CoChat
Sign Up
Cited by 520Pharmaceutical Practices and Patient OutcomesDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index; 22 of the 46 sources its claims cite were checked for support.

Anticholinergic drugs and risk of dementia: case-control study

Open access
Richardson, Kathryn, Fox, Chris, Maidment, Ian, Steel, Nicholas, Loke, Yoon K, Arthur, Antony, Myint, Phyo K, Grossi, Carlota M, Mattishent, Katharina, Bennett, Kathleen, Campbell, Noll L, Boustani, Malaz, Robinson, Louise, Brayne, Carol, Matthews, Fiona E, Savva, George M·2018·BMJ
DOI 10.1136/bmj.k1315PMC PMC5915701
Open this paper in CoChat — free accountOpen PDF

Abstract

Objectives: To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia. Design: Case-control study. Setting: General practices in the UK contributing to the Clinical Practice Research Datalink. Participants: 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia. Interventions: Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia. Main outcome measures: Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates. Results: 14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis. Conclusions: A robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure. Trial registration: Registered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a UK Clinical Practice Research Datalink nested case-control study, certain anticholinergic drug classes with definite anticholinergic activity were associated with incident dementia, with associations persisting up to 20 years after exposure. The strongest signals were for antidepressant, urological, and antiparkinson drugs with an Anticholinergic Cognitive Burden (ACB) score of 3, while gastrointestinal and cardiovascular anticholinergics were not positively associated.

Key findings

  • Among 40,770 dementia cases and 283,933 controls, 14,453 (35%) cases and 86,403 (30%) controls were prescribed at least one ACB score 3 drug; the adjusted odds ratio for any ACB score 3 drug was 1.11 (95% CI 1.08 to 1.14).
  • Dose-response was seen for ACB score 3 drugs: adjusted OR 1.31 (1.22 to 1.41) for >1460 DDDs versus none, and average ACB score >5.0 had adjusted OR 1.28 (1.19 to 1.36). ACB score 1 drugs showed no dose-response.
  • By class, ACB score 3 antidepressants (OR 1.11, 1.08 to 1.14), urologicals (OR 1.18, 1.13 to 1.23), and antiparkinsons (OR 1.29, 1.11 to 1.50) were associated with dementia; gastrointestinal ACB score 3 drugs were not positively associated (OR 0.94, 0.89 to 0.99).
  • Associations persisted 15-20 years before diagnosis for any ACB score 3 drug (OR 1.17, 1.10 to 1.24), antidepressants with ACB score 3 (OR 1.19, 1.10 to 1.29), and urologicals with ACB score 3 (OR 1.27, 1.09 to 1.48).

Methods

  • Nested case-control study using UK general practices in the Clinical Practice Research Datalink; cases were patients aged 65-99 with a dementia diagnosis between April 2006 and July 2015, matched to up to seven controls on sex, year of birth within three years, years of up-to-standard data history, and practice-level deprivation.
  • Anticholinergic exposure was measured as defined daily doses during a drug exposure period ending four years before the index date, classified by the ACB scale and grouped by drug class; exposure categories were 0, 1-13, 14-89, 90-364, 365-1459, and >1460 DDDs.
  • Conditional logistic regression estimated adjusted odds ratios for incident dementia, with covariates measured at the start and end of the exposure period; prespecified secondary analyses examined drug class, time before diagnosis, average ACB score, and sensitivity analyses including a new-user design and the Anticholinergic Drug Scale.

Limitations

  • Stated: dementia is underdiagnosed (up to 50%), so some controls may have undiagnosed dementia or early cognitive impairment, which would bias estimates toward the null; surveillance bias is possible but would be expected across drug classes; anticholinergic activity is difficult to assess and scales differ; adherence is unknown, over-the-counter drugs are not recorded, and DDDs have limitations; residual or unmeasured confounding cannot be excluded; primary care records lack detailed lifestyle and demographic information; estimates generalise to those surviving at least four years after initial anticholinergic exposure.
  • Evident from the design/text: observational case-control data cannot establish causality, and the authors note that class-specific associations could reflect underlying indications, prodromal symptoms, or differences in blood-brain barrier penetration rather than a direct anticholinergic effect.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmj.k1315

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

22 of 46 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    CPRD data are broadly representative of the UK population in terms of sex, age, and ethnicity.

    “CPRD data are broadly representative of the UK population in terms of sex, age, and ethnicity.22”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Premisecitation

    Dementia is known to be under diagnosed, with up to 50% of people with dementia undiagnosed at any time.

