Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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Ancelin  ML, Artero  S, Portet  F, Dupuy  AM, 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.PubMedGoogle ScholarCrossref
Bottiggi  KA, Salazar  JC, Yu  L,  et al.  Long-term cognitive impact of anticholinergic medications in older adults.  Am J Geriatr Psychiatry. 2006;14(11):980-984. PubMedGoogle ScholarCrossref
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.Google ScholarCrossref
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. PubMedGoogle ScholarCrossref
Campbell  N, Boustani  M, Limbil  T,  et al.  The cognitive impact of anticholinergics: a clinical review.  Clin Interv Aging. 2009;4:225-233.PubMedGoogle Scholar
Campbell  NL, Boustani  MA, Lane  KA,  et al.  Use of anticholinergics and the risk of cognitive impairment in an African American population.  Neurology. 2010;75(2):152-159.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
Kashyap  M, Belleville  S, Mulsant  BH,  et al.  Methodological challenges in determining longitudinal associations between anticholinergic drug use and incident cognitive decline.  J Am Geriatr Soc. 2014;62(2):336-341.PubMedGoogle ScholarCrossref
Konishi  K, Hori  K, Uchida  H,  et al Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease.  Psychogeriatrics. 2010;10(1):34-38. PubMedGoogle ScholarCrossref
Lampela  P, Lavikainen  P, Garcia-Horsman  JA, Bell  JS, Huupponen  R, Hartikainen  S.  Anticholinergic drug use, serum anticholinergic activity, and adverse drug events among older people: a population-based study.  Drugs Aging. 2013;30(5):321-330.PubMedGoogle ScholarCrossref
Lechevallier-Michel  N, Molimard  M, Dartigues  JF, Fabrigoule  C, Fourrier-Réglat  A.  Drugs with anticholinergic properties and cognitive performance in the elderly: results from the PAQUID Study.  Br J Clin Pharmacol. 2005;59(2):143-151.PubMedGoogle ScholarCrossref
Shah  RC, Janos  AL, Kline  JE,  et al.  Cognitive decline in older persons initiating anticholinergic medications.  PLoS One. 2013;8(5):e64111.PubMedGoogle ScholarCrossref
Sittironnarit  G, Ames  D, Bush  AI,  et al; AIBL research group.  Effects of anticholinergic drugs on cognitive function in older Australians: results from the AIBL study.  Dement Geriatr Cogn Disord. 2011;31(3):173-178.PubMedGoogle ScholarCrossref
Tannenbaum  C, Paquette  A, Hilmer  S, Holroyd-Leduc  J, Carnahan  R.  A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs.  Drugs Aging. 2012;29(8):639-658.PubMedGoogle Scholar
Uusvaara  J, Pitkala  KH, Kautiainen  H, Tilvis  RS, Strandberg  TE.  Detailed cognitive function and use of drugs with anticholinergic properties in older people: a community-based cross-sectional study.  Drugs Aging. 2013;30(3):177-182.PubMedGoogle ScholarCrossref
Fox  C, Livingston  G, Maidment  ID,  et al.  The impact of anticholinergic burden in Alzheimer’s dementia-the LASER-AD study.  Age Ageing. 2011;40(6):730-735.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
Jessen  F, Kaduszkiewicz  H, Daerr  M,  et al.  Anticholinergic drug use and risk for dementia: target for dementia prevention.  Eur Arch Psychiatry Clin Neurosci. 2010;260(suppl 2):S111-S115.PubMedGoogle ScholarCrossref
Kashyap  M, Mulsant  BH, Tannenbaum  C.  Small longitudinal study of serum anticholinergic activity and cognitive change in community-dwelling older adults.  Am J Geriatr Psychiatry. 2015;23(3):326-329. PubMedGoogle ScholarCrossref
Flicker  C, Ferris  SH, Serby  M.  Hypersensitivity to scopolamine in the elderly.  Psychopharmacology (Berl). 1992;107(2-3):437-441.PubMedGoogle ScholarCrossref
Molchan  SE, Martinez  RA, Hill  JL,  et al.  Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model.  Brain Res Brain Res Rev. 1992;17(3):215-226.PubMedGoogle ScholarCrossref
Teipel  SJ, Bruno  D, Grothe  MJ, Nierenberg  J, Pomara  N.  Hippocampus and basal forebrain volumes modulate effects of anticholinergic treatment on delayed recall in healthy older adults.  Alzheimers Dement. 2015;1(2):216-219. doi:10.1016/j.dadm.2015.01.007.Google Scholar
Jack  CR  Jr, Bernstein  MA, Borowski  BJ,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Update on the magnetic resonance imaging core of the Alzheimer’s Disease Neuroimaging Initiative.  Alzheimers Dement. 2010;6(3):212-220. PubMedGoogle ScholarCrossref
Jagust  WJ, Bandy  D, Chen  K,  et al; Alzheimer’s Disease Neuroimaging Initiative.  The Alzheimer’s Disease Neuroimaging Initiative positron emission tomography core.  Alzheimers Dement. 2010;6(3):221-229. PubMedGoogle ScholarCrossref
Trojanowski  JQ, Vandeerstichele  H, Korecka  M,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Update on the biomarker core of the Alzheimer’s Disease Neuroimaging Initiative subjects.  Alzheimers Dement. 2010;6(3):230-238. PubMedGoogle ScholarCrossref
Petersen  RC, Aisen  PS, Beckett  LA,  et al.  Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization.  Neurology. 2010;74(3):201-209.PubMedGoogle ScholarCrossref
Saykin  AJ, Shen  L, Foroud  TM,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Alzheimer’s Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: genetics core aims, progress, and plans.  Alzheimers Dement. 2010;6(3):265-273. PubMedGoogle ScholarCrossref
Weiner  MW, Aisen  PS, Jack  CR  Jr,,  et al; Alzheimer’s Disease Neuroimaging Initiative.  The Alzheimer’s Disease Neuroimaging Initiative: progress report and future plans.  Alzheimers Dement. 2010;6(3):202-211. PubMedGoogle ScholarCrossref
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053. PubMedGoogle ScholarCrossref
Aging Brain Care. Anticholinergic Cognitive Burden scale: 2012 update. Accessed March 24, 2016.
Drugs on the Anitcholinergic Burden (ACB) scale. Accessed March 24, 2016.
Anticholinergics and the elderly. Pharmacist’s Letter website. Accessed March 24, 2016.
Risacher  SL, Kim  S, Nho  K,  et al; Alzheimer’s Disease Neuroimaging Initiative (ADNI).  APOE effect on Alzheimer’s disease biomarkers in older adults with significant memory concern.  Alzheimers Dement. 2015;11(12):1417-1429. PubMedGoogle ScholarCrossref
Risacher  SL, Kim  S, Shen  L,  et al; Alzheimer’s Disease Neuroimaging Initiative (ADNI)†.  The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI).  Front Aging Neurosci. 2013;5:11.PubMedGoogle ScholarCrossref
Gibbons  LE, Carle  AC, Mackin  RS,  et al; Alzheimer’s Disease Neuroimaging Initiative.  A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment.  Brain Imaging Behav. 2012;6(4):517-527.PubMedGoogle ScholarCrossref
Crane  PK, Carle  A, Gibbons  LE,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).  Brain Imaging Behav. 2012;6(4):502-516.PubMedGoogle ScholarCrossref
Saykin  AJ, Wishart  HA, Rabin  LA,  et al.  Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI.  Neurology. 2006;67(5):834-842.PubMedGoogle ScholarCrossref
Brett  M, Anton  JL, Valabregue  R, Poline  JB. Region of interest analysis using an SPM toolbox [abstract]. Presented at: Eighth International Conference on Functional Mapping of the Human Brain; June 2-6, 2002; Sendai, Japan.
Shaw  LM, Vanderstichele  H, Knapik-Czajka  M,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Cerebrospinal fluid biomarker signature in Alzheimer’s Disease Neuroimaging Initiative subjects.  Ann Neurol. 2009;65(4):403-413.PubMedGoogle ScholarCrossref
Landau  SM, Mintun  MA, Joshi  AD,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Amyloid deposition, hypometabolism, and longitudinal cognitive decline.  Ann Neurol. 2012;72(4):578-586.PubMedGoogle ScholarCrossref
Everitt  BJ, Robbins  TW.  Central cholinergic systems and cognition.  Annu Rev Psychol. 1997;48:649-684.PubMedGoogle ScholarCrossref
Del Pino  J, Zeballos  G, Anadón  MJ,  et al.  Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels [published online May 31, 2015].  Arch Toxicol. doi:10.1007/s00204-015-1540-7.PubMedGoogle Scholar
Capsoni  S, Giannotta  S, Stebel  M,  et al.  Ganstigmine and donepezil improve neurodegeneration in AD11 antinerve growth factor transgenic mice.  Am J Alzheimers Dis Other Demen. 2004;19(3):153-160.PubMedGoogle ScholarCrossref
Geula  C.  Abnormalities of neural circuitry in Alzheimer’s disease: hippocampus and cortical cholinergic innervation.  Neurology. 1998;51(1)(suppl 1):S18-S29; discussion S65-S67. PubMedGoogle ScholarCrossref
Moreau  PH, Cosquer  B, Jeltsch  H, Cassel  JC, Mathis  C.  Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice.  Hippocampus. 2008;18(6):610-622.PubMedGoogle ScholarCrossref
Paul  S, Jeon  WK, Bizon  JL, Han  JS.  Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment.  Front Aging Neurosci. 2015;7:43.PubMedGoogle Scholar
Carroll  JC, Iba  M, Bangasser  DA,  et al.  Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy.  J Neurosci. 2011;31(40):14436-14449.PubMedGoogle ScholarCrossref
Resnick  SM, Pham  DL, Kraut  MA, Zonderman  AB, Davatzikos  C.  Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain.  J Neurosci. 2003;23(8):3295-3301.PubMedGoogle Scholar
Original Investigation
June 2016

Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults

Author Affiliations
  • 1Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indiana University Health Neuroscience Center, Indianapolis
  • 2Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis
  • 3Department of Neurology, Indiana University School of Medicine, Indianapolis
  • 4Department of Psychiatry, Indiana University School of Medicine, Indianapolis
  • 5Department of Biostatistics, Indiana University School of Medicine, Indianapolis
  • 6Indiana University Center for Aging Research, Indianapolis
  • 7Regenstrief Institute Inc, Indianapolis, Indiana
  • 8Eskenzai Health, Indianapolis, Indiana
  • 9Department of Internal Medicine, University of Washington, Seattle
  • 10Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 11Department of Radiology, Mayo Clinic, Rochester, Minnesota
  • 12Department of Neurology, University of California–Berkeley, Berkeley
  • 13Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego
  • 14Departments of Radiology, Medicine, and Psychiatry, University of California–San Francisco, San Francisco
  • 15Department of Veterans Affairs Medical Center, San Francisco, California
JAMA Neurol. 2016;73(6):721-732. doi:10.1001/jamaneurol.2016.0580

Importance  The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications.

Objective  To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS).

Design, Setting, and Participants  The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015.

Main Outcomes and Measures  Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression.

Results  The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale–Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC participants; P = .04) than the 350 AC participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC participants.

Conclusions and Relevance  The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.