CoChat
Sign Up
Cited by 638Pharmaceutical Practices and Patient OutcomesDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

The DOI matches its Crossref record; 41 of the 45 references it cites were found in a registry or an index; 16 of the 25 sources its claims cite were checked for support.

Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study

Open access
Coupland, Carol A. C., Hill, Trevor, Dening, Tom, Morriss, Richard, Moore, Michael, Hippisley-Cox, Julia·2019·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2019.0677PMC PMC6593623
Open this paper in CoChat — free accountOpen PDF

Abstract

IMPORTANCE: Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia. OBJECTIVE: To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older. DESIGN, SETTING, AND PARTICIPANTS: This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018. EXPOSURES: The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date). MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables. RESULTS: Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%. CONCLUSIONS AND RELEVANCE: Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a large UK nested case-control study, higher cumulative exposure to strong anticholinergic drugs was associated with increased dementia risk, with the strongest associations for antidepressants, bladder antimuscarinics, antipsychotics, and antiepileptics. The authors conclude these drugs should be prescribed with caution in middle-aged and older adults, while noting the observational design cannot establish causality.

Key findings

  • Among 58,769 dementia cases and 225,574 matched controls, 56.6% of cases vs 51.0% of controls received at least 1 anticholinergic prescription in the 1 to 11 years before the index date; adjusted OR for >1095 total standardized daily doses (TSDDs) vs nonuse was 1.49 (95% CI, 1.44-1.54), and the population-attributable fraction was 10.3%.
  • In the highest exposure category (>1095 TSDDs), adjusted ORs were 1.29 (95% CI, 1.24-1.34) for antidepressants, 1.52 (95% CI, 1.16-2.00) for antiparkinson drugs, 1.70 (95% CI, 1.53-1.90) for antipsychotics, 1.65 (95% CI, 1.56-1.75) for bladder antimuscarinics, and 1.39 (95% CI, 1.22-1.57) for antiepileptic drugs. No significant increases were found for antihistamines, skeletal muscle relaxants, gastrointestinal antispasmodics, antiarrhythmics, or antimuscarinic bronchodilators.
  • Associations were stronger in cases diagnosed before age 80: for total exposure >1095 TSDDs, adjusted OR was 1.81 (95% CI, 1.71-1.91) before age 80 vs 1.35 (95% CI, 1.30-1.40) at age 80 or older. For vascular dementia vs Alzheimer disease in the 1- to 11-year window, adjusted ORs for >1095 TSDDs were 1.68 (95% CI, 1.57-1.79) and 1.37 (95% CI, 1.30-1.44), respectively.
  • The antipsychotic association was not statistically significant in the 5- to 20-year exposure window: adjusted OR for >1095 TSDDs was 1.23 (95% CI, 0.93-1.62), suggesting possible protopathic bias.

Methods

  • Nested case-control study within the QResearch database, including patients aged 55 years and older registered January 1, 2004, to January 31, 2016. The base cohort comprised 3,638,582 individuals; 128,517 were diagnosed with dementia during 20,005,739 person-years of follow-up. After exclusions, 58,769 cases and 225,574 controls were matched 5:1 by age, sex, general practice, and calendar time; primary analyses required at least 11 years of recorded data before the index date.
  • Exposure was based on 56 anticholinergic drugs identified from Beers criteria, the Anticholinergic Cognitive Burden scale, a systematic review, and the British National Formulary. Total standardized daily doses (TSDDs) were calculated over the 1 to 11 years before the index date, excluding prescriptions in the prior year; sensitivity windows were 3 to 13 years and 5 to 20 years. Exposure categories were 0, 1-90, 91-365, 366-1095, and >1095 TSDDs.
  • Conditional logistic regression estimated adjusted odds ratios, accounting for demographic factors, comorbidities, and other medications. Sensitivity analyses included multiple imputation, WHO-defined daily doses, and restriction to drugs included by Gray et al. Statistical significance was set at P < .01 (2-tailed).