    “However, dementia is known to be under diagnosed, with up to 50% of people with dementia undiagnosed at any time.34”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] source

      The Discussion (page unavailable) says clinically diagnosed dementia rates are lower than rates found through case finding because some people with early dementia may not have been diagnosed. It does not give an estimate that up to 50% of people with dementia are undiagnosed at any time. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Our findings are consistent with these studies, particularly a US cohort study of 3434 participants monitored over an average of seven years.

    “Our findings are consistent with these studies, particularly a US cohort study of 3434 participants monitored over an average of seven years.12”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Premisecitation

    Studies with longer follow-up periods have often failed to detect an association, or have reported weaker associations, between midlife depression and dementia in later life.

    “However, studies with longer follow-up periods have often failed to detect an association, or have reported weaker associations, between midlife depression and dementia in later life.1 20”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] source

      The Abstract mentions depression as a potentially modifiable dementia risk factor, but does not address whether longer follow-up weakens or eliminates an association between midlife depression and later dementia. Searches for midlife depression, follow-up periods, and the depression–dementia association found no passage in our copy that settles the claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [20] source
  • Premisecitation

    Serum anticholinergic activity measured by a receptor bioassay does not correlate well with effects on cognition.

    “Serum anticholinergic activity measured by a receptor bioassay does not correlate well with effects on cognition,16 28”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [16] source
    • cites [28] source
  • Probably not a substantial claim. 20
  • It may state two separate claims as one. 39
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Middle aged and older populations are increasingly taking multiple drugs, but the potential adverse events of long term use are not well understood.

    “Middle aged and older populations are increasingly taking multiple drugs,6 7 but the potential adverse events of long term use are not well understood.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] source

      The supplied Results and Discussion passages concern health conditions and functional deficits among people entering care homes, not medication use. Searches for increasing use of multiple drugs and polypharmacy returned the same unrelated passages, so our copy does not verify the claim attributed to this source. The statement about adverse events follows the citations and is not the part judged here. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [7] Prescribing and Medicines Team. NHS Digital. Prescriptions Dispensed in the Community, Statistics for England - 2005-2016. NHS Digital 2017. http://digital.nhs.uk/catalogue/PUB20664

  • It may state two separate claims as one.

    Premisecitation

    Lower urinary tract symptoms themselves have been linked to future dementia incidence and may be a symptom of early neurodegeneration.

    “Lower urinary tract symptoms themselves have been linked to future dementia incidence and may be a symptom of early neurodegeneration.42 43”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [42] source
    • cites [43] source

  • It may state two separate claims as one.

    Premisecitation

    Many studies have linked anticholinergic drug use with concurrent or short term cognitive effects, but few have examined associations of long term anticholinergic exposure; the latter tend to report positive associations.

    “Many studies have linked anticholinergic drug use with concurrent or short term cognitive effects, but few have examined associations of long term anticholinergic exposure;8 the latter tend to report positive associations.12 14 15”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Tannenbaum, 2012, A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs, Drugs Aging source
    • cites [12] source
    • cites 14 15

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    A typical patient aged 65-70 might normally expect a period incidence of dementia of around 10% over the next 15 years, so the odds ratio for antidepressants with ACB score 3 at 15-20 years (1.19) would be consistent with an absolute risk increase of 2% (1% to 3%) over that period, corresponding to a number needed to harm of 50 (33 to 100).

    “A typical patient aged 65-70 might normally expect a period incidence of dementia of around 10% over the next 15 years,36 so this odds ratio would be consistent with an absolute risk increase of 2% (1% to 3%) over that period, corresponding to a number needed to harm of 50 (33 to 100).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • It may state two separate claims as one.

    Premisecitation

    A cross sectional analysis of ADNI and IMAS data linked anticholinergic drug use to reduced glucose metabolism and increased brain atrophy, and to future mild cognitive impairment or Alzheimer's disease incidence among cognitively normal participants (hazard ratio 2.47, P=0.01).

    “Most recently, a cross sectional analysis of Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Indiana Memory and Ageing Study (IMAS) data linked anticholinergic drug use to reduced glucose metabolism and increased brain atrophy, and to future mild cognitive impairment or Alzheimer’s disease incidence among cognitively normal participants (hazard ratio 2.47, P=0.01).39”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Late life depression is thought to be an early symptom of dementia, whereas studies of whether midlife depression is a risk factor for later life dementia have had mixed findings.

