU.0000000000002804 OpenUrl CrossRef PubMed 29. ↵ Matta R , Gomes T , Juurlink D , et al. Receipt of Overactive Bladder Drugs and Incident Dementia: A Population-based Case-control Study . Eur Urol Focus 2021 doi: 10.1016/j.euf.2021.10.009 [published Online First: 2021/11/08] OpenUrl CrossRef 30. ↵ Triantafylidis LK , Clemons JS , Peron EP , et al. Brain Over Bladder: A Systematic Review of Dual Cholinesterase Inhibitor and Urinary Anticholinergic Use . Drugs & aging 2018 ; 35 ( 1 ): 27 – 41 . doi: 10.1007/s40266-017-0510-6 OpenUrl CrossRef PubMed 31. ↵ Paquette A , Gou P , Tannenbaum C . Systematic Review and Meta-Analysis: Do Clinical Trials Testing Antimuscarinic Agents for Overactive Bladder Adequately Measure Central Nervous System Adverse Events? J Am Geriatr Soc 2011 ; 59 ( 7 ): 1332 – 39 . doi: 10.1111/j.1532-5415.2011.03473.x OpenUrl CrossRef PubMed 32. ↵ Rangganata E , Widia F , Rahardjo HE . Effect of Antimuscarinic Drugs on Cognitive Functions in the Management of Overactive Bladder in Elderly . Acta medica Indonesiana 2020 ; 52 3 : 255 – 63 . OpenUrl PubMed 33. ↵ McMichael AJ , Zafeiridi E , Ryan M , et al. Anticholinergic drug use and risk of mortality for people with dementia in Northern Ireland . Aging & Mental Health 2020 : 1 – 8 . doi: 10.1080/13607863.2020.1830028 OpenUrl CrossRef PubMed 34. ↵ Kachru N , Holmes HM , Johnson ML , et al. Risk of Mortality Associated with Non-selective Antimuscarinic medications in Older Adults with Dementia: a Retrospective Study . Journal of general internal medicine 2020 ; 35 ( 7 ): 2084 – 93 . doi: 10.1007/s11606-020-05634-3 [published Online First: 2020/02/05] OpenUrl CrossRef PubMed 35. ↵ Bishara D , Perera G , Harwood D , et al. Centrally Acting Anticholinergic Drugs Used for Urinary Conditions Associated with Worse Outcomes in Dementia . Journal of the American Medical Directors Association 2021 ; 22 ( 12 ): 2547 – 52 . doi: 10.1016/j.jamda.2021.08.011 [published Online First: 20210830] OpenUrl CrossRef PubMed 36. ↵ Kachru N , Holmes HM , Johnson ML , et al. Comparative risk of adverse outcomes associated with nonselective and selective antimuscarinic medications in older adults with dementia and overactive bladder . International journal of geriatric psychiatry 2021 ; 36 ( 5 ): 684 – 96 . doi: 10.1002/gps.5467 OpenUrl CrossRef PubMed 37. ↵ Heath L , Gray SL , Boudreau DM , et al. Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study . J Am Geriatr Soc 2018 ; 66 ( 10 ): 1948 – 55 . doi: 10.1111/jgs.15508 [published Online First: 2018/09/18] OpenUrl CrossRef PubMed 38. ↵ Heser K , Luck T , Röhr S , et al. Potentially inappropriate medication: Association between the use of antidepressant drugs and the subsequent risk for dementia . J Affect Disord 2018 ; 226 : 28 – 35 . doi: 10.1016/j.jad.2017.09.016 [published Online First: 2017/09/25] OpenUrl CrossRef PubMed 39. ↵ Bishara D , Perera G , Harwood D , et al. Centrally-acting anticholinergic drugs– associations with mortality, hospitalisation and cognitive decline following dementia diagnosis in people receiving antidepressant and antipsychotic drugs . Aging & Mental Health 2021 : 1 – 9 . doi: 10.1080/13607863.2021.1947967 OpenUrl CrossRef 40. ↵ Mate K , Kerr K , Priestley A , et al. Use of tricyclic antidepressants and other anticholinergic medicines by older Aboriginal Australians: association with negative health outcomes . International