European Journal of Clinical Pharmacology

, Volume 75, Issue 12, pp 1631–1644 | Cite as

Association between anticholinergic (atropinic) drug exposure and cognitive function in longitudinal studies among individuals over 50 years old: a systematic review

  • Laurine AndreEmail author
  • Adeline Gallini
  • François Montastruc
  • Jean-Louis Montastruc
  • Antoine Piau
  • Maryse Lapeyre-Mestre
  • Virginie Gardette



With increasing age, adults are often exposed to anticholinergic drugs and are prone to potential adverse drug reaction, among which cognitive impairment. If the short-term cognitive effects of anticholinergic drugs are well established, their long-term cognitive effects have less been studied.


To provide a systematic review of longitudinal studies which assessed the effect of anticholinergic exposure on cognition in individuals over 50 years.


We searched the MEDLINE database for studies with a minimal 6-month follow-up, assessing anticholinergic exposure through a biological measure or a clinical list and reporting at least one cognitive outcome. We used the modified Newcastle-Ottawa scale and additional criteria regarding the anticholinergic exposure to assess studies’ methodological quality. Given the heterogeneity of the studies, we performed a systematic review.


Among the 1574 references retrieved, 25 studies were included. Anticholinergic medications were mostly defined through the Anticholinergic Cognitive Burden Scale (n = 14/25). Six studies evaluated baseline drug collection, 14 used longitudinal aggregated measure, and 5 multiple drug exposure measures over time. Seventeen studies assessed anticholinergic burden. Cognitive function was assessed by mild cognitive impairment/dementia incidence (n = 15) or neuropsychological tests (n = 14). Most studies were of poor quality and retrieved discordant results. However, studies with good quality (n = 4) suggested a relationship between anticholinergic drug exposure and/or burden and cognitive function.


Our review suggests a deleterious effect of anticholinergic exposure on mid/long-term cognitive function but should be confirmed in studies with improved methodology. Meanwhile, prescription of anticholinergic drugs should remain cautious.


Anticholinergic drug exposure  Anticholinergic burden  Cognitive decline  Longitudinal study Systematic review 



The authors would like to thank Dr. Anne-Bahia Abdeljalil for her writing assistance.

Authors’ contribution

All authors contributed to the writing of the manuscript and approved the final version.

Compliance with ethical standards

Conflict of interest

Andre Laurine, Gallini Adeline, Montastruc François, Montastruc Jean-Louis, Piau Antoine, Lapeyre-Mestre Maryse, and Gardette Virginie have no conflicts of interest directly relevant to the content of this study.

Supplementary material

228_2019_2744_MOESM1_ESM.docx (104 kb)
ESM 1 (DOCX 104 kb)


