{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:59:24Z","timestamp":1793289564999,"version":"4.5.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010041","name":"Tianjin Science and Technology Committee","doi-asserted-by":"publisher","award":["18ZXDBSY00120"],"award-info":[{"award-number":["18ZXDBSY00120"]}],"id":[{"id":"10.13039\/501100010041","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Project of the Tianjin Municipal Health Commission","award":["ZD20006"],"award-info":[{"award-number":["ZD20006"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The results of current studies on metabolic-dysfunction associated steatotic liver disease (MASLD)-related diseases, cognition and dementia are inconsistent. This study aimed to elucidate the effects of MASLD-related diseases on cognition and dementia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>By using single-nucleotide polymorphisms (SNPs) associated with different traits of NAFLD (chronically elevated serum alanine aminotransferase levels [cALT], imaging-accessed and biopsy-proven NAFLD), metabolic dysfunction-associated steatohepatitis, and liver fibrosis and cirrhosis, we employed three methods of mendelian randomization (MR) analysis (inverse-variance weighted [IVW], weighted median, and MR-Egger) to determine the causal relationships between MASLD-related diseases and cognition and dementia. We used Cochran\u2019s Q test to examine the heterogeneity, and MR-PRESSO was used to identify outliers (NbDistribution = 10000). The horizontal pleiotropy was evaluated using the MR-Egger intercept test. A leave-one-out analysis was used to assess the impact of individual SNP on the overall MR results. We also repeated the MR analysis after excluding SNPs associated with confounding factors.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The results of MR analysis suggested positive causal associations between MASLD confirmed by liver biopsy (p of IVW = 0.020, OR = 1.660, 95%CI = 1.082\u20132.546) and liver fibrosis and cirrhosis (p of IVW = 0.009, OR = 1.849, 95%CI = 1.169\u20132.922) with vascular dementia (VD). However, there was no evidence of a causal link between MASLD-related diseases and cognitive performance and other types of dementia (any dementia, Alzheimer\u2019s disease, dementia with lewy bodies, and frontotemporal dementia). Sensitivity tests supported the robustness of the results.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This two-sample MR analysis suggests that genetically predicted MASLD and liver fibrosis and cirrhosis may increase the VD risk. Nonetheless, the causal effects of NAFLD-related diseases on VD need more in-depth research.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0297883","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T18:50:25Z","timestamp":1709232625000},"page":"e0297883","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: A two-sample mendelian randomization study"],"prefix":"10.1371","volume":"19","author":[{"given":"Yao-Shuang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ge","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Lan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ran","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Na","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Bo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1772-6903","authenticated-orcid":true,"given":"Jing-Na","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"pone.0297883.ref001","first-page":"S0953","article-title":"Natural history of metabolic dysfunction-associated steatotic liver disease [published online ahead of print, 2023 Nov 6]","author":"V Lekakis","year":"2023","journal-title":"Eur J Intern Med"},{"issue":"12","key":"pone.0297883.ref002","first-page":"2809","article-title":"2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis","volume":"20","author":"MH Le","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"6","key":"pone.0297883.ref003","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1111\/obr.12407","article-title":"Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies.","volume":"17","author":"L Li","year":"2016","journal-title":"Obes Rev"},{"issue":"7","key":"pone.0297883.ref004","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/hep4.1519","article-title":"Prevalence and Profile of Nonalcoholic Fatty Liver Disease in Lean Adults: Systematic Review and Meta-Analysis.","volume":"4","author":"S Young","year":"2020","journal-title":"Hepatol Commun"},{"key":"pone.0297883.ref005","doi-asserted-by":"crossref","first-page":"372","DOI":"10.2337\/dc17-1902","article-title":"Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis.","volume":"41","author":"A Mantovani","year":"2018","journal-title":"Diabetes Care"},{"key":"pone.0297883.ref006","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.jhep.2016.05.013","article-title":"Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis","volume":"65","author":"G Targher","year":"2016","journal-title":"J Hepatol"},{"issue":"5","key":"pone.0297883.ref007","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s00401-015-1522-0","article-title":"Cerebrovascular disease in ageing and Alzheimer\u2019s disease","volume":"131","author":"S Love","year":"2016","journal-title":"Acta Neuropathol"},{"key":"pone.0297883.ref008","doi-asserted-by":"crossref","first-page":"549","DOI":"10.2147\/CIA.S74042","article-title":"Link between type 2 diabetes and Alzheimer\u2019s disease: from epidemiology to mechanism and treatment.","volume":"10","author":"X Li","year":"2015","journal-title":"Clin Interv Aging"},{"issue":"6","key":"pone.0297883.ref009","doi-asserted-by":"crossref","first-page":"e565","DOI":"10.1212\/WNL.0000000000200770","article-title":"Association of Nonalcoholic Fatty Liver Disease and Fibrosis With Incident Dementia and Cognition: The Rotterdam Study","volume":"99","author":"T Xiao","year":"2022","journal-title":"Neurology"},{"key":"pone.0297883.ref010","doi-asserted-by":"crossref","first-page":"738835","DOI":"10.3389\/fmed.2021.738835","article-title":"Non-alcoholic Fatty Liver Disease and Longitudinal Cognitive Changes in Middle-Aged and Elderly Adults.","volume":"8","author":"Q Liu","year":"2022","journal-title":"Front Med (Lausanne)."},{"key":"pone.0297883.ref011","doi-asserted-by":"crossref","first-page":"985109","DOI":"10.3389\/fnagi.2022.985109","article-title":"Risk of dementia or cognitive impairment in non-alcoholic fatty liver disease: A systematic review and meta-analysis.","volume":"14","author":"L Wang","year":"2022","journal-title":"Front Aging Neurosci"},{"issue":"R1","key":"pone.0297883.ref012","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"G Davey Smith","year":"2014","journal-title":"Hum Mol Genet"},{"issue":"3","key":"pone.0297883.ref013","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1002\/hep.32728","article-title":"The associations between modifiable risk factors and nonalcoholic fatty liver disease: A comprehensive Mendelian randomization study","volume":"77","author":"J Xie","year":"2023","journal-title":"Hepatology"},{"issue":"1","key":"pone.0297883.ref014","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.32534","article-title":"Relationship between NAFLD and coronary artery disease: A Mendelian randomization study","volume":"77","author":"Z Ren","year":"2023","journal-title":"Hepatology"},{"issue":"6","key":"pone.0297883.ref015","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/s41588-022-01078-z","article-title":"A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation","volume":"54","author":"M Vujkovic","year":"2022","journal-title":"Nat Genet"},{"issue":"7944","key":"pone.0297883.ref016","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"MI Kurki","year":"2023","journal-title":"Nature"},{"issue":"3","key":"pone.0297883.ref017","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1093\/ije\/dyq151","article-title":"Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants.","volume":"40","author":"BL Pierce","year":"2011","journal-title":"Int J Epidemiol."},{"issue":"12","key":"pone.0297883.ref018","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1038\/s41562-021-01119-3","article-title":"Resource profile and user guide of the Polygenic Index Repository.","volume":"5","author":"J Becker","year":"2021","journal-title":"Nat Hum Behav."},{"issue":"3","key":"pone.0297883.ref019","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/mp.2016.244","article-title":"GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium","volume":"22","author":"JW Trampush","year":"2017","journal-title":"Mol Psychiatry"},{"issue":"2","key":"pone.0297883.ref020","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s10519-022-10127-6","article-title":"A General Cognitive Ability Factor for the UK Biobank","volume":"53","author":"CM Williams","year":"2023","journal-title":"Behav Genet"},{"key":"pone.0297883.ref021","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.intell.2014.01.008","article-title":"Genetic and Environmental Influences of General Cognitive Ability: Is g a valid latent construct?","volume":"43","author":"MS Panizzon","year":"2014","journal-title":"Intelligence."},{"issue":"9","key":"pone.0297883.ref022","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/s41588-021-00921-z","article-title":"A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer\u2019s disease","volume":"53","author":"DP Wightman","year":"2021","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0297883.ref023","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41588-021-00785-3","article-title":"Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture","volume":"53","author":"R Chia","year":"2021","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0297883.ref024","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/ng.536","article-title":"Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions","volume":"42","author":"VM Van Deerlin","year":"2010","journal-title":"Nat Genet"},{"issue":"2","key":"pone.0297883.ref025","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.","volume":"44","author":"J Bowden","year":"2015","journal-title":"Int J Epidemiol."},{"issue":"6","key":"pone.0297883.ref026","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/gepi.22207","article-title":"Implementing MR-PRESSO and GCTA-GSMR for pleiotropy assessment in Mendelian randomization studies from a practitioner\u2019s perspective","volume":"43","author":"JS Ong","year":"2019","journal-title":"Genet Epidemiol"},{"issue":"1","key":"pone.0297883.ref027","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/EDE.0000000000000559","article-title":"Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants.","volume":"28","author":"S Burgess","year":"2017","journal-title":"Epidemiology."