Psychogeriatrics 2022 ; 34 ( 1 ): 71 – 78 . doi: 10.1017/S104161022000174X [published Online First: 2020/09/28] OpenUrl CrossRef PubMed 41. ↵ Saczynski JS , Rosen AB , McCammon RJ , et al. Antidepressant Use and Cognitive Decline: The Health and Retirement Study . The American journal of medicine 2015 ; 128 ( 7 ): 739 – 46 . doi: 10.1016/j.amjmed.2015.01.007 [published Online First: 20150130] OpenUrl CrossRef PubMed 42. ↵ Monroe T , Carter M . Using the Folstein Mini Mental State Exam (MMSE) to explore methodological issues in cognitive aging research . Eur J Ageing 2012 ; 9 ( 3 ): 265 – 74 . doi: 10.1007/s10433-012-0234-8 [published Online First: 20120615] OpenUrl CrossRef PubMed 43. ↵ Doraiswamy PM , Krishnan KRR , Oxman T , et al. Does Antidepressant Therapy Improve Cognition in Elderly Depressed Patients? The Journals of Gerontology: Series A 2003 ; 58 ( 12 ): M1137 – M44 . doi: 10.1093/gerona/58.12.M1137 OpenUrl CrossRef PubMed 44. Cai X , Campbell N , Khan B , et al. Long-term anticholinergic use and the aging brain . Alzheimer’s & dementia : the journal of the Alzheimer’s Association 2013 ; 9 ( 4 ): 377 – 85 . doi: 10.1016/j.jalz.2012.02.005 [published Online First: 2012/11/28] OpenUrl CrossRef PubMed Web of Science 45. Chatterjee S , Bali V , Carnahan RM , et al. Anticholinergic Medication Use and Risk of Dementia Among Elderly Nursing Home Residents with Depression . The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2016 ; 24 ( 6 ): 485 – 95 . doi: 10.1016/j.jagp.2015.12.011 [published Online First: 2016/03/16] OpenUrl CrossRef PubMed 46. Gildengers A , Stoehr GP , Ran X , et al. Anticholinergic Drug Burden and Risk of Incident MCI and Dementia: A Population-based Study . Alzheimer Disease & Associated Disorders 2023 ; 37 (1) 47. Gray SL , Anderson ML , Dublin S , et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study . JAMA Intern Med 2015 ; 175 ( 3 ): 401 – 7 . doi: 10.1001/jamainternmed.2014.7663 [published Online First: 2015/01/27] OpenUrl CrossRef PubMed 48. Grossi CM , Richardson K , Fox C , et al. Anticholinergic and benzodiazepine medication use and risk of incident dementia: a UK cohort study . BMC geriatrics 2019 ; 19 ( 1 ): 276 . doi: 10.1186/s12877-019-1280-2 [published Online First: 2019/10/23] OpenUrl CrossRef 49. Hafdi M , Hoevenaar-Blom MP , Beishuizen CRL , et al. Association of Benzodiazepine and Anticholinergic Drug Usage With Incident Dementia: A Prospective Cohort Study of Community-Dwelling Older Adults . Journal of the American Medical Directors Association 2020 ; 21 ( 2 ): 188 – 93 .e3. doi: 10.1016/j.jamda.2019.05.010 [published Online First: 2019/07/14] OpenUrl CrossRef PubMed 50. Hsu WH , Wen YW , Chen LK , et al. Comparative Associations Between Measures of Anti-cholinergic Burden and Adverse Clinical Outcomes . Ann Fam Med 2017 ; 15 ( 6 ): 561 – 69 . doi: 10.1370/afm.2131 [published Online First: 2017/11/15] OpenUrl Abstract / FREE Full Text 51. Hsu W-H , Huang S-T , Lu W-H , et al. Impact of Multiple Prescriptions With Anticholinergic Properties on Adverse Clinical Outcomes in the Elderly: A Longitudinal Cohort Study in Taiwan . Clinical Pharmacology & Therapeutics 2021 ; 110 ( 4 ): 966 – 74 . doi: 10.1002/cpt.2217 OpenUrl CrossRef PubMed 52. Jessen F , Kaduszkiewicz H , Daerr M , et al. Anticholinergic drug use and risk for dementia: target for dementia prevention . Eur Arch Psychiatry Clin Neurosci 2010 ; 260 