[Skip to Content]
[Skip to Content Landing]

Anticholinergic Drug Exposure and the Risk of DementiaA Nested Case-Control Study

Educational Objective
To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.
1 Credit CME
Key Points

Question  Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication?

Findings  In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables.

Meaning  The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.

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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: February 19, 2019

Published Online: June 24, 2019. doi:10.1001/jamainternmed.2019.0677

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Coupland CAC et al. JAMA Internal Medicine.

Corresponding Author: Carol A. C. Coupland, PhD, Division of Primary Care, University of Nottingham, University Park, 13th Floor, Tower Building, Nottingham NG7 2RD, United Kingdom (carol.coupland@nottingham.ac.uk).

Author Contributions: Dr Coupland had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Coupland, Dening, Morriss, Moore, Hippisley-Cox.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Coupland, Dening, Hippisley-Cox.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Coupland, Hill.

Obtained funding: Coupland, Morriss, Hippisley-Cox.

Administrative, technical, or material support: Dening, Morriss, Moore, Hippisley-Cox.

Study supervision: Coupland.

Conflict of Interest Disclosures: Dr Coupland reported personal fees from ClinRisk Ltd outside the submitted work. Julia Hippisley-Cox reported nonfinancial support from QResearch and personal fees from ClinRisk Ltd outside the submitted work. No other disclosures were reported.

Funding/Support: The project was funded by the National Institute for Health Research (NIHR) School for Primary Care Research (project number 265). Additional funding was provided by the Faculty of Medicine and Health Sciences Research Board, University of Nottingham. QResearch receives support from the NIHR Nottingham Biomedical Research Centre. Dr Morriss’s contribution to the study has been funded through the NIHR Collaboration for Leadership in Applied Health Research and Care East 15 Midlands (CLAHRC EM), NIHR MindTech, MedTech, and In Vitro Cooperative. Drs Hippisley-Cox, Coupland, and Morriss acknowledge funding from the NIHR Nottingham Biomedical Research Centre.

Role of the Funder/Sponsor: The NIHR approved the study design, but did not play a role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: This article presents independent research funded by the NIHR School for Primary Care Research. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The Office for National Statistics bears no responsibility for the analysis or interpretation of the data.

Additional Contributions: We acknowledge the contribution of practices who contribute to the QResearch database and to Egton Medical Information Systems (EMIS) and the University of Nottingham for expertise in establishing, developing, and supporting the database. We thank the Office for National Statistics for providing the mortality data. This work uses data provided by patients and collected by the NHS as part of their care and support. None of the additional contributors who assisted with the study received compensation.

Data Sharing Statement: The patient level data from the QResearch database are specifically licensed according to its governance framework. See http://www.qresearch.org for further details.

