{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:45:50Z","timestamp":1793295950952,"version":"4.5.0"},"reference-count":55,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["10.46540\/3100\u201000007B"],"award-info":[{"award-number":["10.46540\/3100\u201000007B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU_00032\/1"],"award-info":[{"award-number":["MC_UU_00032\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp; Dementia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"Abstract<\/jats:title>\n \n INTRODUCTION<\/jats:title>\n We tested whether genetically proxied non\u2010high\u2010density lipoprotein cholesterol (non\u2010HDL\u2010C)\u2013lowering drug targets reduce risk of all\u2010cause dementia.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n We included 1,091,775 individuals from three prospective general population cohorts with individual\u2010level data and two consortia with summary\u2010level data. We selected genetic variants within\n HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL<\/jats:italic>\n , and\n CETP<\/jats:italic>\n associated with non\u2010HDL\u2010C. These variants were used as exposures in Cox regression and one\u2010 and two\u2010sample Mendelian randomization. Results were meta\u2010analyzed.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Meta\u2010analysis of one\u2010sample Mendelian randomization odds ratios per 1 mmol\/L (39 mg\/dL) lower non\u2010HDL\u2010C was 0.24 (0.18\u20130.31) for\n HMGCR<\/jats:italic>\n , 0.18 (0.12\u20130.25) for\n NPC1L1<\/jats:italic>\n , 0.97 (0.70\u20131.35) for\n PCSK9<\/jats:italic>\n , 1.66 (0.52\u20135.36) for\n ANGPTL4<\/jats:italic>\n , 1.41 (0.63\u20133.16) for\n LPL<\/jats:italic>\n , and 0.30 (0.26\u20130.34) for\n CETP<\/jats:italic>\n . Cox regression and two\u2010sample Mendelian randomization results were mostly directionally consistent.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n \n Genetic lowering of non\u2010HDL cholesterol via\n HMGCR, NPC1L1<\/jats:italic>\n , and\n CETP<\/jats:italic>\n reduces the risk of dementia. This reflects the effect of lifelong differences in non\u2010HDL cholesterol on risk of dementia.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n \n Variants in\n HMGCR, NPC1L1<\/jats:italic>\n , and\n CETP<\/jats:italic>\n reduce the risk of dementia via non\u2010high\u2010density lipoprotein cholesterol (non\u2010HDL\u2010C).\n <\/jats:p>\n <\/jats:list-item>\n \n \n An effect of\n PCSK9, ANGPTL4<\/jats:italic>\n , and\n LPL<\/jats:italic>\n variants on dementia risk cannot be excluded.\n <\/jats:p>\n <\/jats:list-item>\n \n This reflects the effect of lifelong lower non\u2010HDL\u2010C on risk of dementia.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70638","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T11:01:13Z","timestamp":1759921273000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cholesterol\u2010lowering drug targets reduce risk of dementia: Mendelian randomization and meta\u2010analyses of 1 million individuals"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5490-0034","authenticated-orcid":false,"given":"Liv Tybj\u00e6rg","family":"Nordestgaard","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Herlev and Gentofte Herlev Denmark"},{"name":"Medical Research Council Integrative Epidemiology Unit Population Health Sciences, University of Bristol Bristol 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