Suppl 2 : S111 – 5 . doi: 10.1007/s00406-010-0156-4 [published Online First: 2010/10/21] OpenUrl CrossRef PubMed 53. Joung KI , Kim S , Cho YH , et al. Association of Anticholinergic Use with Incidence of Alzheimer’s Disease: Population-based Cohort Study . Sci Rep 2019 ; 9 ( 1 ): 6802 . doi: 10.1038/s41598-019-43066-0 [published Online First: 2019/05/03] OpenUrl CrossRef PubMed 54. Liu YP , Chien WC , Chung CH , et al. Are Anticholinergic Medications Associated With Increased Risk of Dementia and Behavioral and Psychological Symptoms of Dementia? A Nationwide 15-Year Follow-Up Cohort Study in Taiwan . Front Pharmacol 2020 ; 11 : 30 . doi: 10.3389/fphar.2020.00030 [published Online First: 2020/03/03] OpenUrl CrossRef PubMed 55. Lockery JE , Broder JC , Ryan J , et al. A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults . Journal of General Internal Medicine 2021 ; 36 ( 6 ): 1629 – 37 . doi: 10.1007/s11606-020-06550-2 OpenUrl CrossRef PubMed 56. Mur J , Russ TC , Cox SR , et al. Association between anticholinergic burden and dementia in UK Biobank . Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2022 ; 8 ( 1 ): e12290 . doi: 10.1002/trc2.12290 OpenUrl CrossRef 57. Park H-Y , Park J-W , Song HJ , et al. The Association between Polypharmacy and Dementia: A Nested Case-Control Study Based on a 12-Year Longitudinal Cohort Database in South Korea . PloS one 2017 ; 12 ( 1 ): e0169463 . doi: 10.1371/journal.pone.0169463 OpenUrl CrossRef PubMed 58. By the American Geriatrics Society Beers Criteria Update Expert P . American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults . J Am Geriatr Soc 2015 ; 63 ( 11 ): 2227 – 46 . doi: 10.1111/jgs.13702 OpenUrl CrossRef PubMed 59. Richardson K , Fox C , Maidment I , et al. Anticholinergic drugs and risk of dementia: case-control study . BMJ 2018 ; 361 : k1315 . doi: 10.1136/bmj.k1315 OpenUrl Abstract / FREE Full Text 60. Suh Y , Ah YM , Han E , et al. Dose response relationship of cumulative anticholinergic exposure with incident dementia: validation study of Korean anticholinergic burden scale . BMC geriatrics 2020 ; 20 ( 1 ): 265 . doi: 10.1186/s12877-020-01671-z [published Online First: 2020/07/31] OpenUrl CrossRef PubMed 61. Trevisan C , Limongi F , Siviero P , et al. Mild polypharmacy and MCI progression in older adults: the mediation effect of drug–drug interactions . Aging Clinical and Experimental Research 2021 ; 33 ( 1 ): 49 – 56 . doi: 10.1007/s40520-019-01420-2 OpenUrl CrossRef PubMed 62. Wang Y-C , Chen Y-L , Huang C-C , et al. Cumulative use of therapeutic bladder anticholinergics and the risk of dementia in patients with lower urinary tract symptoms: a nationwide 12-year cohort study . BMC geriatrics 2019 ; 19 ( 1 ): 380 . doi: 10.1186/s12877-019-1401-y OpenUrl CrossRef PubMed 63. Wilczyński K , Gorczyca M , Gołębiowska J , et al. Anticholinergic Burden of Geriatric Ward Inpatients . Medicina (Kaunas) 2021 ; 57 ( 10 ): 1115 . doi: 10.3390/medicina57101115 OpenUrl CrossRef PubMed 64. Andre L , Gallini A , Montastruc F , et al. Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3-year analysis of the multidomain Alzheimer preventive trial (MAPT) study . Br J Clin Pharmacol 2019 ; 85 ( 1 ): 71 – 99 . doi: 10.1111/bcp.13734 [published Online First: 2018/08/12] OpenUrl CrossRef PubMed 65. Broder JC , Ryan J , Shah RC , et al. Anticholinergic medication burden and cognitive function in participants of the ASPREE study . Pharmacotherapy 2022 ; 42 ( 2 ): 134 – 44 . doi: 10.1002/phar.2652 [published Online First: 2021/12/14] OpenUrl CrossRef PubMed 66. Campbell NL , Perkins AJ , Bradt P , et al. Association of Anticholinergic Burden with Cognitive Impairment and Health Care Utilization Among a Diverse Ambulatory Older Adult Population . Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2016 ; 36 ( 11 ): 1123 – 31 . doi: 10.1002/phar.1843 OpenUrl CrossRef 67. Campbell NL , Lane KA , Gao S , et al. Anticholinergics Influence Transition from Normal Cognition to Mild Cognitive Impairment in Older Adults in Primary Care . Pharmacotherapy 2018 ; 38 ( 5 ): 511 – 19 . doi: 10.1002/phar.2106 [published Online First: 2018/03/31] OpenUrl CrossRef PubMed 68. Chatterjee S , Bali V , Carnahan RM , et al. Anticholinergic burden and risk of cognitive impairment in elderly nursing home residents with depression . Research in Social and Administrative Pharmacy 2020 ; 16 ( 3 ): 329 – 35 . doi: 10.1016/j.sapharm.2019.05.020 OpenUrl CrossRef PubMed 69. Dauphinot V , Mouchoux C , Veillard S , et al. Anticholinergic drugs and functional, cognitive impairment and behavioral disturbances in patients from a memory clinic with subjective cognitive decline or neurocognitive disorders . Alzheimers Res Ther 2017 ; 9 ( 1 ): 58 – 58 . doi: 10.1186/s13195-017-0284-4 OpenUrl CrossRef PubMed 70. Dyer AH , Laird E , Hoey L , et al. Long-term anticholinergic, benzodiazepine and Z-drug use in community-dwelling older adults: What is the impact on cognitive and neuropsychological performance? International journal of geriatric psychiatry 2021 ; 36 ( 11 ): 1767 – 77 . doi: 10.1002/gps.5598 OpenUrl CrossRef PubMed 71. Gnjidic D , Le Couteur DG , Naganathan V , et al. Effects of Drug Burden Index on Cognitive Function in Older Men . Journal of Clinical Psychopharmacology 2012 ; 32 (2) 72. Grande G , Tramacere I , Vetrano DL , et al. Role of anticholinergic burden in primary care patients with first cognitive complaints . Eur J Neurol 2017 ; 24 ( 7 ): 950 – 55 . doi: 10.1111/ene.13313 [published Online First: 2017/05/16] OpenUrl CrossRef PubMed 73. Jamsen KM , Gnjidic D , Hilmer SN , et al. Drug Burden Index and change in cognition over time in community-dwelling older men: the CHAMP study . Annals of Medicine 2017 ; 49 ( 2 ): 157 – 64 . doi: 10.1080/07853890.2016.1252053 OpenUrl CrossRef PubMed 74. Koyama A , Steinman M , Ensrud K , et al. Long-term cognitive and functional effects of potentially inappropriate medications in older women . The journals of gerontology Series A, Biological sciences and medical sciences 2014 ; 69 ( 4 ): 423 – 9 . doi: 10.1093/gerona/glt192 [published Online First: 2013/12/03] OpenUrl CrossRef PubMed Web of Science 75. Kusljic S , Woolley A , Lowe M , et al. How do cognitive and functional impairment relate to the use of anticholinergic medications in hospitalised patients aged 65 years and over? Aging Clinical and Experimental Research 2020 ; 32 ( 3 ): 423 – 31 . doi: 10.1007/s40520-019-01225-3 OpenUrl CrossRef PubMed 76. López-Matons N , Conill Badell D , Obrero Cusidó G , et al. Anticholinergic drugs and cognitive impairment in the elderly . Med Clin (Barc) 2018 ; 151 ( 4 ): 141 – 44 . doi: 10.1016/j.medcli.2018.01.014 [published Online First: 2018/03/12] OpenUrl CrossRef PubMed 77. Papenberg G , Bäckman L , Fratiglioni L , et al. Anticholinergic drug use is