},{"issue":"5","key":"pone.0297883.ref028","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"M Verbanck","year":"2018","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0297883.ref029","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in Mendelian randomization studies.","volume":"42","author":"MJ Brion","year":"2013","journal-title":"Int J Epidemiol."},{"issue":"20","key":"pone.0297883.ref030","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1093\/bioinformatics\/btw373","article-title":"PhenoScanner: a database of human genotype-phenotype associations","volume":"32","author":"JR Staley","year":"2016","journal-title":"Bioinformatics"},{"issue":"22","key":"pone.0297883.ref031","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1093\/bioinformatics\/btz469","article-title":"PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations","volume":"35","author":"MA Kamat","year":"2019","journal-title":"Bioinformatics"},{"key":"pone.0297883.ref032","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3389\/fnagi.2019.00146","article-title":"Modifiable Risk Factors for Alzheimer\u2019s Disease.","volume":"11","author":"GA Edwards Iii","year":"2019","journal-title":"Front Aging Neurosci."},{"key":"pone.0297883.ref033","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jad.2022.07.008","article-title":"Modifiable risk factors for incident dementia and cognitive impairment: An umbrella review of evidence","volume":"314","author":"YR Zhang","year":"2022","journal-title":"J Affect Disord"},{"issue":"12","key":"pone.0297883.ref034","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1038\/ng.3437","article-title":"Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci","volume":"47","author":"KJ Gaulton","year":"2015","journal-title":"Nat Genet"},{"issue":"6","key":"pone.0297883.ref035","doi-asserted-by":"crossref","first-page":"e574","DOI":"10.1212\/WNL.0000000000200853","article-title":"Nonalcoholic Fatty Liver Disease and Risk of Dementia: A Population-Based Cohort Study","volume":"99","author":"Y Shang","year":"2022","journal-title":"Neurology"},{"issue":"9","key":"pone.0297883.ref036","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1111\/ene.15416","article-title":"Nonalcoholic fatty liver disease, serum cytokines, and dementia among rural-dwelling older adults in China: A population-based study.","volume":"29","author":"Y Wang","year":"2022","journal-title":"Eur J Neurol"},{"issue":"1","key":"pone.0297883.ref037","first-page":"100056","article-title":"Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease","volume":"3","author":"Z Miao","year":"2021","journal-title":"HGG Adv"},{"key":"pone.0297883.ref038","doi-asserted-by":"crossref","first-page":"154770","DOI":"10.1016\/j.metabol.2021.154770","article-title":"Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk","volume":"119","author":"E Muzurovi\u0107","year":"2021","journal-title":"Metabolism"},{"issue":"37","key":"pone.0297883.ref039","doi-asserted-by":"crossref","first-page":"13306","DOI":"10.3748\/wjg.v20.i37.13306","article-title":"Nonalcoholic fatty liver disease and vascular disease: state-of-the-art","volume":"20","author":"S Fargion","year":"2014","journal-title":"World J Gastroenterol"},{"issue":"3","key":"pone.0297883.ref040","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/oby.21767","article-title":"Nonalcoholic fatty liver disease and measures of early brain health in middle-aged adults: The CARDIA study.","volume":"25","author":"LB VanWagner","year":"2017","journal-title":"Obesity (Silver Spring)."},{"issue":"3","key":"pone.0297883.ref041","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1002\/hep.23046","article-title":"Adipokines in liver diseases","volume":"50","author":"F Marra","year":"2009","journal-title":"Hepatology"},{"issue":"5","key":"pone.0297883.ref042","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1161\/STROKEAHA.113.004534","article-title":"Multimodal markers of inflammation in the subcortical ischemic vascular disease type of vascular cognitive impairment","volume":"45","author":"GA Rosenberg","year":"2014","journal-title":"Stroke"},{"key":"pone.0297883.ref043","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3389\/fnagi.2014.00171","article-title":"Systemic inflammation, blood-brain barrier vulnerability and cognitive\/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy.","volume":"6","author":"S Takeda","year":"2014","journal-title":"Front Aging Neurosci"},{"issue":"6","key":"pone.0297883.ref044","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1053\/jhep.2003.50229","article-title":"Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values","volume":"37","author":"P Mofrad","year":"2003","journal-title":"Hepatology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0297883","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T18:50:55Z","timestamp":1709232655000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0297883"}},"subtitle":[],"editor":[{"given":"Ming-Lung","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,2,29]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0297883","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,29]]}}}