    “In particular, late life depression is thought to be an early symptom of dementia,18 19 whereas studies of whether midlife depression is a risk factor for later life dementia have had mixed findings.20 21”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [18] source

      The Discussion says depressive symptoms in older adults may be a reaction to early cognitive decline or a sign of an underlying neurodegenerative process, supporting the late-life part of the sentence as a possibility. The paper studies older adults and does not report mixed findings about midlife depression as a risk factor for later-life dementia (searched: midlife; mixed findings). (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] source
    • cites [20] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Anticholinergic antidepressants were linked to dementia incidence, consistent with our results, however, the authors did not test specific classes of the remaining anticholinergics.

    “Anticholinergic antidepressants were linked to dementia incidence, consistent with our results, however, the authors did not test specific classes of the remaining anticholinergics.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Most patients (89% of cases and 87% of controls) received at least one prescription for a drug with an ACB score of 1 during the DEP, with cardiovascular drugs accounting for 63% of these prescriptions.

    “Most patients (89% of cases and 87% of controls) received at least one prescription for a drug with an ACB score of 1 during the DEP, with cardiovascular drugs accounting for 63% of these prescriptions.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1.
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    When analysed by drug class, the findings were very similar with antidepressant, antiparkinson, and urological drugs with an ADS score of 3 and antidepressants with an ADS score of 1 consistently associated with greater dementia incidence, but no association with other ADS classes.

    “However, when analysed by the drug class, the findings were very similar with the antidepressant, antiparkinson, and urological drugs with an ADS score of 3 and antidepressants with an ADS score of 1 consistently associated with greater dementia incidence (data not shown), but no association with other ADS classes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    A small association between antihistamine use and dementia was observed that did not meet our threshold for statistical significance.

    “A small association between antihistamine use and dementia was observed that did not meet our threshold for statistical significance.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    There was a dose-response effect linking average anticholinergic load, measured by the average ACB score over the DEP, with dementia incidence, although this is only evident for those with an average score of 3 or more.

    “There was a dose-response effect linking average anticholinergic load, measured by the average ACB score over the DEP, with dementia incidence, although this is only evident for those with an average score of 3 or more (table 2).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1.
    • The authors state this as an assumption: Tricyclic antidepressants have an ACB score of 3.
    • The authors state this as an assumption: Creams, eye drops, and ear drops have an ACB score of 0.
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • The quote only partly states this claim.

    Findingown data

    There is some evidence for an association between dementia incidence and prescription of antiparkinson drugs with an ACB score of 2.

    “but there is some evidence for an association between dementia incidence and prescription of antiparkinson drugs.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    The associations are attenuated from the crude rates when adjusting for drug use at the start of the DEP, and are further reduced only slightly when adjusting for covariates at the end of the DEP.

    “The associations are attenuated from the crude rates when adjusting for drug use at the start of the DEP, and are further reduced only slightly when adjusting for covariates at the end of the DEP.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1.
    • The authors state this as an assumption: Tricyclic antidepressants have an ACB score of 3.
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    There were positive associations for antidepressant drugs with an ACB score of 1 with an increased risk of dementia, but not with any other drugs with an ACB score of 1.

    “We found positive associations for antidepressant drugs with an ACB score of 1 with an increased risk of dementia, but not with any other drugs with an ACB score of 1.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1.
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    In the new-user restricted analysis, antidepressants and urologicals with an ACB score of 3 and antidepressants with an ACB score of 1 remained noticeably associated with dementia.

    “In particular, antidepressants and urologicals with an ACB score of 3 and antidepressants with an ACB score of 1 remained noticeably associated with dementia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    There were relatively high proportions of missing data for the body mass index, smoking, and alcohol variables.

    “There were relatively high proportions of missing data for the body mass index, smoking, and alcohol variables.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Only 1429 (3.5%) cases and 7909 (2.8%) controls were prescribed drugs with an ACB score of 2, with carbamazepine accounting for 87% of these prescriptions.

    “Only 1429 (3.5%) cases and 7909 (2.8%) controls were prescribed drugs with an ACB score of 2, with carbamazepine accounting for 87% of these prescriptions.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    Prescriptions for drugs with an ACB score of 2 were relatively rare, and so results are imprecise in this group.

    “Prescriptions for drugs with an ACB score of 2 were relatively rare, and so results are imprecise in this group”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    We find a slight negative association between gastrointestinal drugs with an ACB score of 1 and 3 and dementia with an apparent dose-response effect.