Limitations

  • The paper states that some patients may not have taken prescribed medication or the prescribed dose, leading to exposure misclassification; if nondifferential, this would tend to reduce odds ratios and might explain the lack of association for antihistamines and the highest antivertigo exposure category.
  • Dementia identification relied on recorded diagnoses or acetylcholinesterase-inhibitor treatment rather than screening the entire population, so there will be underascertainment of dementia cases and some controls may have had undiagnosed dementia, again likely underestimating associations.
  • The paper notes potential residual confounding and indication bias in an observational study. Protopathic bias was reduced by excluding prescriptions in the year before diagnosis and in 3- and 5-year sensitivity analyses, but the antipsychotic association was not significant when prescriptions in the 5 years before diagnosis were excluded, suggesting possible protopathic bias; some prodromal symptoms can emerge up to 10 years before diagnosis.
  • The paper states the observational study cannot evaluate causality. The text also makes evident that some drug-type analyses had small numbers—skeletal muscle relaxants and antiarrhythmics—giving imprecise estimates.

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

Integrity signals

Registry

Crossref · 10.1001/jamainternmed.2019.0677

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

16 of 25 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Richardson K, Fox C, Maidment I, Anticholinergic drugs and risk of dementia: case-control study. BMJ. 2018; 361: k1315. doi: 10.1136/bmj.k1315 29695481 PMC5915701 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
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.
  • Interpretationcitation

    Our findings are consistent with a US cohort study of 3434 participants (Gray et al) which reported a hazard ratio of 1.54 (95% CI, 1.21-1.96) for the highest exposure category (>1095 TSDDs).

    “Our findings are consistent with other studies, including a US cohort study of 3434 participants,11 which reported a hazard ratio of 1.54 (95% CI, 1.21-1.96) for the highest exposure category (>1095 TSDDs), similar to our AOR of 1.49 (95% CI, 1.44-1.54).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Gray SL, Anderson ML, Dublin S, Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015; 175(3): 401- 407. doi: 10.1001/jamainternmed.2014.7663 25621434 PMC4358759 source
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.
  • Study design and conductcitation

    The analysis adjusted for potential confounding variables identified as risk factors for dementia or indications for anticholinergic drug use, including body mass index, smoking status, alcohol consumption, Townsend deprivation score, ethnic group, comorbidities, and use of other medications.

    “We accounted for potential confounding variables identified as risk factors for dementia or indications for anticholinergic drug use,19,20,21,22,23,24,25 including body mass index, calculated as weight in kilograms divided by height in meters squared,20 smoking status,26 alcohol consumption,27 Townsend deprivation score,21 self-assigned ethnic group,28 comorbidities”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [19] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E Alzheimer’s disease. Lancet. 2011; 377(9770): 1019- 1031. doi: 10.1016/S0140-6736(10)61349-9 21371747 source
    • cites [20] Anstey KJ, Cherbuin N, Budge M, Young J Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev. 2011; 12(5): e426- e437. doi: 10.1111/j.1467-789X.2010.00825.x 21348917 source
    • cites [21] Walters K, Hardoon S, Petersen I, Predicting dementia risk in primary care: development and validation of the Dementia Risk Score using routinely collected data. BMC Med. 2016; 14(1): 6. doi: 10.1186/s12916-016-0549-y 26797096 PMC4722622 source
  • Interpretationreasoning

    If the association is causal, around 20,000 of the 209,600 new cases of dementia per year in the United Kingdom are attributable to anticholinergic drug exposure.

    “which would equate, for example, to around 20 000 of the 209 600 new cases of dementia per year in the United Kingdom.32”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Matthews FE, Stephan BCM, Robinson L,; Cognitive Function and Ageing Studies (CFAS) Collaboration A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. Nat Commun. 2016; 7: 11398. doi: 10.1038/ncomms11398 27092707 PMC4838896 source

      The Results section (‘Population estimates of incidence cases’; page unavailable) estimates 209,600 new dementia cases per year in the UK among people aged 65 and over. The paper does not estimate that 20,000 cases are attributable to anticholinergic drug exposure; that conditional calculation goes beyond what this source reports. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.
  • Findingown data

    Sensitivity analyses using multiply imputed data or restricted to anticholinergic drugs included in the study by Gray et al did not change study findings.

    “Sensitivity analyses using multiply imputed data (eTable 13 in the Supplement) or restricted to anticholinergic drugs included in the study by Gray et al11 (eTable 14 in the Supplement) did not change study findings.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Gray SL, Anderson ML, Dublin S, Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015; 175(3): 401- 407. doi: 10.1001/jamainternmed.2014.7663 25621434 PMC4358759 source
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.
  • Probably not a substantial claim. 20
  • It may state two separate claims as one. 24

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

    Premisecitation

    QResearch is the most nationally representative United Kingdom database, while CPRD is more geographically restricted.

    “While both CPRD and QResearch are large United Kingdom databases, QResearch is the most nationally representative, while CPRD is more geographically restricted.36”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Kontopantelis E, Stevens RJ, Helms PJ, Edwards D, Doran T, Ashcroft DM Spatial distribution of clinical computer systems in primary care in England in 2016 and implications for primary care electronic medical record databases: a cross-sectional population study. BMJ Open. 2018; 8(2): e020738. doi: 10.1136/bmjopen-2017-020738 29490968 PMC5855245 source

  • It may state two separate claims as one.

    Interpretationcitation

    The proportion of dementia attributable to anticholinergic drug exposure is sizeable and comparable with estimates for other modifiable risk factors for dementia, such as 5% for midlife hypertension, 3% for diabetes, 14% for later-life smoking, and 6.5% for physical inactivity.

    “This proportion is sizeable and is comparable with estimates for other modifiable risk factors for dementia, such as 5% for midlife hypertension, 3% for diabetes, 14% for later-life smoking, and 6.5% for physical inactivity.1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Livingston G, Sommerlad A, Orgeta V, Dementia prevention, intervention, and care. Lancet. 2017; 390(10113): 2673- 2734. doi: 10.1016/S0140-6736(17)31363-6 28735855 source

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

      Experimental — accuracy not yet measured
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

  • It may state two separate claims as one.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Richardson K, Fox C, Maidment I, Anticholinergic drugs and risk of dementia: case-control study. BMJ. 2018; 361: k1315. doi: 10.1136/bmj.k1315 29695481 PMC5915701 source

      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

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

    Premisecitation

    A recent larger study found varying risks associated with different types of anticholinergic drugs and concluded that further research should examine individual anticholinergic drug classes.

    “A recent larger study12 found varying risks associated with different types of anticholinergic drugs and concluded that further research should examine individual anticholinergic drug classes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Richardson K, Fox C, Maidment I, Anticholinergic drugs and risk of dementia: case-control study. BMJ. 2018; 361: k1315. doi: 10.1136/bmj.k1315 29695481 PMC5915701 source

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

    Premisecitation

    A cohort study that reduced protopathic bias by excluding prescriptions in the final year of follow-up found that higher cumulative anticholinergic drug use was associated with a significantly increased risk of dementia but had limited power for analysis of separate types of anticholinergic drug.

    “A cohort study11 that reduced protopathic bias by excluding prescriptions in the final year of follow-up found that higher cumulative anticholinergic drug use was associated with a significantly increased risk of dementia but had limited power for analysis of separate types of anticholinergic drug.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Gray SL, Anderson ML, Dublin S, Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015; 175(3): 401- 407. doi: 10.1001/jamainternmed.2014.7663 25621434 PMC4358759 source

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

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Observational studies of anticholinergic drugs and dementia risk have generally been relatively small, only assessed short-term exposure, or were subject to recall bias.

    “Observational studies of anticholinergic drugs and dementia risk7,8,9,10 have generally been relatively small, only assessed short-term exposure, or were subject to recall bias.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [7] Cai X, Campbell N, Khan B, Callahan C, Boustani M Long-term anticholinergic use and the aging brain. Alzheimers Dement. 2013; 9(4): 377- 385. doi: 10.1016/j.jalz.2012.02.005 23183138 PMC3674201 source

      The Introduction and Discussion describe limited long-term evidence and short observation windows, including this study’s one-year design and a prior study’s 3- to 12-month follow-up. The Discussion also identifies a small exposed subgroup. Our copy does not identify recall bias as a limitation of these studies, so it supports only part of the attributed characterization. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [8] Ancelin ML, Artero S, Portet F, Dupuy A-M, Touchon J, Ritchie K Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ. 2006; 332(7539): 455- 459. doi: 10.1136/bmj.38740.439664.DE 16452102 PMC1382539 source
    • cites [9] Carrière I, Fourrier-Reglat A, Dartigues JF, Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study. Arch Intern Med. 2009; 169(14): 1317- 1324. doi: 10.1001/archinternmed.2009.229 19636034 PMC2933398 source

      The Anticholinergic drug use section says medication use was inventoried for the preceding month, and the Limitations section says precise treatment duration was unavailable. That supports the short-term exposure-measurement concern, but this was a large study with four-year follow-up (Study population), not a small study assessing only short-term outcomes. The Limitations section identifies possible recall bias in self-reported covariates, while the Strengths section says medication use was checked against prescriptions and medications. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Study design and conductcitation

    The study used the approach of Gray et al, which included drugs identified as having strong anticholinergic properties by the American Geriatrics Society 2012 Beers Criteria Update Expert Panel.

