{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T11:32:34Z","timestamp":1776511954696,"version":"3.51.2"},"reference-count":69,"publisher":"BMJ","issue":"7","funder":[{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A1515011546"],"award-info":[{"award-number":["2022A1515011546"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103930"],"award-info":[{"award-number":["82103930"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82373661"],"award-info":[{"award-number":["82373661"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Epidemiol Community Health"],"accepted":{"date-parts":[[2024,3,9]]},"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Circulating antioxidants are associated with a lower risk of Alzheimer\u2019s disease (AD) in observational studies, suggesting potential target areas for intervention. However, whether the associations are causal remains unclear. Here, we studied the causality between antioxidants and AD or cognitive function using two-sample Mendelian randomisation (MR).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Single nucleotide polymorphisms strongly (p&lt;5\u00d710<jats:sup>\u22128<\/jats:sup>) associated with antioxidants (vitamin A, vitamin C, zinc, selenium, \u03b2-carotene and urate) and outcomes (AD, cognitive performance and reaction time) were obtained from the largest and most recent genome-wide association studies (GWAS). MR inverse variance weighting (IVW) and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used for data analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Higher genetically determined selenium level was associated with 5% higher risk of AD (OR 1.047, 95% CI 1.005 to 1.091, p=0.028) using IVW. Higher genetically determined urate level was associated with worse cognitive performance (\u03b2=\u22120.026, 95%\u2009CI \u22120.044 to \u22120.008, p=0.005) using MR-PRESSO. No association between the other antioxidants and AD, cognitive performance and reaction time was found. Similar results were found in the sensitivity analyses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our results suggest that lifelong exposure to higher selenium may be associated with a higher risk of AD, and higher urate levels could be associated with worse cognitive performance. Further analyses using larger GWAS of antioxidants are warranted to confirm these observations. Our results suggest that caution is needed in the interpretation of traditional observational evidence on the neuroprotective effects of antioxidants.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jech-2023-221184","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T13:25:38Z","timestamp":1712582738000},"page":"424-430","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Causal associations of antioxidants with Alzheimer\u2019s disease and cognitive function: a Mendelian randomisation study"],"prefix":"10.1136","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7883-0341","authenticated-orcid":false,"given":"Jiao","family":"Wang","sequence":"first","affiliation":[{"name":"School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyue","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhua","family":"Bei","sequence":"additional","affiliation":[{"name":"School of Public Health, Guilin Medical University, Guilin, Guangxi, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiling","family":"Yang","sequence":"additional","affiliation":[{"name":"Eastern-fusion Master Studio of Hezhou, Hezhou, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihong","family":"Lin","sequence":"additional","affiliation":[{"name":"Hezhou Research Institute of Longevity Health Science, Hezhou, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0537-922X","authenticated-orcid":false,"given":"Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China"},{"name":"School of Public Health, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"2025100301541276000_78.7.424.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"2025100301541276000_78.7.424.2","unstructured":"Alzheimer\u2019s Disease International . World Alzheimer Report 2019: Attitudes to Dementia. London: Alzheimer\u2019s Disease International, 2019."},{"key":"2025100301541276000_78.7.424.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2016.07.005"},{"key":"2025100301541276000_78.7.424.4","doi-asserted-by":"crossref","DOI":"10.1098\/rsob.200084","article-title":"Role of antioxidants and a nutrient rich diet in Alzheimer\u2019s disease","volume":"10","author":"Veurink","year":"2020","journal-title":"Open Biol"},{"key":"2025100301541276000_78.7.424.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.05.1771"},{"key":"2025100301541276000_78.7.424.6","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jtemb.2017.04.005","article-title":"A systematic review and meta-analysis of the circulatory, Erythrocellular and CSF selenium levels in Alzheimer\u2019s disease: A metal meta-analysis (AMMA study-I)","volume":"42","author":"Reddy","year":"2017","journal-title":"J Trace Elem Med Biol"},{"key":"2025100301541276000_78.7.424.7","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3233\/JAD-170758","article-title":"Plasma antioxidant status in patients with Alzheimer\u2019s disease and cognitively intact elderly: A meta-analysis of case-control studies","volume":"62","author":"Mullan","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2025100301541276000_78.7.424.8","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-013-0541-7"},{"key":"2025100301541276000_78.7.424.9","doi-asserted-by":"crossref","unstructured":"Jim\u00e9nez-Jim\u00e9nez FJ , Alonso-Navarro H , Garc\u00eda-Mart\u00edn E , et al . n.d. Coenzyme Q10 and dementia: A systematic review. Antioxidants 12:533. doi:10.3390\/antiox12020533","DOI":"10.3390\/antiox12020533"},{"key":"2025100301541276000_78.7.424.10","article-title":"Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment","volume":"11","author":"McCleery","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"2025100301541276000_78.7.424.11","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1590\/1980-57642020dn14-030008","article-title":"Dietary interventions and cognition of Alzheimer\u2019s disease patients: a systematic review of randomized controlled trial","volume":"14","author":"Moreira","year":"2020","journal-title":"Dement Neuropsychol"},{"key":"2025100301541276000_78.7.424.12","article-title":"Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life","volume":"12","author":"Rutjes","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"2025100301541276000_78.7.424.13","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3002609","article-title":"Testing the right target and right drug at the right stage","volume":"3","author":"Sperling","year":"2011","journal-title":"Sci Transl Med"},{"key":"2025100301541276000_78.7.424.14","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3034"},{"key":"2025100301541276000_78.7.424.15","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1093\/ajcn\/nqy225","article-title":"Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study","volume":"109","author":"Williams","year":"2019","journal-title":"Am J Clin Nutr"},{"key":"2025100301541276000_78.7.424.16","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41588-020-00776-w","article-title":"Genome-wide meta-analysis, fine-mapping and integrative Prioritization implicate new Alzheimer\u2019s disease risk genes","volume":"53","author":"Schwartzentruber","year":"2021","journal-title":"Nat Genet"},{"key":"2025100301541276000_78.7.424.17","doi-asserted-by":"publisher","DOI":"10.1037\/a0029857"},{"key":"2025100301541276000_78.7.424.18","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.119.012738","article-title":"Genetically determined uric acid and the risk of cardiovascular and neurovascular diseases: A Mendelian randomization study of outcomes investigated in randomized trials","volume":"8","author":"Efstathiadou","year":"2019","journal-title":"J Am Heart Assoc"},{"key":"2025100301541276000_78.7.424.19","doi-asserted-by":"crossref","DOI":"10.3390\/antiox10091439","article-title":"Chronic stress and oxidative stress as common factors of the pathogenesis of depression and Alzheimer\u2019s disease: the role of antioxidants in prevention and treatment","volume":"10","author":"Juszczyk","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"2025100301541276000_78.7.424.20","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr296"},{"key":"2025100301541276000_78.7.424.21","doi-asserted-by":"crossref","DOI":"10.1093\/hmg\/ddw134","article-title":"Genome-wide Association study of serum coenzyme Q10 levels identifies susceptibility Loci linked to neuronal diseases","volume":"25","author":"Degenhardt","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2025100301541276000_78.7.424.22","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr387"},{"key":"2025100301541276000_78.7.424.23","doi-asserted-by":"publisher","DOI":"10.2337\/dc20-1328"},{"key":"2025100301541276000_78.7.424.24","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt239"},{"key":"2025100301541276000_78.7.424.25","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu546"},{"key":"2025100301541276000_78.7.424.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.12.019"},{"key":"2025100301541276000_78.7.424.27","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2500"},{"key":"2025100301541276000_78.7.424.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0147-3"},{"key":"2025100301541276000_78.7.424.29","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-04362-x","article-title":"Study of 300,486 individuals identifies 148 independent genetic Loci influencing general cognitive function","volume":"9","author":"Davies","year":"2018","journal-title":"Nat Commun"},{"key":"2025100301541276000_78.7.424.30","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new Loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat Genet"},{"key":"2025100301541276000_78.7.424.31","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2020.610852","article-title":"Use of multivariable Mendelian randomization to address biases due to competing risk before recruitment","volume":"11","author":"Schooling","year":"2020","journal-title":"Front Genet"},{"key":"2025100301541276000_78.7.424.32","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1007\/s10654-023-01015-2","article-title":"The influence of growth and sex hormones on risk of Alzheimer\u2019s disease: a Mendelian randomization study","volume":"38","author":"Yeung","year":"2023","journal-title":"Eur J Epidemiol"},{"key":"2025100301541276000_78.7.424.33","unstructured":"Pan-UKB team . Pan-ancestry genetic analysis of the UK Biobank, 2020. Available: https:\/\/pan.ukbb.broadinstitute.org"},{"key":"2025100301541276000_78.7.424.34","doi-asserted-by":"publisher","DOI":"10.1093\/IJE\/DYW220"},{"key":"2025100301541276000_78.7.424.35","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyq151"},{"key":"2025100301541276000_78.7.424.36","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1038\/s41416-020-01236-2","article-title":"Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian Randomisation study","volume":"124","author":"Zhang","year":"2021","journal-title":"Br J Cancer"},{"key":"2025100301541276000_78.7.424.37","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.j5375","article-title":"Modifiable pathways in Alzheimer\u2019s disease: Mendelian Randomisation analysis","volume":"359","author":"Larsson","year":"2017","journal-title":"BMJ"},{"key":"2025100301541276000_78.7.424.38","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s00125-023-05914-7","article-title":"Investigating causality in the association between DNA methylation and type 2 diabetes using Bidirectional two-sample Mendelian Randomisation","volume":"66","author":"Juvinao-Quintero","year":"2023","journal-title":"Diabetologia"},{"key":"2025100301541276000_78.7.424.39","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21965"},{"key":"2025100301541276000_78.7.424.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2014.09.005"},{"key":"2025100301541276000_78.7.424.41","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6522"},{"key":"2025100301541276000_78.7.424.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0099-7"},{"key":"2025100301541276000_78.7.424.43","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw373"},{"key":"2025100301541276000_78.7.424.44","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-018-0662-z"},{"key":"2025100301541276000_78.7.424.45","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1016\/j.clnu.2018.11.034","article-title":"Probiotic and selenium Co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer\u2019s disease: A randomized, double-blind, controlled trial","volume":"38","author":"Tamtaji","year":"2019","journal-title":"Clin Nutr"},{"key":"2025100301541276000_78.7.424.46","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1001\/jamaneurol.2016.5778","article-title":"Association of antioxidant supplement use and dementia in the prevention of Alzheimer\u2019s disease by vitamin E and selenium trial (Preadvise)","volume":"74","author":"Kryscio","year":"2017","journal-title":"JAMA Neurol"},{"key":"2025100301541276000_78.7.424.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2008.02.003"},{"key":"2025100301541276000_78.7.424.48","doi-asserted-by":"crossref","DOI":"10.3390\/nu14153205","article-title":"Effects of selenium supplementation in patients with mild cognitive impairment or Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"14","author":"Pereira","year":"2022","journal-title":"Nutrients"},{"key":"2025100301541276000_78.7.424.49","doi-asserted-by":"crossref","first-page":"126684","DOI":"10.1016\/j.jtemb.2020.126684","article-title":"Arsenic and selenium measurements in nail and hair show important relationships to Alzheimer\u2019s disease in the elderly","volume":"64","author":"Koseoglu","year":"2021","journal-title":"J Trace Elem Med Biol"},{"key":"2025100301541276000_78.7.424.50","doi-asserted-by":"crossref","DOI":"10.1186\/s13195-017-0323-1","article-title":"A selenium species in cerebrospinal fluid predicts conversion to Alzheimer\u2019s dementia in persons with mild cognitive impairment","volume":"9","author":"Vinceti","year":"2017","journal-title":"Alzheimers Res