    “We find a slight negative association between gastrointenstinal drugs with an ACB score of 1 and 3 and dementia with an apparent dose-response effect, although there is no mechanistic explanation for this.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Associations between dementia incidence and number of DDDs by drug class are consistent with the findings in table 3, except that a tentative effect of antihistamines with an ACB score of 3 is seen for patients with more than 365 DDDs prescribed during the DEP.

    “These associations are consistent with the findings in table 3, except that a tentative effect of antihistamines with an ACB score of 3 is seen for patients with more than 365 DDDs prescribed during the DEP.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Tricyclic antidepressants have an ACB score of 3.
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    In each case (antidepressants, antiparkinsons, and urologicals with an ACB score of 3) a dose-response effect is seen with a smaller, but noticeable, positive association between dementia and recorded use of less than 90 DDDs.

    “In each case (antidepressants, antiparkinsons, and urologicals with an ACB score of 3) a dose-response effect is seen with a smaller, but noticeable, positive association between dementia and recorded use of less than 90 DDDs (see supplementary materials, table 2).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Antidepressant, urological, and antiparkinson drugs with definite anticholinergic activity are linked to future dementia incidence, with associations persisting up to 20 years after exposure.

    “Antidepressant, urological, and antiparkinson drugs with definite anticholinergic activity are linked to future dementia incidence, with associations persisting up to 20 years after exposure”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Use of gastrointestinal drugs with an ACB score of 1 or 3, and cardiovascular drugs with an ACB score of 1 was associated with a minor reduction in the risk of dementia.

    “Use of gastrointestinal drugs with an ACB score of 1 or 3, and cardiovascular drugs with an ACB score of 1 was associated with a minor reduction in the risk of dementia.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1.
    • The authors state this as an assumption: Tricyclic antidepressants have an ACB score of 3.
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • It may state two separate claims as one.

    Findingown data

    Diagnoses of conditions related to dementia and indications for anticholinergics increased during the DEP.

    “Table 1 shows that diagnoses of conditions related to dementia and indications for anticholinergics increased during the DEP.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

  • Probably not a substantial claim.

    Study design and conductnone given

    Although we carefully adjusted for depression diagnosis, severity, symptoms, and duration, residual confounding cannot be excluded.

    “Although we carefully adjusted for depression diagnosis, severity, symptoms, and duration (see supplementary materials, appendix 4), residual confounding cannot be excluded.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Evidence from anticholinergic cessation trials have not shown improvements in cognitive function, but these have been underpowered and focused on short term outcomes.

    “Evidence from anticholinergic cessation trials have not shown improvements in cognitive function, but these have been underpowered and focused on short term outcomes.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] source

  • It may state two separate claims as one.

    Study design and conductnone given

    Our study uses a longer patient history in a larger sample of patients.

    “Our study uses a longer patient history in a larger sample of patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductcitation

    The dementia code list used in this study was derived by comparing a previous published list with the Department of Health's Quality and Outcomes Framework list; the two lists overlapped almost completely, and the combined list was reviewed by the clinical team.

    “Dementia codes were derived by comparing a previous published list with the Department of Health’s Quality and Outcomes Framework list of business codes for dementia.23 24 These two code lists overlapped almost completely. The combined list was reviewed by our clinical team, and all codes were included in our final definition—except those that related explicitly to alcohol related dementia”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] source
    • cites [24] Health and Social Care Information Centre. NHS Outcomes Framework. 2013. http://www.hscic.gov.uk/catalogue/PUB13054 (accessed 24 Jun 2014).

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    Although set in the UK, our findings are likely generalisable to other developed countries.

    “Although set in the UK, our findings are likely generalisable to other developed countries.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    P<0.01 was prespecified as the threshold for statistical significance owing to the large number of subgroups examined.

    “P<0.01 was prespecified as a threshold for statistical significance owing to the large number of subgroups being examined.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The anticholinergic effects of drugs are usually classified using scales developed by expert consensus aided by a literature review.

    “the anticholinergic effects of drugs are usually classified using scales developed by expert consensus aided by a literature review.29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductreasoning

    In the primary analysis, confounders were measured up to the end of the DEP to best capture the indications of the drugs, and also coded up to the start of the DEP because some variables could be consequences of drug exposure.

