{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:01:51Z","timestamp":1790373711461,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000143","name":"UK Alzheimer\u2019s Society","doi-asserted-by":"publisher","award":["AS-PG-2013-017"],"award-info":[{"award-number":["AS-PG-2013-017"]}],"id":[{"id":"10.13039\/501100000143","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom\u2019s Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4\u201320 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence.<\/jats:p>","DOI":"10.1093\/aje\/kwz073","type":"journal-article","created":{"date-parts":[[2019,3,21]],"date-time":"2019-03-21T08:32:03Z","timestamp":1553157123000},"page":"1228-1236","source":"Crossref","is-referenced-by-count":37,"title":["History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study"],"prefix":"10.1093","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0741-8413","authenticated-orcid":false,"given":"Kathryn","family":"Richardson","sequence":"first","affiliation":[{"name":"School of Health Sciences, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Mattishent","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon K","family":"Loke","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Steel","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Fox","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlota M","family":"Grossi","sequence":"additional","affiliation":[{"name":"School of Health Sciences, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Bennett","sequence":"additional","affiliation":[{"name":"Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4152-9704","authenticated-orcid":false,"given":"Ian","family":"Maidment","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Aston University, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malaz","family":"Boustani","sequence":"additional","affiliation":[{"name":"School of Medicine, Indiana University, Indianapolis, Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona E","family":"Matthews","sequence":"additional","affiliation":[{"name":"Institute of Health and Society\/Institute for Ageing, Newcastle University, Newcastle, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyo K","family":"Myint","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noll L","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, Purdue University, Lafayette, Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Brayne","sequence":"additional","affiliation":[{"name":"Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Robinson","sequence":"additional","affiliation":[{"name":"Institute of Health and Society\/Institute for Ageing, Newcastle University, Newcastle, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George M","family":"Savva","sequence":"additional","affiliation":[{"name":"School of Health Sciences, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,27]]},"reference":[{"issue":"3","key":"2019070110025569800_kwz073C1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.jalz.2015.02.003","article-title":"2015 Alzheimer\u2019s disease facts and figures","volume":"11","author":"Alzheimer\u2019s Association","year":"2015","journal-title":"Alzheimers Dement"},{"issue":"1","key":"2019070110025569800_kwz073C2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1474-4422(18)30403-4","article-title":"Global, regional, and national burden of Alzheimer\u2019s disease and other dementias, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"GBD 2016 Dementia Collaborators","year":"2019","journal-title":"Lancet Neurol"},{"issue":"10113","key":"2019070110025569800_kwz073C3","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1016\/S0140-6736(17)31363-6","article-title":"Dementia prevention, intervention, and care","volume":"390","author":"Livingston","year":"2017","journal-title":"Lancet"},{"issue":"6","key":"2019070110025569800_kwz073C4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s40263-018-0535-3","article-title":"A systematic review and meta-analysis of the risk of dementia associated with benzodiazepine use, after controlling for protopathic bias","volume":"32","author":"Penninkilampi","year":"2018","journal-title":"CNS Drugs"},{"issue":"4","key":"2019070110025569800_kwz073C5","doi-asserted-by":"crossref","first-page":"686","DOI":"10.2105\/AJPH.2016.303061","article-title":"Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996\u20132013","volume":"106","author":"Bachhuber","year":"2016","journal-title":"Am J Public Health"},{"issue":"4","key":"2019070110025569800_kwz073C6","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.jamda.2014.10.010","article-title":"Sedative load and frailty among community-dwelling population aged \u226565 years","volume":"16","author":"Peklar","year":"2015","journal-title":"J Am Med Dir Assoc"},{"issue":"11","key":"2019070110025569800_kwz073C7","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1111\/jgs.13702","article-title":"American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults","volume":"63","author":"American Geriatrics Society 2015 Beers Criteria Update Expert Panel","year":"2015","journal-title":"J Am Geriatr Soc"},{"issue":"10","key":"2019070110025569800_kwz073C8","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1111\/jgs.13666","article-title":"Benzodiazepine