associated with episodic memory decline in older adults without dementia . Neurobiology of Aging 2017 ; 55 : 27 – 32 . doi: 10.1016/j.neurobiolaging.2017.03.009 OpenUrl CrossRef PubMed 78. Skoldunger A , Fastbom J , Wimo A , et al. Impact of Inappropriate Drug Use on Hospitalizations, Mortality, and Costs in Older Persons and Persons with Dementia: Findings from the SNAC Study . Drugs & aging 2015 ; 32 ( 8 ): 671 – 8 . doi: 10.1007/s40266-015-0287-4 [published Online First: 2015/08/02] OpenUrl CrossRef PubMed 79. Pasina L , Lucca U , Tettamanti M. Relation between anticholinergic burden and cognitive impairment: Results from the Monzino 80-plus population-based study . 2020 ; 29 ( 12 ): 1696 – 702 . doi: 10.1002/pds.5159 OpenUrl CrossRef 80. Pfistermeister B , Tümena T , Gaßmann K-G , et al. Anticholinergic burden and cognitive function in a large German cohort of hospitalized geriatric patients . PloS one 2017 ; 12 ( 2 ): e0171353 . doi: 10.1371/journal.pone.0171353 OpenUrl CrossRef PubMed 81. Risacher SL , McDonald BC , Tallman EF , et al. Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults . JAMA Neurology 2016 ; 73 ( 6 ): 721 – 32 . doi: 10.1001/jamaneurol.2016.0580 OpenUrl CrossRef 82. Shah RC , Janos AL , Kline JE , et al. Cognitive Decline in Older Persons Initiating Anticholinergic Medications . PloS one 2013 ; 8 ( 5 ): e64111 . doi: 10.1371/journal.pone.0064111 OpenUrl CrossRef PubMed 83. Swami S , Cohen RA , Kairalla JA , et al. Anticholinergic Drug Use and Risk to Cognitive Performance in Older Adults with Questionable Cognitive Impairment: A Cross-Sectional Analysis . Drugs & aging 2016 ; 33 ( 11 ): 809 – 18 . doi: 10.1007/s40266-016-0400-3 OpenUrl CrossRef PubMed 84. Tsoutsoulas C , Mulsant BH , Kumar S , et al. Anticholinergic Burden and Cognition in Older Patients With Schizophrenia . The Journal of clinical psychiatry 2017 ; 78 ( 9 ): e1284 – e90 . doi: 10.4088/JCP.17m11523 [published Online First: 2017/12/01] OpenUrl CrossRef PubMed 85. Weigand AJ , Bondi MW , Thomas KR , et al. Association of anticholinergic medications and AD biomarkers with incidence of MCI among cognitively normal older adults . Neurology 2020 ; 95 ( 16 ): e2295 – e304 . doi: 10.1212/wnl.0000000000010643 [published Online First: 2020/09/04] OpenUrl Abstract / FREE Full Text 86. Wu YH , Wang CJ , Hung CH , et al. Association between using medications with anticholinergic properties and short-term cognitive decline among older men: A retrospective cohort study in Taiwan . Geriatr Gerontol Int 2017 ; 17 Suppl 1 : 57 – 64 . doi: 10.1111/ggi.13032 [published Online First: 2017/04/25] OpenUrl CrossRef PubMed 87. Yarnall AJ , Lawson RA , Duncan GW , et al. Anticholinergic Load: Is there a Cognitive Cost in Early Parkinson’s Disease? Journal of Parkinson’s Disease 2015 ; 5 : 743 – 47 . doi: 10.3233/JPD-150664 OpenUrl CrossRef 88. Esin E , Ergen A , Cankurtaran M , et al. Influence of antimuscarinic therapy on cognitive functions and quality of life in geriatric patients treated for overactive bladder . Aging & Mental Health 2015 ; 19 ( 3 ): 217 – 23 . doi: 10.1080/13607863.2014.922528 OpenUrl CrossRef PubMed 89. Geller EJ , Crane AK , Wells EC , et al. Effect of anticholinergic use for the treatment of overactive bladder on cognitive function in postmenopausal women . Clin Drug Investig 2012 ; 32 ( 10 ): 697 – 705 . doi: 10.2165/11635010-000000000-00000 OpenUrl CrossRef