  1. 1.
    Mintzer J, Burns A (2000) Anticholinergic side-effects of drugs in elderly people. J R Soc Med 93:457–462PubMedPubMedCentralGoogle Scholar
  2. 2.
    McNeely SS, Bhattacharya R, Aparasu RR (2013) Prevalence of anticholinergic use among older home health patients. J Clin Nurs 22:285–288PubMedGoogle Scholar
  3. 3.
    Lu W-H, Wen Y-W, Chen L-K, Hsiao FY (2015) Effect of polypharmacy, potentially inappropriate medications and anticholinergic burden on clinical outcomes: a retrospective cohort study. CMAJ 187:E130–E137PubMedPubMedCentralGoogle Scholar
  4. 4.
    Marcum ZA, Perera S, Thorpe JM, Switzer GE, Gray SL, Castle NG, Strotmeyer ES, Simonsick EM, Bauer DC, Shorr RI, Studenski SA, Hanlon JT, Health ABC Study, USA (2015) Anticholinergic use and recurrent falls in community-dwelling older adults: findings from the health ABC study. Ann Pharmacother 49:1214–1221PubMedPubMedCentralGoogle Scholar
  5. 5.
    Kachru N, Carnahan RM, Johnson ML, Aparasu RR (2015) Potentially inappropriate anticholinergic medication use in community-dwelling older adults: a national cross-sectional study. Drugs Aging 32:379–389PubMedGoogle Scholar
  6. 6.
    Lechevallier-Michel N, Molimard M, Dartigues J-F, Fabrigoule C, Fourrier-Reglat A (2005) Drugs with anticholinergic properties and cognitive performance in the elderly: results from the PAQUID study. Br J Clin Pharmacol 59:143–151PubMedPubMedCentralGoogle Scholar
  7. 7.
    Flicker C, Ferris SH, Serby M (1992) Hypersensitivity to scopolamine in the elderly. Psychopharmacology 107:437–441PubMedGoogle Scholar
  8. 8.
    Molchan SE, Martinez RA, Hill JL, Weingartner HJ, Thompson K, Vitiello B, Sunderland T (1992) Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model. Brain Res Brain Res Rev 17:215–226PubMedGoogle Scholar
  9. 9.
    Ray PG, Meador KJ, Loring DW et al (1992) Central anticholinergic hypersensitivity in aging. J Geriatr Psychiatry Neurol 5:72–77PubMedGoogle Scholar
  10. 10.
    Commissaris CJ, Ponds RW, Jolles J (1998) Subjective forgetfulness in a normal Dutch population: possibilities for health education and other interventions. Patient Educ Couns 34:25–32PubMedGoogle Scholar
  11. 11.
    Derouesné C, Lacomblez L, Thibault S, Leponcin M (1999) Memory complaints in young and elderly subjects. Int J Geriatr Psychiatry 14:291–301PubMedGoogle Scholar
  12. 12.
    Tune L, Coyle JT (1980) Serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects. Arch Gen Psychiatry 37:293–297PubMedGoogle Scholar
  13. 13.
    Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR (2006) The anticholinergic drug scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol 46:1481–1486PubMedGoogle Scholar
  14. 14.
    Rudolph JL, Salow MJ, Angelini MC, McGlinchey R (2008) The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med 168:508–513PubMedGoogle Scholar
  15. 15.
    Boustani M, Campbell N, Munger S, Maidment I, Fox C (2008) Impact of anticholinergics on the aging brain: a review and practical application. Aging Health 4(3):311–320Google Scholar
  16. 16.
    Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, Kirshner MA, Sorisio DA, Bies RR, Gharabawi G (2008) Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc 56:1333–1341PubMedGoogle Scholar
  17. 17.
    Durán CE, Azermai M, Vander Stichele RH (2013) Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 69:1485–1496PubMedGoogle Scholar
  18. 18.
    Han L, Agostini JV, Allore HG (2008) Cumulative anticholinergic exposure is associated with poor memory and executive function in older men. J Am Geriatr Soc 56:2203–2210PubMedPubMedCentralGoogle Scholar
  19. 19.
    Hilmer SN, Mager DE, Simonsick EM, Cao Y, Ling SM, Windham BG, Harris TB, Hanlon JT, Rubin SM, Shorr RI, Bauer DC, Abernethy DR (2007) A drug burden index to define the functional burden of medications in older people. Arch Intern Med 167:781–787PubMedGoogle Scholar