References
1.
Livingston  G, Sommerlad  A, Orgeta  V,  et al.  Dementia prevention, intervention, and care.  Lancet. 2017;390(10113):2673-2734. doi:10.1016/S0140-6736(17)31363-6PubMedGoogle ScholarCrossref
2.
Alzheimer’s Association.  2018 Alzheimer’s disease facts and figures.  Alzheimers Dement. 2018;14(3):367-429. doi:10.1016/j.jalz.2018.02.001Google ScholarCrossref
3.
Fox  C, Richardson  K, Maidment  ID,  et al.  Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study.  J Am Geriatr Soc. 2011;59(8):1477-1483. doi:10.1111/j.1532-5415.2011.03491.xPubMedGoogle ScholarCrossref
4.
Fox  C, Smith  T, Maidment  I,  et al.  Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review.  Age Ageing. 2014;43(5):604-615. doi:10.1093/ageing/afu096PubMedGoogle ScholarCrossref
5.
National Institute for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers.https://www.nice.org.uk/guidance/ng97/resources/dementia-assessment-management-and-support-for-people-living-with-dementia-and-their-carers-pdf-1837760199109. Published June 20, 2018. Accessed May 16, 2018.
6.
Gerretsen  P, Pollock  BG.  Drugs with anticholinergic properties: a current perspective on use and safety.  Expert Opin Drug Saf. 2011;10(5):751-765. doi:10.1517/14740338.2011.579899PubMedGoogle ScholarCrossref
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.2012.02.005PubMedGoogle ScholarCrossref
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.DEPubMedGoogle ScholarCrossref
9.
Carrière  I, Fourrier-Reglat  A, Dartigues  JF,  et al.  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.2009.229PubMedGoogle ScholarCrossref
10.
Jessen  F, Kaduszkiewicz  H, Daerr  M,  et al.  Anticholinergic drug use and risk for dementia: target for dementia prevention.  Eur Arch Psychiatry Clin Neurosci. 2010;260(2)(suppl 2):S111-S115. doi:10.1007/s00406-010-0156-4PubMedGoogle ScholarCrossref
11.
Gray  SL, Anderson  ML, Dublin  S,  et al.  Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study.  JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663PubMedGoogle ScholarCrossref
12.
Richardson  K, Fox  C, Maidment  I,  et al.  Anticholinergic drugs and risk of dementia: case-control study.  BMJ. 2018;361:k1315. doi:10.1136/bmj.k1315PubMedGoogle ScholarCrossref
13.
Vandenbroucke  JP, Pearce  N.  Case-control studies: basic concepts.  Int J Epidemiol. 2012;41(5):1480-1489. doi:10.1093/ije/dys147PubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.13702PubMedGoogle ScholarCrossref
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.4.3.311Google ScholarCrossref
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/s00228-013-1499-3PubMedGoogle ScholarCrossref
18.
Semla  TP, Beizer  JL, Higbee  MD, eds.  Geriatric Dosage Handbook: Including Clinical Recommendations and Monitoring Guidelines. 15th ed. Hudson, OH: Lexi-Comp; 2010.
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)61349-9PubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
21.
Walters  K, Hardoon  S, Petersen  I,  et al.  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-yPubMedGoogle ScholarCrossref
22.
Justin  BN, Turek  M, Hakim  AM.  Heart disease as a risk factor for dementia.  Clin Epidemiol. 2013;5:135-145.PubMedGoogle Scholar
23.
Bendlin  BB, Carlsson  CM, Gleason  CE,  et al.  Midlife predictors of Alzheimer’s disease.  Maturitas. 2010;65(2):131-137. doi:10.1016/j.maturitas.2009.12.014PubMedGoogle ScholarCrossref
24.
Diniz  BS, Butters  MA, Albert  SM, Dew  MA, Reynolds  CF  III.  Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies.  Br J Psychiatry. 2013;202(5):329-335. doi:10.1192/bjp.bp.112.118307PubMedGoogle ScholarCrossref
25.
da Silva  J, Gonçalves-Pereira  M, Xavier  M, Mukaetova-Ladinska  EB.  Affective disorders and risk of developing dementia: systematic review.  Br J Psychiatry. 2013;202(3):177-186. doi:10.1192/bjp.bp.111.101931PubMedGoogle ScholarCrossref
