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Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (\u03bcg\/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson\u2019s dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson\u2019s dementia risk (OR 0.26, 95%CI 0.14; 0.48).\n                      <jats:italic>APOE4<\/jats:italic>\n                      stratified analyses suggested the LBD effect was most pronounced in\n                      <jats:italic>APOE-<\/jats:italic>\n                      \u03b54\u2009+\u2009participants (OR 0.61 95%CI 0.51; 0.73), compared to\n                      <jats:italic>APOE-<\/jats:italic>\n                      \u03b54- (OR 0.89 95%CI 0.79; 1.01); interaction\n                      <jats:italic>p<\/jats:italic>\n                      -value 5.81\u2009\u00d7\u200910\n                      <jats:sup>\u2212\u20094<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in\n                      <jats:italic>APOE-<\/jats:italic>\n                      \u03b54 carriers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13195-024-01594-6","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:02:01Z","timestamp":1729036921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis"],"prefix":"10.1186","volume":"16","author":[{"given":"Amand F.","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ditmarsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Kastelein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Finan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"1594_CR1","doi-asserted-by":"crossref","unstructured":"Kastelein JJ, Kereiakes DJ, Cannon CP, Bays HE, Minini P, Lee LV et al. 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The wording erroneously states that CETP inhibitors decreases Apo-E concentration instead of increasing effect as shown in reference [4]. The correct wording should read: However, all CETP inhibitors, including the novel CETP-inhibitor obicetrapib, increase plasma concentrations of apolipoprotein-E (Apo-E) [4], which is associated with decreased risk of dementia, in particular for Alzheimer\u2019s disease (AD).","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 December 2024","order":7,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":8,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":9,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1186\/s13195-024-01639-w","URL":"https:\/\/doi.org\/10.1186\/s13195-024-01639-w","order":10,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The presented analyses exclusively sourced aggregated genetic data and did not analyse individual participants data. The underlying GWAS received appropriate ethical approval, please consult the individual publications. This research received approval by UCL Research Ethics Committee (UCL REC) under application number 27095\/001, and was conducted in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AFS and CF have received funding from New Amsterdam Pharma for this project. New Amsterdam Pharma is developing the CETP inhibitor Obicetrapib. MHD, MD, JK are employed by New Amsterdam Pharma, as chief executive officer, chief development officer, and chief scientific officer, respectively.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"228"}}