  20. 20.
    Ehrt U, Broich K, Larsen JP, Ballard C, Aarsland D (2010) Use of drugs with anticholinergic effect and impact on cognition in Parkinson’s disease: a cohort study. J Neurol Neurosurg Psychiatry 81:160–165PubMedGoogle Scholar
  21. 21.
    Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, Ritchie K (2006) Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ 332:455–459PubMedPubMedCentralGoogle Scholar
  22. 22.
    Nebes RD, Pollock BG, Meltzer CC, Saxton JA, Houck PR, Halligan EM, DeKosky ST (2005) Serum anticholinergic activity, white matter hyperintensities, and cognitive performance. Neurology 65:1487–1489PubMedGoogle Scholar
  23. 23.
    Cao Y-J, Mager DE, Simonsick EM, Hilmer SN, Ling SM, Windham BG, Crentsil V, Yasar S, Fried LP, Abernethy DR (2008) Physical and cognitive performance and burden of anticholinergics, sedatives, and ACE inhibitors in older women. Clin Pharmacol Ther 83:422–429PubMedGoogle Scholar
  24. 24.
    Cancelli I, Gigli GL, Piani A, Zanchettin B, Janes F, Rinaldi A, Valente M (2008) Drugs with anticholinergic properties as a risk factor for cognitive impairment in elderly people: a population-based study. J Clin Psychopharmacol 28:654–659PubMedGoogle Scholar
  25. 25.
    Uusvaara J, Pitkala KH, Kautiainen H, Tilvis RS, Strandberg TE (2013) Detailed cognitive function and use of drugs with anticholinergic properties in older people: a community-based cross-sectional study. Drugs Aging 30:177–182PubMedGoogle Scholar
  26. 26.
    Sittironnarit G, Ames D, Bush AI, Faux N, Flicker L, Foster J, Hilmer S, Lautenschlager NT, Maruff P, Masters CL, Martins RN, Rowe C, Szoeke C, Ellis KA (2011) Effects of anticholinergic drugs on cognitive function in older Australians: results from the AIBL study. Dement Geriatr Cogn Disord 31:173–178PubMedGoogle Scholar
  27. 27.
    Lampela P, Lavikainen P, Garcia-Horsman JA, Bell JS, Huupponen R, Hartikainen S (2013) Anticholinergic drug use, serum anticholinergic activity, and adverse drug events among older people: a population-based study. Drugs Aging 30:321–330PubMedGoogle Scholar
  28. 28.
    Cruce R, Vosoughi R, Freedman MS (2012) Cognitive impact of anticholinergic medication in MS: adding insult to injury? Mult Scler Relat Disord 1:156–161PubMedGoogle Scholar
  29. 29.
    Merchant RA, Li B, Yap K-B, Ng TP (2009) Use of drugs with anticholinergic effects and cognitive impairment in community-living older persons. Age Ageing 38:105–108PubMedGoogle Scholar
  30. 30.
    Campbell N, Boustani M, Limbil T et al (2009) The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging 4:225–233PubMedPubMedCentralGoogle Scholar
  31. 31.
    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, available from: (accessed 5 October 2018)
  32. 32.
    Campbell NL, Boustani MA, Lane KA, Gao S, Hendrie H, Khan BA, Murrell JR, Unverzagt FW, Hake A, Smith-Gamble V, Hall K (2010) Use of anticholinergics and the risk of cognitive impairment in an African American population. Neurology 75:152–159PubMedPubMedCentralGoogle Scholar
  33. 33.
    Carrière I, Fourrier-Reglat A, Dartigues J-F, Rouaud O, Pasquier F, Ritchie K, Ancelin ML (2009) Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study. Arch Intern Med 169:1317–1324PubMedPubMedCentralGoogle Scholar
  34. 34.
    Chuang Y-F, Elango P, Gonzalez CE, Thambisetty M (2017) Midlife anticholinergic drug use, risk of Alzheimer’s disease, and brain atrophy in community-dwelling older adults. Alzheimers Dement (N Y) 3:471–479Google Scholar
  35. 35.
    Fox C, Richardson K, Maidment ID, Savva GM, Matthews FE, Smithard D, Coulton S, Katona C, Boustani MA, Brayne C (2011) Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc 59:1477–1483PubMedGoogle Scholar