    “Our primary analysis measured confounders recorded up to the end of the DEP to best capture the indications of the drugs. We also coded the status of each patient with respect to each covariate up to the start of the DEP, as some variables could be consequences of drug exposure.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    It is difficult to accurately assess the anticholinergic activity of each drug, and anticholinergic scales differ with respect to how they classify drugs.

    “It is difficult to accurately assess the anticholinergic activity of each drug, and anticholinergic scales differ with respect to how they classify drugs.29”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisereasoning

    Previous studies have been limited in their ability to determine if the increased risk is specific to the anticholinergic action itself, and whether or not the association is owing to the drugs or the underlying conditions for which they were prescribed.

    “However, these studies have been limited in their ability to determine if the increased risk is specific to the anticholinergic action itself, and whether or not the association is owing to the drugs or the underlying conditions for which they were prescribed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Sample size was determined by the maximum available data within CPRD.

    “Sample size was determined by the maximum available data within CPRD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Use of anticholinergic drugs among people with dementia is recognised as inappropriate by both the Beers and the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria.

    “Use of anticholinergic drugs among people with dementia is recognised as inappropriate by both the Beers and the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria.10 11”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] source
    • cites [11] source

  • It may state two separate claims as one.

    Interpretationown data

    The association between other antidepressants with an ACB score of 1 and dementia was greater for prescriptions close to dementia incidence, suggesting that reverse causation could be a possible explanation for this observed association.

    “Other antidepressants (predominantly selective serotonin reuptake inhibitors) with an ACB score of 1 were associated with dementia, but that association was greater for prescriptions close to dementia incidence, suggesting that reverse causation could be a possible explanation for this observed association.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    This misclassification would shrink estimated effects towards the null (odds ratio of 1) but would not remove them completely.

    “This misclassification would shrink estimated effects towards the null (odds ratio of 1) but would not remove them completely.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Mechanistic evidence for a link between anticholinergic drugs and dementia incidence is limited, but neuropathological studies in humans and mice do support a role of anticholinergics affecting neurodegenerative pathology.

    “Mechanistic evidence for a link between anticholinergic drugs and dementia incidence is limited, but neuropathological studies in humans and mice do support a role of anticholinergics affecting neurodegenerative pathology.37 38”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] source
    • cites [38] source

  • Probably not a substantial claim. It may state two separate claims as one.

    Interpretationreasoning

    This enables a much more granular disaggregation of the effects of specific drug classes in different periods before diagnosis, and in the depth of confounding control possible using complete primary care records, which enables exploration of alternative explanations for observed associations.

    “This enables a much more granular disaggregation of the effects of specific drug classes in different periods before diagnosis, and in the depth of confounding control possible using complete primary care records, which enables exploration of alternative explanations for observed associations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    Together these aspects substantially narrow the target of potential harm.

    “Together these aspects substantially narrow the target of potential harm.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    These relations were seen even for exposures 15-20 years before the diagnosis of dementia, suggesting that reverse causation or confounding with early dementia symptoms are less likely explanations for the effect.

    “These relations were seen even for exposures 15-20 years before the diagnosis of dementia, suggesting that reverse causation or confounding with early dementia symptoms are less likely explanations for the effect.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    Excluding patients who were prevalent users at the start of each DEP resulted in little difference in results, ensuring potential confounders preceded drug initiation.

    “Secondly, to be certain that potential confounders preceded drug initiation and not vice versa, we further excluded patients who were prevalent users at the start of each DEP, again with little difference in results.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    It is well known that anticholinergics affect cognition, and guidelines suggest they are to be avoided among frail older people.

    “It is well known that anticholinergics affect cognition,8 and guidelines suggest they are to be avoided among frail older people.9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Tannenbaum, 2012, A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs, Drugs Aging source
    • cites [9] National Institute for Health and Care Excellence. Urinary incontinence in women: management. NICE guideline CG171. 2015.https://www.nice.org.uk/guidance/cg171?unlid= (accessed 10 Feb 2017).

  • It may state two separate claims as one.

    Interpretationreasoning

    The associations reported here are moderate (odds ratios for different exposures between 1.1 and 1.3), but given the high incidence of dementia they reflect an appreciable risk to patients.

    “The associations reported here are moderate (odds ratios for different exposures between 1.1 and 1.3), but given the high incidence of dementia they reflect an appreciable risk to patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductreasoning

    Seven controls per case were used to maximise power to detect associations with potentially rare exposures or covariates and to adhere to the data provider's maximum sample size limits.