PubMed 90. Hampel C , Betz D , Burger M , et al. Solifenacin in the Elderly: Results of an Observational Study Measuring Efficacy, Tolerability and Cognitive Effects . Urol Int 2017 ; 98 ( 3 ): 350 – 57 . doi: 10.1159/000455257 [published Online First: 20170202] OpenUrl CrossRef PubMed 91. Iyer S , Lozo S , Botros C , et al. Cognitive changes in women starting anticholinergic medications for overactive bladder: a prospective study . International Urogynecology Journal 2020 ; 31 ( 12 ): 2653 – 60 . doi: 10.1007/s00192-019-04140-3 OpenUrl CrossRef PubMed 92. Wagg A , Khullar V , Marschall-Kehrel D , et al. Flexible-Dose Fesoterodine in Elderly Adults with Overactive Bladder: Results of the Randomized, Double-Blind, Placebo-Controlled Study of Fesoterodine in an Aging Population Trial . J Am Geriatr Soc 2013 ; 61 ( 2 ): 185 – 93 . doi: 10.1111/jgs.12088 OpenUrl CrossRef 93. Welk B , McArthur E . Increased risk of dementia among patients with overactive bladder treated with an anticholinergic medication compared to a beta-3 agonist: a population-based cohort study . BJU Int 2020 ; 126 ( 1 ): 183 – 90 . doi: 10.1111/bju.15040 [published Online First: 2020/03/14] OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted March 19, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Anticholinergic drugs and clinical outcomes in older people with and without dementia- A systematic Review Delia Bishara , Katrina Davis , Christoph Mueller , Olubanke Dzahini , Nicola Funnell , Justin Sauer , Daniel Harwood , David Taylor , Robert Stewart medRxiv 2025.03.14.25323976; doi: https://doi.org/10.1101/2025.03.14.25323976 Share This Article: Copy Citation Tools Anticholinergic drugs and clinical outcomes in older people with and without dementia- A systematic Review Delia Bishara , Katrina Davis , Christoph Mueller , Olubanke Dzahini , Nicola Funnell , Justin Sauer , Daniel Harwood , David Taylor , Robert Stewart medRxiv 2025.03.14.25323976; doi: https://doi.org/10.1101/2025.03.14.25323976 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Pharmacology and Therapeutics Subject Areas All Articles Addiction Medicine (566) Allergy and Immunology (863) Anesthesia (295) Cardiovascular Medicine (4408) Dentistry and Oral Medicine (443) Dermatology (379) Emergency Medicine (606) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1505) Epidemiology (15201) Forensic Medicine (30) Gastroenterology (1119) Genetic and Genomic Medicine (6568) Geriatric Medicine (666) Health Economics (994) Health Informatics (4508) Health Policy (1365) Health Systems and Quality Improvement (1606) Hematology (537) HIV/AIDS (1262) Infectious Diseases (except HIV/AIDS) (15901) Intensive Care and Critical Care Medicine (1103) Medical Education (619) Medical Ethics (144) Nephrology (665) Neurology (6571) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1139) Occupational and Environmental Health (954) Oncology (3319) Ophthalmology (967) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (662) Pediatrics (1686) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5419) Public and Global Health (9200) Radiology and Imaging (2190) Rehabilitation Medicine and Physical Therapy (1367) Respiratory Medicine (1191) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (288) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fe660bd9b820db4',t:'MTc3OTIyODA2Mg=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();