  36. 36.
    Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB (2015) Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 175:401–407PubMedPubMedCentralGoogle Scholar
  37. 37.
    Jamsen KM, Gnjidic D, Hilmer SN, Ilomäki J, le Couteur DG, Blyth FM, Handelsman DJ, Naganathan V, Waite LM, Cumming RG, Bell JS (2017) Drug Burden Index and change in cognition over time in community-dwelling older men: the CHAMP study. Ann Med 49:157–164PubMedGoogle Scholar
  38. 38.
    Jessen F, Kaduszkiewicz H, Daerr M et al (2010) Anticholinergic drug use and risk for dementia: target for dementia prevention. Eur Arch Psychiatry Clin Neurosci 260(Suppl 2):S111–S115PubMedGoogle Scholar
  39. 39.
    Kashyap M, Belleville S, Mulsant BH, Hilmer SN, Paquette A, Tu LM, Tannenbaum C (2014) Methodological challenges in determining longitudinal associations between anticholinergic drug use and incident cognitive decline. J Am Geriatr Soc 62:336–341PubMedGoogle Scholar
  40. 40.
    Koyama A, Steinman M, Ensrud K, Hillier TA, Yaffe K (2013) Ten-year trajectory of potentially inappropriate medications in very old women: importance of cognitive status. J Am Geriatr Soc 61:258–263PubMedPubMedCentralGoogle Scholar
  41. 41.
    Koyama A, Steinman M, Ensrud K, Hillier TA, Yaffe K (2014) Long-term cognitive and functional effects of potentially inappropriate medications in older women. J Gerontol A Biol Sci Med Sci 69:423–429PubMedGoogle Scholar
  42. 42.
    Low L-F, Anstey KJ, Sachdev P (2009) Use of medications with anticholinergic properties and cognitive function in a young-old community sample. Int J Geriatr Psychiatry 24:578–584PubMedGoogle Scholar
  43. 43.
    Papenberg G, Bäckman L, Fratiglioni L, Laukka EJ, Fastbom J, Johnell K (2017) Anticholinergic drug use is associated with episodic memory decline in older adults without dementia. Neurobiol Aging 55:27–32PubMedGoogle Scholar
  44. 44.
    Risacher SL, McDonald BC, Tallman EF et al (2016) Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively Normal older adults. JAMA Neurol 73:721–732PubMedPubMedCentralGoogle Scholar
  45. 45.
    Ritchie K, Ancelin M-L, Beaino E, Portet F, Brickman AM, Dartigues JF, Tzourio C, Dupuy AM, Ritchie CW, Berr C, Artero S (2010) Retrospective identification and characterization of mild cognitive impairment from a prospective population cohort. Am J Geriatr Psychiatry 18:692–700PubMedPubMedCentralGoogle Scholar
  46. 46.
    Shah RC, Janos AL, Kline JE, Yu L, Leurgans SE, Wilson RS, Wei P, Bennett DA, Heilman KM, Tsao JW (2013) Cognitive decline in older persons initiating anticholinergic medications. PLoS One 8:e64111PubMedPubMedCentralGoogle Scholar
  47. 47.
    Bottiggi KA, Salazar JC, Yu L, Caban-Holt AM, Mendiondo MS, Schmitt FA, Ryan M (2006) Long-term cognitive impact of anticholinergic medications in older adults. Am J Geriatr Psychiatry 14:980–984PubMedGoogle Scholar
  48. 48.
    Richardson K, Fox C, Maidment I et al (2018) Anticholinergic drugs and risk of dementia: case-control study. BMJ 361:k1315PubMedPubMedCentralGoogle Scholar
  49. 49.
    Campbell NL, Perkins AJ, Bradt P, Perk S, Wielage RC, Boustani MA, Ng DB (2016) Association of Anticholinergic Burden with cognitive impairment and health care utilization among a diverse ambulatory older adult population. Pharmacotherapy 36:1123–1131PubMedPubMedCentralGoogle Scholar
  50. 50.
    Campbell NL, Lane KA, Gao S et al (2018) Anticholinergics influence transition from normal cognition to mild cognitive impairment in older adults in primary care. Pharmacotherapy 13:1191Google Scholar
  51. 51.
    Cruz-Oliver DM, Malmstrom TK, Roegner M et al (2014) Cognitive deficit reversal as shown by changes in the Veterans Affairs Saint Louis University Mental Status (SLUMS) examination scores 7.5 years later. J Am Med Dir Assoc 15:687.e5–10PubMedGoogle Scholar
  52. 52.
    Hsu W-H, Wen Y-W, Chen L-K, Hsiao FY (2017) Comparative associations between measures of anti-cholinergic burden and adverse clinical outcomes. Ann Fam Med 15:561–569PubMedPubMedCentralGoogle Scholar
  53. 53.
    Wu Y-H, Wang C-J, Hung C-H, Chen LY, Lin MH, Wang PN, Chen LK (2017) Association between using medications with anticholinergic properties and short-term cognitive decline among older men: a retrospective cohort study in Taiwan. Geriatr Gerontol Int 17(Suppl 1):57–64PubMedGoogle Scholar
  54. 54.
    Cai X, Campbell N, Khan B, Callahan C, Boustani M (2013) Long-term anticholinergic use and the aging brain. Alzheimers Dement 9:377–385PubMedGoogle Scholar
  55. 55.
    Han L, McCusker J, Cole M, Abrahamowicz M, Primeau F, Élie M (2001) Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 161:1099–1105PubMedGoogle Scholar
  56. 56.
    Richardson K, Bennett K, Maidment ID, Fox C, Smithard D, Kenny RA (2015) Use of medications with anticholinergic activity and self-reported injurious falls in older community-dwelling adults. J Am Geriatr Soc 63:1561–1569PubMedGoogle Scholar
  57. 57.
    Moride Y, Abenhaim L, Yola M et al (1994) Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research. J Clin Epidemiol 47:731–737PubMedGoogle Scholar
  58. 58.
    Naples JG, Marcum ZA, Perera S, Gray SL, Newman AB, Simonsick EM, Yaffe K, Shorr RI, Hanlon JT, the Health, Aging and Body Composition Study (2015) Concordance between anticholinergic burden scales. J Am Geriatr Soc 63:2120–2124PubMedPubMedCentralGoogle Scholar
  59. 59.
    Pont LG, Nielen JTH, McLachlan AJ et al (2015) Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures. Br J Clin Pharmacol 80:1169–1175PubMedPubMedCentralGoogle Scholar
  60. 60.
    Klamer TT, Wauters M, Azermai M, Durán C, Christiaens T, Elseviers M, Vander Stichele R (2017) A novel scale linking potency and dosage to estimate anticholinergic exposure in older adults: the muscarinic acetylcholinergic receptor antagonist exposure scale. Basic Clin Pharmacol Toxicol 120:582–590PubMedGoogle Scholar
  61. 61.
    Mesulam MM, Volicer L, Marquis JK, Mufson EJ, Green RC (1986) Systematic regional differences in the cholinergic innervation of the primate cerebral cortex: distribution of enzyme activities and some behavioral implications. Ann Neurol 19:144–151PubMedGoogle Scholar
  62. 62.
    Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, Thomas RG, Weiner M, Aisen PS, Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Cooperative Study (2014) The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol 71:961–970PubMedPubMedCentralGoogle Scholar
  63. 63.
    Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80:1778–1783PubMedPubMedCentralGoogle Scholar
  64. 64.
    Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563PubMedGoogle Scholar
  65. 65.
    Sumukadas D, McMurdo MET, Mangoni AA et al (2014) Temporal trends in anticholinergic medication prescription in older people: repeated cross-sectional analysis of population prescribing data. Age Ageing 43:515–521PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.UMR INSERM 1027, Université de ToulouseCentre Hospitalo-Universitaire de Toulouse (CHU Toulouse)ToulouseFrance
  2. 2.Service d’EpidémiologieCentre Hospitalo-Universitaire de Toulouse (CHU Toulouse)ToulouseFrance
  3. 3.Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, Pharmacoépidémiologie et d’Informations sur le MédicamentCentre Hospitalo-Universitaire de Toulouse (CHU Toulouse)ToulouseFrance
  4. 4.Gérontopôle de Toulouse, Institut du VieillissementCentre Hospitalo-Universitaire de Toulouse (CHU Toulouse)ToulouseFrance

Personalised recommendations