    “Seven controls were used to maximise the power to detect associations with potentially rare exposures or covariates, and to adhere to the limits of the data provider regarding the maximum sample size for a single study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationnone given

    Patients with fewer than 365 DDDs of antihistamines may also have a substantial over-the-counter use that is not recorded.

    “Although very few patients (around 0.3% of the sample) are prescribed more than 365 DDDs of antihistamines in our study, those with fewer prescriptions may also have a substantial over-the-counter use that is not recorded.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Drugs obtained over-the-counter are not recorded in our data, hence we will have likely underestimated the use of certain antihistamines.

    “Drugs obtained over-the-counter are not recorded in our data, hence we will have likely underestimated the use of certain antihistamines.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    Our study used a large, population representative, primary care database that allowed a detailed analysis of the association between dementia incidence and prescriptions of different drugs classes up to 20 years before a diagnosis of dementia.

    “Our study used a large, population representative, primary care database that allowed a detailed analysis of the association between dementia incidence and prescriptions of different drugs classes up to 20 years before a diagnosis of dementia.”
    Quote in the paperSubstantial claim
49 of 49

  • The authors state this as an assumption.

    Thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1.

    “thiazide diuretics, loop diuretics, and antihistamines have an ACB score of 1”

  • The authors state this as an assumption.

    Tricyclic antidepressants have an ACB score of 3.

    “tricyclic antidepressants have an ACB score of 3”

  • The authors state this as an assumption.

    Creams, eye drops, and ear drops have an ACB score of 0.

    “creams, eye drops, and ear drops have an ACB score of 0”

  • The authors state this as an assumption.

    Diagnosed health conditions or other drugs are absent if there is no mention in the primary care record.

    “diagnosed health conditions or other drugs are assumed absent if there is no mention in the primary care record.”

  • The paper relies on this without support.

    It is not known if the reported associations between the use of anticholinergic drugs and future cognitive decline and dementia incidence can be attributed to anticholinergic activity.

    “It is not known if the reported associations between the use of anticholinergic drugs and future cognitive decline and dementia incidence can be attributed to anticholinergic activity”

  • The paper relies on this without support.

    This is the first study to individually estimate the effect of classes of anticholinergic drugs with respect to dementia incidence.

    “This is the first study to individually estimate the effect of classes of anticholinergic drugs with respect to dementia incidence.”

  • The paper relies on this without support.

    In the UK, most diagnoses of dementia are made by memory services specialists and communicated back to primary care.

    “In the UK, most diagnoses of dementia are made by memory services specialists. The diagnoses are then communicated back to primary care.”

  • The paper relies on this without support.

    Use of drugs with anticholinergic activity is associated with impaired cognition in the short term.

    “Use of drugs with anticholinergic activity is associated with impaired cognition in the short term”

  • The paper relies on this without support.

    Primary care records include detailed records of diagnoses and symptoms that have allowed good confounding control.

    “Primary care records do not hold detailed lifestyle or demographic information, but do include detailed records of diagnoses and symptoms that have allowed good confounding control.”

  • The paper relies on this without support.

    Defined daily doses represent the best available method for comparing the levels of exposure of different drug classes.

    “Defined daily doses (DDDs) can be difficult to establish for certain drugs yet represent the best available method for comparing the levels of exposure of different drug classes.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Richardson et al also found increases in dementia risk for the groups of antidepressant, urological, and antiparkinson drugs considered and no associations for gastrointestinal or antihistamine drugs.

    “Despite these differences, Richardson et al12 also found increases in dementia risk for the groups of antidepressant, urological, and antiparkinson drugs considered and no associations for gastrointestinal or antihistamine drugs.”

    From Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study (2019) · cites this paper as [12]

    The Results (Exposure by drug class) report significant associations with dementia for antidepressant, antiparkinson, and urological drugs with an ACB score of 3, and no overall association for antihistamines in that group. But the blanket claim of no associations for gastrointestinal or antihistamine drugs is too broad: gastrointestinal drugs were associated with a minor reduction in risk, and a tentative antihistamine association appeared at more than 365 prescribed daily doses. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • A study by Richardson et al, using another United Kingdom primary care database (CPRD), reported findings similar to ours, despite some differences in the drugs included, exposure measures used, exposure windows, and the confounding variables accounted for.

    “A study by Richardson et al,12 using another United Kingdom primary care database (CPRD), reported findings similar to ours, despite some differences in the drugs included, exposure measures used, exposure windows, and the confounding variables accounted for.”