26.
Anstey  KJ, von Sanden  C, Salim  A, O’Kearney  R.  Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies.  Am J Epidemiol. 2007;166(4):367-378. doi:10.1093/aje/kwm116PubMedGoogle ScholarCrossref
27.
Peters  R, Peters  J, Warner  J, Beckett  N, Bulpitt  C.  Alcohol, dementia and cognitive decline in the elderly: a systematic review.  Age Ageing. 2008;37(5):505-512. doi:10.1093/ageing/afn095PubMedGoogle ScholarCrossref
28.
Mehta  KM, Yeo  GW.  Systematic review of dementia prevalence and incidence in United States race/ethnic populations.  Alzheimers Dement. 2017;13(1):72-83. doi:10.1016/j.jalz.2016.06.2360PubMedGoogle ScholarCrossref
29.
Rubin  DB.  Multiple Imputation for Nonresponse in Surveys. Hoboken, NJ: John Wiley & Sons; 1987. doi:10.1002/9780470316696
30.
Bruzzi  P, Green  SB, Byar  DP, Brinton  LA, Schairer  C.  Estimating the population attributable risk for multiple risk factors using case-control data.  Am J Epidemiol. 1985;122(5):904-914. doi:10.1093/oxfordjournals.aje.a114174PubMedGoogle ScholarCrossref
31.
Mansournia  MA, Altman  DG.  Population attributable fraction.  BMJ. 2018;360:k757. doi:10.1136/bmj.k757PubMedGoogle ScholarCrossref
32.
Matthews  FE, Stephan  BCM, Robinson  L,  et al; 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/ncomms11398PubMedGoogle ScholarCrossref
33.
Guerriero  F, Sgarlata  C, Francis  M,  et al.  Neuroinflammation, immune system and Alzheimer disease: searching for the missing link.  Aging Clin Exp Res. 2017;29(5):821-831. doi:10.1007/s40520-016-0637-zPubMedGoogle ScholarCrossref
34.
McGeer  PL, Rogers  J, McGeer  EG.  Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years.  J Alzheimers Dis. 2016;54(3):853-857. doi:10.3233/JAD-160488PubMedGoogle ScholarCrossref
35.
Campbell  NL, Maidment  I, Fox  C, Khan  B, Boustani  M.  The 2012 update to the anticholinergic cognitive burden scale.  J Am Geriatr Soc. 2013;61(S1):S142-S143.Google Scholar
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-2017-020738PubMedGoogle ScholarCrossref
37.
Wilkinson  D, Stave  C, Keohane  D, Vincenzino  O.  The role of general practitioners in the diagnosis and treatment of Alzheimer’s disease: a multinational survey.  J Int Med Res. 2004;32(2):149-159. doi:10.1177/147323000403200207PubMedGoogle ScholarCrossref
38.
van Vliet  D, de Vugt  ME, Bakker  C,  et al.  Time to diagnosis in young-onset dementia as compared with late-onset dementia.  Psychol Med. 2013;43(2):423-432. doi:10.1017/S0033291712001122PubMedGoogle ScholarCrossref
39.
Amieva  H, Le Goff  M, Millet  X,  et al.  Prodromal Alzheimer’s disease: successive emergence of the clinical symptoms.  Ann Neurol. 2008;64(5):492-498. doi:10.1002/ana.21509PubMedGoogle ScholarCrossref
40.
Singh-Manoux  A, Dugravot  A, Fournier  A,  et al.  Trajectories of depressive symptoms before diagnosis of dementia: a 28-year follow-up study.  JAMA Psychiatry. 2017;74(7):712-718. doi:10.1001/jamapsychiatry.2017.0660PubMedGoogle ScholarCrossref
41.
Livingston  G, Sommerlad  A, Schneider  L, Mukadam  N, Costafreda  S.  Prevention of dementia by targeting risk factors: authors’ reply.  Lancet. 2018;391(10130):1575-1576. doi:10.1016/S0140-6736(18)30570-1PubMedGoogle ScholarCrossref
42.
Warren  K, Burden  H, Abrams  P.  Mirabegron in overactive bladder patients: efficacy review and update on drug safety.  Ther Adv Drug Saf. 2016;7(5):204-216. doi:10.1177/2042098616659412PubMedGoogle ScholarCrossref
43.
Olivera  CK, Meriwether  K, El-Nashar  S,  et al; Systematic Review Group for the Society of Gynecological Surgeons.  Nonantimuscarinic treatment for overactive bladder: a systematic review.  Am J Obstet Gynecol. 2016;215(1):34-57. doi:10.1016/j.ajog.2016.01.156PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements