{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:48:03Z","timestamp":1791859683640,"version":"4.3.4"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council","award":["MC_PC_17213"],"award-info":[{"award-number":["MC_PC_17213"]}]},{"name":"Medical Research Council","award":["MR\/W014386\/1"],"award-info":[{"award-number":["MR\/W014386\/1"]}]},{"name":"NIHR Applied Research Collaboration (ARC) East of England"},{"name":"UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre"},{"name":"Gnodde Goldman Sachs Giving to the University of Cambridge"}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dementia is the leading cause of death in elderly Western populations. Preventative interventions that could delay dementia onset even modestly would provide a major public health impact. There are no disease-modifying treatments currently available. Lithium has been proposed as a potential treatment. We assessed the association between lithium use and the incidence of dementia and its subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>We conducted a retrospective cohort study comparing patients treated between January 1, 2005 and December 31, 2019, using data from electronic clinical records of secondary care mental health (MH) services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), United Kingdom (catchment area population approximately 0.86 million). Eligible patients were those aged 50 years or over at baseline and who had at least 1 year follow-up, excluding patients with a diagnosis of mild cognitive impairment (MCI) or dementia before, or less than 1 year after, their start date. The intervention was the use of lithium. The main outcomes were dementia and its subtypes, diagnosed and classified according to the International Classification of Diseases-10th Revision (ICD-10).<\/jats:p>\n                    <jats:p>In this cohort, 29,618 patients (of whom 548 were exposed to lithium) were included. Their mean age was 73.9 years. A total of 40.2% were male, 33.3% were married or in a civil partnership, and 71.0% were of white ethnicity. Lithium-exposed patients were more likely to be married, cohabiting or in a civil partnership, to be a current\/former smoker, to have used antipsychotics, and to have comorbid depression, mania\/bipolar affective disorder (BPAD), hypertension, central vascular disease, diabetes mellitus, or hyperlipidemias. No significant difference between the 2 groups was observed for other characteristics, including age, sex, and alcohol-related disorders. In the exposed cohort, 53 (9.7%) patients were diagnosed with dementia, including 36 (6.8%) with Alzheimer disease (AD) and 13 (2.6%) with vascular dementia (VD). In the unexposed cohort, corresponding numbers were the following: dementia 3,244 (11.2%), AD 2,276 (8.1%), and VD 698 (2.6%). After controlling for sociodemographic factors, smoking status, other medications, other mental comorbidities, and physical comorbidities, lithium use was associated with a lower risk of dementia (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.40 to 0.78), including AD (HR 0.55, 95% CI 0.37 to 0.82) and VD (HR 0.36, 95% CI 0.19 to 0.69). Lithium appeared protective in short-term (\u22641-year exposure) and long-term lithium users (&gt;5-year exposure); a lack of difference for intermediate durations was likely due to lack of power, but there was some evidence for additional benefit with longer exposure durations. The main limitation was the handling of BPAD, the most common reason for lithium prescription but also a risk factor for dementia. This potential confounder would most likely cause an increase in dementia in the exposed group, whereas we found the opposite, and the sensitivity analysis confirmed the primary results. However, the specific nature of the group of patients exposed to lithium means that caution is needed in extending these findings to the general population. Another limitation is that our sample size of patients using lithium was small, reflected in the wide CIs for results relating to some durations of lithium exposure, although again sensitivity analyses remained consistent with our primary findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We observed an association between lithium use and a decreased risk of developing dementia. This lends further support to the idea that lithium may be a disease-modifying treatment for dementia and that this is a promising treatment to take forwards to larger randomised controlled trials (RCTs) for this indication.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1003941","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T13:33:26Z","timestamp":1647524006000},"page":"e1003941","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":78,"title":["Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4724-4892","authenticated-orcid":true,"given":"Shanquan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3427-9487","authenticated-orcid":true,"given":"Benjamin R.","family":"Underwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0387-880X","authenticated-orcid":true,"given":"Peter B.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1821-3824","authenticated-orcid":true,"given":"Jonathan R.