    From Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study (2019) · cites this paper as [12]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Anticholinergic drugs block acetylcholine, a neurotransmitter essential for cognitive function.

    “Anticholinergic drugs block acetylcholine, a neurotransmitter essential for cognitive function, and have been associated with an increased risk of dementia in older adults [15, 31, 32].”

    From Long-Term Antidepressant Use and Dementia Risk: A Propensity Score-Matched Study of Swiss Older Adults, with an Anticholinergic-Specific Analysis (2026) · cites this paper as [32]

  • Anticholinergic drugs have been associated with an increased risk of dementia in older adults.

    “Anticholinergic drugs block acetylcholine, a neurotransmitter essential for cognitive function, and have been associated with an increased risk of dementia in older adults [15, 31, 32].”

    From Long-Term Antidepressant Use and Dementia Risk: A Propensity Score-Matched Study of Swiss Older Adults, with an Anticholinergic-Specific Analysis (2026) · cites this paper as [32]

  • Previous longitudinal cohort studies indicate that anticholinergic medications negatively affect cognitive performance.

    “This association between anticholinergic antidepressants and dementia aligns with previous longitudinal cohort studies indicating that anticholinergic medications negatively affect cognitive performance [15, 31, 32, 43, 44].”

    From Long-Term Antidepressant Use and Dementia Risk: A Propensity Score-Matched Study of Swiss Older Adults, with an Anticholinergic-Specific Analysis (2026) · cites this paper as [32]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ACB score 2 association increased, rather than decreased, in the new-user analysis

    Minor

    The text says the new-user restriction produced small reductions for both ACB scores 3 and 2. For ACB score 2, however, the end-of-period adjusted odds ratio rose from 1.10 in the primary analysis to 1.12.

  • Highest average ACB category has conflicting boundaries

    Minor

    The methods say the highest category includes scores of 5 or more, but Table 2 labels it greater than 5.0. Under the table's stated boundaries, an average score of exactly 5.0 falls into neither of its two highest categories.

2 of 2

Citations

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Metadata

Authors
Richardson, K., Fox, C., Maidment, I., Steel, N., Loke, Y. K., Arthur, A., Myint, P. K., Grossi, C. M., Mattishent, K., Bennett, K., Campbell, N. L., Boustani, M., Robinson, L., Brayne, C., Matthews, F. E., & Savva, G. M.
Affiliations
  • University of East Anglia (GB)
  • Aston University (GB)
  • University of Aberdeen (GB)
  • Royal College of Surgeons in Ireland (IE)
  • Purdue University West Lafayette (US)
  • Indiana University Indianapolis (US)
  • Newcastle University (GB)
  • University of Cambridge (GB)
Corresponding author
Richardson, Kathryn
ORCID
Venue
BMJ
Publisher
BMJ
Published
2018-04-25
Volume
361
Pages
k1315
ISSN
  • 1756-1833 (ISSN-L)
  • 0959-8138
DOI
10.1136/bmj.k1315
PMC
PMC5915701
OpenAlex
W2800521692
Cited by
520
References
44
Citations by year
2026: 36 · 2025: 48 · 2024: 56 · 2023: 49 · 2022: 45 · 2021: 71 · 2020: 127 · 2019: 61 · 2018: 25
FWCI
54.35
Type
journal article
Language
en
Update notices
correction (2019-10-31)
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Aston Publications Explorer (Aston University) (acceptedVersion)
  • UEA Digital Repository (University of East Anglia) (acceptedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • Repository@Hull (Worktribe) (University of Hull) (submittedVersion, cc-by)
  • HighWire Press Open Archive (submittedVersion)
  • Apollo
Funders
  • Alzheimer's Society (AS-PG-2013-017)
  • National Institute for Health and Care Research (NF-SI-0616-10090, NF-SI-0611-10084, ACF-2014-15-001)
  • Aston University
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords
anticholinergic agents, dementia, Anticholinergic Cognitive Burden Scale, antidepressants, antiparkinsonian drugs, urological drugs, gastrointestinal drugs, drug exposure duration, older adults, incident dementia risk
MeSH terms
Aged, Aged, 80 and over, Antidepressive Agents, Tricyclic, Dementia, Female, United Kingdom, Health Services Research, Humans, Male, Odds Ratio, Case-Control Studies, Risk Assessment, Cholinergic Antagonists

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review