    “We used the approach of Gray et al,11 which included drugs identified as having strong anticholinergic properties by the American Geriatrics Society 2012 Beers Criteria Update Expert Panel.14”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [11] Gray SL, Anderson ML, Dublin S, Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015; 175(3): 401- 407. doi: 10.1001/jamainternmed.2014.7663 25621434 PMC4358759 source
    • cites [14] American Geriatrics Society 2012 Beers Criteria Update Expert Panel American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012; 60(4): 616- 631. doi: 10.1111/j.1532-5415.2012.03923.x 22376048 PMC3571677 source

  • Probably not a substantial claim.

    Study design and conductcitation

    Each case patient was matched to 5 controls by age within 1 year, sex, general practice, and calendar time using incidence density sampling.

    “Each case patient was matched to 5 controls by age (within 1 year), sex, general practice, and calendar time using incidence density sampling.13”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Vandenbroucke JP, Pearce N Case-control studies: basic concepts. Int J Epidemiol. 2012; 41(5): 1480- 1489. doi: 10.1093/ije/dys147 23045208 source

      The sections on cohorts versus dynamic populations and density sampling (page numbers unavailable) explain selecting controls when each case occurs and matching on calendar time. They do not document this study’s five-controls-per-case ratio or its matching criteria of age within one year, sex, and general practice. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    Total cumulative anticholinergic drug exposure in the 1 to 11 years before the index date is associated with increased dementia risk in a dose-response manner, with adjusted odds ratios from 1.06 (95% CI 1.03-1.09) for 1-90 TSDDs to 1.49 (95% CI 1.44-1.54) for more than 1095 TSDDs compared with nonuse.

    “The AOR associated with total cumulative anticholinergic exposure in the 1 to 11 years before the index date increased from 1.06 (95% CI, 1.03-1.09) for 1 to 90 TSDDs to 1.49 (95% CI, 1.44-1.54) for more than 1095 TSDDs, compared with nonuse (Table 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Clinical codes recorded in QResearch practice records or linked Office of National Statistics death records accurately identify dementia cases.
    • Rests on an assumption: Prescriptions recorded in QResearch accurately reflect actual anticholinergic drug exposure.
    • Rests on an assumption: The measured confounding variables sufficiently control for confounding of the association between anticholinergic drug use and dementia.

  • It may state two separate claims as one.

    Findingown data

    For antipsychotic drug exposure in the 5-20 year window, there were no statistically significant increases in dementia risk; the adjusted odds ratio for more than 1095 TSDDs was 1.23 (95% CI 0.93-1.62).

    “Patterns of risk were similar in the 3- to 13- and 5- to 20-year exposure windows (eTable 6 in the Supplement), except for antipsychotic drug exposure in the 5- to 20-year window, where there were no statistically significant increases in risk; the AOR for more than 1095 TSDDs was 1.23 (95% CI, 0.93-1.62).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical codes recorded in QResearch practice records or linked Office of National Statistics death records accurately identify dementia cases.
    • Rests on an assumption: Prescriptions recorded in QResearch accurately reflect actual anticholinergic drug exposure.
    • Rests on an assumption: The measured confounding variables sufficiently control for confounding of the association between anticholinergic drug use and dementia.

  • It may state two separate claims as one.

    Findingown data

    Antivertigo/antiemetic anticholinergic drug use at 366 to 1095 TSDDs is associated with increased dementia risk, but there is no significant increase at more than 1095 TSDDs.

    “For antivertigo/antiemetic drugs, as detailed in Table 5, there was a significantly increased risk associated with 366 to 1095 TSDDs, but not for the highest exposure category.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical codes recorded in QResearch practice records or linked Office of National Statistics death records accurately identify dementia cases.
    • Rests on an assumption: Prescriptions recorded in QResearch accurately reflect actual anticholinergic drug exposure.
    • Rests on an assumption: The measured confounding variables sufficiently control for confounding of the association between anticholinergic drug use and dementia.