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf N.","family":"Cardinal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"issue":"10248","key":"pmed.1003941.ref001","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0140-6736(20)30367-6","article-title":"Dementia prevention, intervention, and care: 2020 report of the Lancet Commission","volume":"396","author":"G Livingston","year":"2020","journal-title":"Lancet"},{"issue":"1","key":"pmed.1003941.ref002","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1515\/fhep-2014-0013","article-title":"The Value of Delaying Alzheimer\u2019s Disease Onset.","volume":"18","author":"J Zissimopoulos","year":"2014","journal-title":"Forum Health Econ Policy"},{"issue":"3","key":"pmed.1003941.ref003","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3233\/JAD-190197","article-title":"Lithium as a Treatment for Alzheimer\u2019s Disease: The Systems Pharmacology Perspective","volume":"69","author":"H Hampel","year":"2019","journal-title":"J Alzheimers Dis"},{"issue":"1\u20133","key":"pmed.1003941.ref004","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00213-008-1311-8","article-title":"Lithium and cognitive enhancement: leave it or take it","volume":"202","author":"E Tsaltas","year":"2009","journal-title":"Psychopharmacology (Berl)."},{"issue":"5","key":"pmed.1003941.ref005","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2165\/11599180-000000000-00000","article-title":"Does lithium prevent Alzheimer\u2019s disease?","volume":"29","author":"OV Forlenza","year":"2012","journal-title":"Drugs Aging"},{"issue":"3","key":"pmed.1003941.ref006","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/bdi.12260","article-title":"Longer lithium exposure is associated with better white matter integrity in older adults with bipolar disorder","volume":"17","author":"AG Gildengers","year":"2015","journal-title":"Bipolar Disord."},{"issue":"8","key":"pmed.1003941.ref007","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1038\/npp.2010.41","article-title":"Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study","volume":"35","author":"IK Lyoo","year":"2010","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"pmed.1003941.ref008","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41398-021-01492-7","article-title":"Translational evidence for lithium-induced brain plasticity and neuroprotection in the treatment of neuropsychiatric disorders","volume":"11","author":"S Puglisi-Allegra","year":"2021","journal-title":"Transl Psychiatry"},{"issue":"2","key":"pmed.1003941.ref009","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1192\/bjp.199.2.166","article-title":"Understanding the neuroprotective mechanisms of lithium may have clinical significance","volume":"199","author":"BR Underwood","year":"2011","journal-title":"Br J Psychiatry"},{"issue":"2","key":"pmed.1003941.ref010","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3233\/JAD-150437","article-title":"Lithium as a Treatment for Alzheimer\u2019s Disease: A Systematic Review and Meta-Analysis","volume":"48","author":"S Matsunaga","year":"2015","journal-title":"J Alzheimers Dis"},{"issue":"6","key":"pmed.1003941.ref011","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1111\/acps.13153","article-title":"Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses","volume":"141","author":"J Velosa","year":"2020","journal-title":"Acta Psychiatr Scand"},{"issue":"5","key":"pmed.1003941.ref012","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1192\/bjp.2019.76","article-title":"Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial","volume":"215","author":"OV Forlenza","year":"2019","journal-title":"Br J Psychiatry"},{"issue":"1","key":"pmed.1003941.ref013","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/01.wad.0000155068.23937.9b","article-title":"Does lithium therapy protect against the onset of dementia?","volume":"19","author":"N Dunn","year":"2005","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"2","key":"pmed.1003941.ref014","doi-asserted-by":"crossref","first-page":"e139","DOI":"10.4088\/JCP.15m10304","article-title":"Association Between Lithium Use and Risk of Alzheimer\u2019s Disease","volume":"78","author":"C Cheng","year":"2017","journal-title":"J Clin Psychiatry"},{"key":"pmed.1003941.ref015","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1192\/bjp.bp.106.029868","article-title":"Lithium and risk for Alzheimer\u2019s disease in elderly patients with bipolar disorder.","volume":"190","author":"PV Nunes","year":"2007","journal-title":"Br J Psychiatry"},{"issue":"1","key":"pmed.1003941.ref016","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1192\/bjp.bp.114.154047","article-title":"Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study","volume":"207","author":"T Gerhard","year":"2015","journal-title":"Br J Psychiatry"},{"issue":"10","key":"pmed.1003941.ref017","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1001\/jamapsychiatry.2017.2362","article-title":"Association of Lithium in Drinking Water With the Incidence of Dementia","volume":"74","author":"LV Kessing","year":"2017","journal-title":"JAMA Psychiat"},{"issue":"11","key":"pmed.1003941.ref018","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1001\/archpsyc.65.11.1331","article-title":"Lithium treatment and risk of dementia","volume":"65","author":"LV Kessing","year":"2008","journal-title":"Arch Gen Psychiatry"},{"issue":"1","key":"pmed.1003941.ref019","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1399-5618.2009.00788.x","article-title":"Does lithium protect against dementia?","volume":"12","author":"LV Kessing","year":"2010","journal-title":"Bipolar Disord"},{"issue":"6","key":"pmed.1003941.ref020","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nrneurol.2011.60","article-title":"Depression and risk of developing dementia","volume":"7","author":"AL Byers","year":"2011","journal-title":"Nat Rev Neurol"},{"issue":"1","key":"pmed.1003941.ref021","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s12911-017-0437-1","article-title":"Clinical records anonymisation and text extraction (CRATE): an open-source software system","volume":"17","author":"RN Cardinal","year":"2017","journal-title":"BMC Med Inform Decis