prescribing in older adults in U.S. ambulatory clinics and emergency departments (2001\u201310)","volume":"63","author":"Marra","year":"2015","journal-title":"J Am Geriatr Soc"},{"issue":"2","key":"2019070110025569800_kwz073C9","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1055\/s-0044-100523","article-title":"Prescription of benzodiazepines and related drugs in patients with mild cognitive deficits and Alzheimer\u2019s disease","volume":"52","author":"Hessmann","year":"2019","journal-title":"Pharmacopsychiatry"},{"issue":"7","key":"2019070110025569800_kwz073C10","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1017\/S1041610217002447","article-title":"A cross-sectional examination of the prevalence of psychotropic medications for people living with dementia in Australian long-term care facilities: issues of concern","volume":"30","author":"McMaster","year":"2018","journal-title":"Int Psychogeriatr"},{"key":"2019070110025569800_kwz073C11","author":"Cartagena Farias","year":"2017"},{"issue":"8","key":"2019070110025569800_kwz073C12","first-page":"639","article-title":"A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs","volume":"29","author":"Tannenbaum","year":"2012","journal-title":"Drugs Aging"},{"issue":"7","key":"2019070110025569800_kwz073C13","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1093\/arclin\/acx120","article-title":"The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis","volume":"33","author":"Crowe","year":"2018","journal-title":"Arch Clin Neuropsychol"},{"key":"2019070110025569800_kwz073C14","doi-asserted-by":"crossref","first-page":"e6231","DOI":"10.1136\/bmj.e6231","article-title":"Benzodiazepine use and risk of dementia: prospective population based study","volume":"345","author":"Billioti de Gage","year":"2012","journal-title":"BMJ"},{"key":"2019070110025569800_kwz073C15","doi-asserted-by":"crossref","first-page":"g5205","DOI":"10.1136\/bmj.g5205","article-title":"Benzodiazepine use and risk of Alzheimer\u2019s disease: case-control study","volume":"349","author":"Billioti de Gage","year":"2014","journal-title":"BMJ"},{"issue":"7","key":"2019070110025569800_kwz073C16","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1097\/JGP.0b013e3181a65210","article-title":"The association between dementia and long-term use of benzodiazepine in the elderly: nested case-control study using claims data","volume":"17","author":"Wu","year":"2009","journal-title":"Am J Geriatr Psychiatry"},{"key":"2019070110025569800_kwz073C17","doi-asserted-by":"crossref","first-page":"i90","DOI":"10.1136\/bmj.i90","article-title":"Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study","volume":"352","author":"Gray","year":"2016","journal-title":"BMJ"},{"issue":"10","key":"2019070110025569800_kwz073C18","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s40264-015-0319-3","article-title":"Benzodiazepine use and risk of developing Alzheimer\u2019s disease or vascular dementia: a case-control analysis","volume":"38","author":"Imfeld","year":"2015","journal-title":"Drug Saf"},{"issue":"3","key":"2019070110025569800_kwz073C19","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/pds.1360","article-title":"Application of lag-time into exposure definitions to control for protopathic bias","volume":"16","author":"Tamim","year":"2007","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2019070110025569800_kwz073C20","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jclinepi.2016.04.014","article-title":"Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses","volume":"79","author":"Hernan","year":"2016","journal-title":"J Clin Epidemiol"},{"issue":"9","key":"2019070110025569800_kwz073C21","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1093\/aje\/kwg231","article-title":"Evaluating medication effects outside of clinical trials: new-user designs","volume":"158","author":"Ray","year":"2003","journal-title":"Am J Epidemiol"},{"issue":"10","key":"2019070110025569800_kwz073C22","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1093\/aje\/kwv225","article-title":"Point: incident exposures, prevalent exposures, and causal inference: does limiting studies to persons who are followed from first exposure onward damage epidemiology?","volume":"182","author":"Vandenbroucke","year":"2015","journal-title":"Am J Epidemiol"},{"issue":"2","key":"2019070110025569800_kwz073C23","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1093\/aje\/155.2.176","article-title":"Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology","volume":"155","author":"Hern\u00e1n","year":"2002","journal-title":"Am J Epidemiol"},{"issue":"4","key":"2019070110025569800_kwz073C24","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1023\/A:1026595011371","article-title":"Equivalence of the mediation, confounding and suppression effect","volume":"1","author":"MacKinnon","year":"2000","journal-title":"Prev Sci"},{"issue":"10","key":"2019070110025569800_kwz073C25","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1007\/s10654-015-0069-7","article-title":"From bad to worse: collider stratification amplifies confounding bias in the \u201cobesity paradox.