Ther"},{"key":"2025100301541276000_78.7.424.51","doi-asserted-by":"crossref","DOI":"10.3390\/ijerph17217941","article-title":"Environmental risk factors for early-onset Alzheimer\u2019s dementia and Frontotemporal dementia: A case-control study in northern Italy","volume":"17","author":"Adani","year":"2020","journal-title":"Int J Environ Res Public Health"},{"key":"2025100301541276000_78.7.424.52","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s12011-018-1492-x","article-title":"Brain selenium in Alzheimer\u2019s disease (BRAIN SEAD study): a systematic review and meta-analysis","volume":"189","author":"Varikasuvu","year":"2019","journal-title":"Biol Trace Elem Res"},{"key":"2025100301541276000_78.7.424.53","doi-asserted-by":"publisher","DOI":"10.1097\/01.ede.0000248202.83695.4e"},{"key":"2025100301541276000_78.7.424.54","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1017\/S0029665118002501","article-title":"Relationship between nutritional status and the systemic inflammatory response: Micronutrients","volume":"78","author":"McMillan","year":"2019","journal-title":"Proc Nutr Soc"},{"key":"2025100301541276000_78.7.424.55","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.toxlet.2013.11.016","article-title":"Selenium neurotoxicity in humans: bridging laboratory and epidemiologic studies","volume":"230","author":"Vinceti","year":"2014","journal-title":"Toxicol Lett"},{"key":"2025100301541276000_78.7.424.56","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61452-9"},{"key":"2025100301541276000_78.7.424.57","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neurobiolaging.2020.02.018","article-title":"Impact of Modifiable risk factors on Alzheimer\u2019s disease: A two-sample Mendelian randomization study","volume":"91","author":"Wang","year":"2020","journal-title":"Neurobiol Aging"},{"key":"2025100301541276000_78.7.424.58","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3233\/JAD-180538","article-title":"Genetically determined serum uric acid and Alzheimer\u2019s disease risk","volume":"65","author":"Yuan","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2025100301541276000_78.7.424.59","doi-asserted-by":"publisher","DOI":"10.1159\/000346606"},{"key":"2025100301541276000_78.7.424.60","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1480-16.2016"},{"key":"2025100301541276000_78.7.424.61","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1002\/jcp.25509","article-title":"Uric acid Amplifies Abeta Amyloid effects involved in the cognitive dysfunction\/dementia: evidences from an experimental model in vitro","volume":"232","author":"Desideri","year":"2017","journal-title":"J Cell Physiol"},{"key":"2025100301541276000_78.7.424.62","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42344"},{"key":"2025100301541276000_78.7.424.63","doi-asserted-by":"crossref","DOI":"10.3390\/nu11020378","article-title":"Mineral nutrition and the risk of chronic diseases: A Mendelian randomization study","volume":"11","author":"Cheng","year":"2019","journal-title":"Nutrients"},{"key":"2025100301541276000_78.7.424.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2021.08.020"},{"key":"2025100301541276000_78.7.424.65","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21998"},{"key":"2025100301541276000_78.7.424.66","doi-asserted-by":"crossref","unstructured":"Taylor AE , Burgess S , Ware JJ , et al . Investigating causality in the association between 25(OH)D and schizophrenia. Sci Rep 2016;6. doi:10.1038\/srep26496","DOI":"10.1038\/srep26496"},{"key":"2025100301541276000_78.7.424.67","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx206"},{"key":"2025100301541276000_78.7.424.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.12.021"},{"key":"2025100301541276000_78.7.424.69","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1093\/ije\/dyaa266","article-title":"Bias in two-sample Mendelian randomization when using Heritable Covariable-adjusted summary associations","volume":"50","author":"Hartwig","year":"2021","journal-title":"Int J Epidemiol"}],"container-title":["Journal of Epidemiology and Community Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jech-2023-221184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T08:54:23Z","timestamp":1759481663000},"score":1,"resource":{"primary":{"URL":"https:\/\/jech.bmj.com\/lookup\/doi\/10.1136\/jech-2023-221184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,8]]},"references-count":69,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,6,10]]},"published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1136\/jech-2023-221184"],"URL":"https:\/\/doi.org\/10.1136\/jech-2023-221184","relation":{},"ISSN":["0143-005X","1470-2738"],"issn-type":[{"value":"0143-005X","type":"print"},{"value":"1470-2738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,8]]}}}