  • It may state two separate claims as one.

    Findingown data

    The increased risks identified for specific drug groups in the main analysis remained in these sensitivity analyses except for the association with antipsychotic drugs.

    “The increased risks identified for specific drug groups in the main analysis remained in these sensitivity analyses except for the association with antipsychotic drugs”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

  • It may state two separate claims as one.

    Findingown data

    There were no significantly increased risks for antihistamines, gastrointestinal antispasmodics, antimuscarinic bronchodilators, antiarrhythmics, or skeletal muscle relaxants, although the numbers of patients prescribed skeletal muscle relaxants and antiarrhythmic drugs were small, giving imprecise estimates.

    “There were no significantly increased risks for antihistamines, gastrointestinal antispasmodics, antimuscarinic bronchodilators, antiarrhythmics, or skeletal muscle relaxants, although the numbers of patients prescribed skeletal muscle relaxants and antiarrhythmic drugs were small, giving imprecise estimates.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

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

    Findingown data

    Associations were similar in men and women.

    “Associations were similar in men and women (eTable 9 in the Supplement).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

  • It may state two separate claims as one.

    Findingown data

    Patterns of dementia risk for specific anticholinergic drug types were similar in the 3-13 and 5-20 year exposure windows, except for antipsychotic drug exposure in the 5-20 year window.

    “Patterns of risk were similar in the 3- to 13- and 5- to 20-year exposure windows (eTable 6 in the Supplement), except for antipsychotic drug exposure in the 5- to 20-year window, where there were no statistically significant increases in risk; the AOR for more than 1095 TSDDs was 1.23 (95% CI, 0.93-1.62).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical codes recorded in QResearch practice records or linked Office of National Statistics death records accurately identify dementia cases.
    • Rests on an assumption: Prescriptions recorded in QResearch accurately reflect actual anticholinergic drug exposure.
    • Rests on an assumption: The measured confounding variables sufficiently control for confounding of the association between anticholinergic drug use and dementia.

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

    Interpretationreasoning

    This misclassification, if nondifferential, would tend to reduce ORs and might explain the lack of association for antihistamines and the highest exposure category of antivertigo drugs.

    “This misclassification, if nondifferential, would tend to reduce ORs and might explain the lack of association for antihistamines and the highest exposure category of antivertigo drugs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

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

    Study design and conductnone given

    Some patients may not have taken their prescribed medication or not taken the dose prescribed, leading to exposure misclassification.

    “A limitation is that some patients may not have taken their prescribed medication or not taken the dose prescribed, leading to exposure misclassification.”
    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.

    Study design and conductown data

    The study used multiple imputation by chained equations to replace missing values for body mass index, smoking status, and alcohol consumption, creating 10 multiply imputed data sets and combining results using Rubin rules.

    “(4) we used multiple imputation by chained equations to replace missing values for body mass index, smoking status, and alcohol consumption. We created 10 multiply imputed data sets and combined results using Rubin rules29; and”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Rubin DB Multiple Imputation for Nonresponse in Surveys. Hoboken, NJ: John Wiley & Sons; 1987. doi: 10.1002/9780470316696 source

  • It may state two separate claims as one.

    Study design and conductreasoning

    The analysis accounted for a wide range of potential confounding variables, but in an observational study, there is potential for residual confounding and indication bias.

    “The analysis accounted for a wide range of potential confounding variables, but in an observational study, there is potential for residual confounding and indication bias.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Case patients with diagnostic codes for specific subtypes of dementia associated with Huntington disease, Parkinson disease, Creutzfeldt-Jakob disease, or HIV were excluded, as were patients diagnosed with Parkinson disease, Huntington disease, or multiple sclerosis, to reduce indication bias.

    “Case patients with diagnostic codes for specific subtypes of dementia associated with Huntington disease, Parkinson disease, Creutzfeldt-Jakob disease, or human immunodeficiency virus (HIV) were excluded, as were patients diagnosed with Parkinson disease, Huntington disease, or multiple sclerosis to reduce indication bias.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    As a sensitivity analysis, the study used World Health Organization-defined daily dose values to standardize the prescribed doses.