\u201d","volume":"30","author":"Banack","year":"2015","journal-title":"Eur J Epidemiol"},{"issue":"4","key":"2019070110025569800_kwz073C26","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1097\/EDE.0b013e3181a819a1","article-title":"Overadjustment bias and unnecessary adjustment in epidemiologic studies","volume":"20","author":"Schisterman","year":"2009","journal-title":"Epidemiology"},{"key":"2019070110025569800_kwz073C27","doi-asserted-by":"crossref","first-page":"k1315","DOI":"10.1136\/bmj.k1315","article-title":"Anticholinergic drugs and risk of dementia: case-control study","volume":"361","author":"Richardson","year":"2018","journal-title":"BMJ"},{"issue":"5","key":"2019070110025569800_kwz073C28","doi-asserted-by":"crossref","first-page":"e0125620","DOI":"10.1371\/journal.pone.0125620","article-title":"The REporting of studies Conducted using Observational Routinely-collected health data (RECORD) statement: methods for arriving at consensus and developing reporting guidelines","volume":"10","author":"Nicholls","year":"2015","journal-title":"PLoS One"},{"issue":"3","key":"2019070110025569800_kwz073C29","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1093\/ije\/dyv098","article-title":"Data resource profile: Clinical Practice Research Datalink (CPRD)","volume":"44","author":"Herrett","year":"2015","journal-title":"Int J Epidemiol"},{"key":"2019070110025569800_kwz073C30","author":"Ministry of Housing, Communities & Local Government","year":"2015"},{"issue":"3","key":"2019070110025569800_kwz073C31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.5770\/cgj.15.42","article-title":"A review of barriers and enablers to diagnosis and management of persons with dementia in primary care","volume":"15","author":"Aminzadeh","year":"2012","journal-title":"Can Geriatr J"},{"issue":"1","key":"2019070110025569800_kwz073C32","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2012-002080","article-title":"Trends in the prevalence of antipsychotic drug use among patients with Alzheimer\u2019s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study","volume":"3","author":"Martinez","year":"2013","journal-title":"BMJ Open"},{"issue":"6","key":"2019070110025569800_kwz073C33","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jalz.2015.05.016","article-title":"Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective","volume":"11","author":"Baumgart","year":"2015","journal-title":"Alzheimers Dement"},{"issue":"11","key":"2019070110025569800_kwz073C34","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1002\/pds.4028","article-title":"The association between benzodiazepines and influenza-like illness-related pneumonia and mortality: a survival analysis using UK Primary Care data","volume":"25","author":"Nakafero","year":"2016","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2019070110025569800_kwz073C35","doi-asserted-by":"crossref","first-page":"j2941","DOI":"10.1136\/bmj.j2941","article-title":"Benzodiazepines and risk of all cause mortality in adults: cohort study","volume":"358","author":"Patorno","year":"2017","journal-title":"BMJ"},{"issue":"7","key":"2019070110025569800_kwz073C36","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1093\/aje\/kwn391","article-title":"Different methods of balancing covariates leading to different effect estimates in the presence of effect modification","volume":"169","author":"Lunt","year":"2009","journal-title":"Am J Epidemiol"},{"issue":"4","key":"2019070110025569800_kwz073C37","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/sim.4067","article-title":"Multiple imputation using chained equations: Issues and guidance for practice","volume":"30","author":"White","year":"2011","journal-title":"Stat Med"},{"issue":"3","key":"2019070110025569800_kwz073C38","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s40263-016-0404-x","article-title":"Benzodiazepine use and risk of developing Alzheimer\u2019s disease: a case-control study based on Swiss claims data","volume":"31","author":"Bietry","year":"2017","journal-title":"CNS Drugs"},{"issue":"5","key":"2019070110025569800_kwz073C39","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.jalz.2015.10.006","article-title":"Benzodiazepine, psychotropic medication, and dementia: a population-based cohort study","volume":"12","author":"Shash","year":"2016","journal-title":"Alzheimers Dement"},{"issue":"6","key":"2019070110025569800_kwz073C40","first-page":"1866","article-title":"Triangulation in aetiological epidemiology","volume":"45","author":"Lawlor","year":"2016","journal-title":"Int J Epidemiol"}],"container-title":["American Journal of Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/aje\/advance-article-pdf\/doi\/10.1093\/aje\/kwz073\/28679081\/kwz073.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/aje\/article-pdf\/188\/7\/1228\/28890386\/kwz073.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T08:27:07Z","timestamp":1569313627000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/aje\/article\/188\/7\/1228\/5421030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,27]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,3,27]]},"published-print":{"date-parts":[[2019,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/aje\/kwz073","relation":{},"ISSN":["0002-9262","1476-6256"],"issn-type":[{"value":"0002-9262","type":"print"},{"value":"1476-6256","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,7]]},"published":{"date-parts":[[2019,3,27]]}}}