Mak"},{"issue":"11","key":"pmed.1003941.ref022","doi-asserted-by":"crossref","first-page":"e017504","DOI":"10.1136\/bmjopen-2017-017504","article-title":"Mortality in dementia with Lewy bodies compared with Alzheimer\u2019s dementia: a retrospective naturalistic cohort study","volume":"7","author":"A Price","year":"2017","journal-title":"BMJ Open"},{"issue":"12","key":"pmed.1003941.ref023","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1002\/gps.4101","article-title":"Associations between risk of mortality and atypical antipsychotic use in vascular dementia: a clinical cohort study","volume":"29","author":"J Sultana","year":"2014","journal-title":"Int J Geriatr Psychiatry"},{"key":"pmed.1003941.ref024","volume-title":"Inverse Probability Censoring Weights for Routine Outcome Monitoring Data","author":"SJ Willems","year":"2014"},{"issue":"12","key":"pmed.1003941.ref025","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1089\/aid.2014.0037","article-title":"Women\u2019s Interagency HIVS. Worth the weight: using inverse probability weighted Cox models in AIDS research","volume":"30","author":"AL Buchanan","year":"2014","journal-title":"AIDS Res Hum Retroviruses"},{"issue":"3","key":"pmed.1003941.ref026","first-page":"1","article-title":"mice: Multivariate Imputation by Chained Equations in R.","volume":"45","author":"S van Buuren","year":"2011","journal-title":"J Stat Softw"},{"key":"pmed.1003941.ref027","volume-title":"Lithium. StatPearls.","author":"K Chokhawala","year":"2021"},{"issue":"446","key":"pmed.1003941.ref028","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A Proportional Hazards Model for the Subdistribution of a Competing Risk","volume":"94","author":"JP Fine","year":"1999","journal-title":"J Am Stat Assoc"},{"key":"pmed.1003941.ref029","unstructured":"STROBE. STROBE checklist for cohort studies 2007 [cited 2020 07\/30]. Available from: https:\/\/www.strobe-statement.org\/fileadmin\/Strobe\/uploads\/checklists\/STROBE_checklist_v4_cohort.pdf."},{"issue":"6","key":"pmed.1003941.ref030","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.mehy.2008.03.049","article-title":"Lithium may be useful in the prevention of Alzheimer\u2019s disease in individuals at risk of presenile familial Alzheimer\u2019s disease","volume":"71","author":"HL Yeh","year":"2008","journal-title":"Med Hypotheses"},{"issue":"1","key":"pmed.1003941.ref031","doi-asserted-by":"crossref","DOI":"10.1136\/bcr-2018-227741","article-title":"Lithium neurotoxicity presenting as dementia with therapeutic serum lithium levels","volume":"12","author":"S. Soni","year":"2019","journal-title":"BMJ Case Rep"},{"issue":"1","key":"pmed.1003941.ref032","doi-asserted-by":"crossref","first-page":"e55471","DOI":"10.1371\/journal.pone.0055471","article-title":"Lithium chloride inhibits vascular smooth muscle cell proliferation and migration and alleviates injury-induced neointimal hyperplasia via induction of PGC-1alpha","volume":"8","author":"Z Wang","year":"2013","journal-title":"PLoS ONE"},{"issue":"5\u20136","key":"pmed.1003941.ref033","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.vph.2010.09.004","article-title":"Atherosclerosis induced by a high-fat diet is alleviated by lithium chloride via reduction of VCAM expression in ApoE-deficient mice.","volume":"53","author":"SE Choi","year":"2010","journal-title":"Vascul Pharmacol"},{"issue":"6","key":"pmed.1003941.ref034","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1111\/j.1476-5381.2010.01152.x","article-title":"Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques","volume":"162","author":"I De Meyer","year":"2011","journal-title":"Br J Pharmacol"},{"issue":"1","key":"pmed.1003941.ref035","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00213-009-1510-y","article-title":"Lithium treatment in Alzheimer\u2019s disease does not promote cognitive enhancement, but may exert long-term neuroprotective effects","volume":"205","author":"N. Pomara","year":"2009","journal-title":"Psychopharmacology"},{"issue":"5","key":"pmed.1003941.ref036","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1192\/bjp.bp.110.080044","article-title":"Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial","volume":"198","author":"OV Forlenza","year":"2011","journal-title":"Br J Psychiatry"},{"issue":"3","key":"pmed.1003941.ref037","doi-asserted-by":"crossref","first-page":"649","DOI":"10.3233\/JAD-2009-1004","article-title":"Increase of BDNF serum concentration in lithium treated patients with early Alzheimer\u2019s disease","volume":"16","author":"T Leyhe","year":"2009","journal-title":"J Alzheimers Dis"},{"issue":"6","key":"pmed.1003941.ref038","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.pnpbp.2006.04.020","article-title":"Lithium and dementia: a preliminary study","volume":"30","author":"T Terao","year":"2006","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"pmed.1003941.ref039","unstructured":"Public Health England. Dementia Profile 2020 [cited 2020 11\/08]. Available from: https:\/\/fingertips.phe.org.uk\/profile-group\/mental-health\/profile\/dementia."},{"key":"pmed.1003941.ref040","volume-title":"A guide to treatments that work","author":"PE Nathan","year":"2015"}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003941","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T13:34:12Z","timestamp":1647524052000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003941"}},"subtitle":[],"editor":[{"given":"Vikram","family":"Patel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,3,17]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1003941","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.741845661.793592210","asserted-by":"object"}]},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,17]]}}}