    “As a sensitivity analysis we used World Health Organization (WHO)-defined daily dose (DDD) values (https://www.whocc.no/atc_ddd_index/) to standardize the prescribed doses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    We endeavored to reduce protopathic bias by excluding prescriptions in the year before diagnosis and in the 3 and 5 years before diagnosis in sensitivity analyses.

    “We endeavored to reduce protopathic bias by excluding prescriptions in the year before diagnosis and in the 3 and 5 years before diagnosis in sensitivity analyses.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    There will be underascertainment of dementia cases, so some controls may have had undiagnosed dementia, which again would tend to underestimate associations with drug exposure.

    “This means that there will be underascertainment of dementia cases, so some controls may have had undiagnosed dementia, which again would tend to underestimate associations with drug exposure.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

  • It may state two separate claims as one.

    Interpretationown data

    The present study adds further evidence of potential risks associated with strong anticholinergic drugs, particularly those that are antidepressants, bladder antimuscarinic drugs, antiparkinson drugs, and epilepsy drugs.

    “The present study adds further evidence of potential risks associated with strong anticholinergic drugs, particularly those that are antidepressants, bladder antimuscarinic drugs, antiparkinson drugs, and epilepsy drugs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.
    • Rests on an assumption: Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

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

    Study design and conductnone given

    The possibility of residual confounding remains, and it is impossible to entirely exclude protopathic effects arising from treatment for very early preclinical effects of dementia.

    “Nevertheless, the possibility of residual confounding remains, and it is impossible to entirely exclude protopathic effects arising from treatment for very early preclinical effects of dementia.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    For some anticholinergic drug types, the numbers of patients were too small to allow analysis for the 5 to 20 years before the index date.

    “For some drug types, numbers were too small to allow analysis for the 5 to 20 years before the index date (eTable 7 in the Supplement).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical codes recorded in QResearch practice records or linked Office of National Statistics death records accurately identify dementia cases.
    • Rests on an assumption: Prescriptions recorded in QResearch accurately reflect actual anticholinergic drug exposure.

  • It may state two separate claims as one.

    Study design and conductnone given

    We included a large representative sample of people diagnosed with dementia and matched controls.

    “We included a large representative sample of people diagnosed with dementia and matched controls.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductreasoning

    Data were recorded prospectively, so results are not susceptible to recall bias.

    “data were recorded prospectively, so results are not susceptible to recall bias.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    Comprehensive data on prescriptions meant that we could derive a measure of total anticholinergic drug exposure, which accounted for the quantity and dose prescribed.

    “Comprehensive data on prescriptions meant that we could derive a measure of total anticholinergic drug exposure, which accounted for the quantity and dose prescribed.”
    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.

    Study design and conductown data

    With our larger sample size we could also examine specific types of anticholinergic drugs and account for a broader range of confounders.

    “With our larger sample size we could also examine specific types of anticholinergic drugs and account for a broader range of confounders.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductreasoning

    All eligible case patients and controls were included, so there is no selection bias due to nonresponse.

    “All eligible case patients and controls were included, so there is no selection bias due to nonresponse”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    Prescriptions issued in the year before the index date were excluded to reduce protopathic bias.

    “To reduce protopathic biases, we did not include prescriptions issued in the year before the index date.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Controls were excluded if they had a diagnosis of Parkinson disease, Huntington disease, or multiple sclerosis.

    “Controls were excluded if they had a diagnosis of Parkinson disease, Huntington disease, or multiple sclerosis.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The study also included additional drugs from the Beers 2015 updated list of strong anticholinergic drugs, the Anticholinergic Cognitive Burden scale, a systematic review, and the British National Formulary.

    “We also included additional drugs in the Beers 2015 updated list of strong anticholinergic drugs,15 drugs listed as having a high anticholinergic burden in the Anticholinergic Cognitive Burden scale,16 or identified as high-potency anticholinergics in a systematic review,17 and some further drugs identified as having substantial anticholinergic properties in the British National Formulary”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] By the American Geriatrics Society 2015 Beers Criteria Update Expert Panel American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015; 63(11): 2227- 2246. doi: 10.1111/jgs.13702 26446832 source
    • cites [16] Boustani M, Campbell N, Munger S, Maidment I, Fox C Impact of anticholinergics on the aging brain: a review and practical application. Aging Health. 2008; 4(3): 311- 320. doi: 10.2217/1745509X.4.3.311 source
    • cites [17] Durán CE, Azermai M, Vander Stichele RH Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol. 2013; 69(7): 1485- 1496. doi: 10.1007/s00228-013-1499-3 23529548 source

  • Probably not a substantial claim.

    Study design and conductreasoning

    For the primary analyses, case patients and controls were included only if they had at least 11 years of recorded data prior to the index date, so that anticholinergic drug exposure could be assessed over a complete 10-year period excluding the 1-year period prior to the index date.

    “For the primary analyses, case patients and controls were only included if they had at least 11 years of recorded data prior to the index date, so that anticholinergic drug exposure could be assessed over a complete period of 10 years (excluding the 1-year period prior to the index date).”
    Quote in the paperSubstantial claim
35 of 35

  • The paper relies on this without support.

    Clinical codes recorded in QResearch practice records or linked Office of National Statistics death records accurately identify dementia cases.

    “Case patients were those diagnosed with dementia during follow-up, identified using clinical codes recorded in the practice records or linked Office of National Statistics death records.”

  • The paper relies on this without support.

    Prescriptions recorded in QResearch accurately reflect actual anticholinergic drug exposure.

    “We extracted details of prescriptions for the included anticholinergic drugs.”

  • The paper relies on this without support.

    The measured confounding variables sufficiently control for confounding of the association between anticholinergic drug use and dementia.

    “We used conditional logistic regression to estimate odds ratios (ORs) adjusted for the confounding variables.”

  • The paper relies on this without support.

    The QResearch cohort is representative of the British population aged 55 years and older.

    “This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population.”

  • The paper relies on this without support.

    Excluding prescriptions issued in the year before the index date is sufficient to remove protopathic bias.

    “To reduce protopathic biases, we did not include prescriptions issued in the year before the index date.”

  • The paper relies on this without support.

    Prescribed anticholinergic medication is a valid proxy for actual anticholinergic drug exposure in the study population.

    “A limitation is that some patients may not have taken their prescribed medication or not taken the dose prescribed, leading to exposure misclassification.”

  • The paper relies on this without support.

    Recorded diagnoses of dementia or prescriptions for acetylcholinesterase-inhibiting drugs in QResearch accurately identify cases of dementia.

    “Our identification of patients with dementia was based on recorded diagnoses or treatment with acetylcholinesterase-inhibiting drugs rather than screening of the entire study population.”
7 of 7

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?

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.

  • Reference accessed before its stated publication date

    Minor

    Reference 5 says the document was accessed on May 16, 2018, but gives its publication date as June 20, 2018.

1 of 1

Citations

Cites

Flagged first, then by citations

4 of the 45 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. American Geriatrics Society 2012 Beers Criteria Update Expert Panel, 2012, American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults., J Am Geriatr Soc, 60, 616, 10.1111/jgs.2012.60.issue-4 · DOI
  2. Semla, 2010, Geriatric Dosage Handbook: Including Clinical Recommendations and Monitoring Guidelines

Cited by

Sorted by citations

Related

Metadata

Authors
Coupland, C. A. C., Hill, T., Dening, T., Morriss, R., Moore, M., & Hippisley-Cox, J.
Affiliations
  • University of Nottingham (GB)
  • University of Southampton (GB)
  • Division of Primary Care, University of Nottingham, Nottingham, England
Corresponding author
Coupland, Carol A. C.
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2019-08-01
Volume
179
Issue
8
Pages
1084
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2019.0677
PMC
PMC6593623
OpenAlex
W2939971450
Semantic Scholar
a4a5dce2c4cc646d992a72675f810f737c1db9c4
Cited by
637
References
45
Citations by year
2026: 81 · 2025: 80 · 2024: 93 · 2023: 61 · 2022: 78 · 2021: 93 · 2020: 122 · 2019: 27
FWCI
55.93
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Internal Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repository@Nottingham (University of Nottingham) (publishedVersion, cc-by)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by)
Funders
  • National Institute for Health and Care Research (NF-SI-0617-10016)
  • NIHR School for Primary Care Research
  • NIHR Nottingham Biomedical Research Centre
  • Faculty of Medicine and Health, University of Sydney
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 risk, cumulative drug exposure, antipsychotic drugs, antiparkinsonian drugs, anticholinergic effects, older adults, QResearch database, cognitive decline, polypharmacy, Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, vascular dementia

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