{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T05:58:30Z","timestamp":1781330310707,"version":"3.54.1"},"reference-count":53,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Traditional Chinese Medicine Discipline Project of Henan Province's \"Double First Class\" Creation Project","award":["HSRP-DFCTCM-2022-3-11"],"award-info":[{"award-number":["HSRP-DFCTCM-2022-3-11"]}]},{"name":"the National Administration of Traditional Chinese Medicine Science and Technology Project \"Zhang Zhongjing Inheritance and Innovation Special Project\"","award":["GZY-KJS-2022-043-3"],"award-info":[{"award-number":["GZY-KJS-2022-043-3"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer's Disease Reports"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although observational studies have reported correlations between lipid, circulating metabolites, and Alzheimer's disease (AD), the causality of these associations remain unresolved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the effects of lipids and circulating metabolites on AD risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We applied a two-step Mendelian randomization (MR) framework to evaluate the causal effects of lipids on AD and to assess whether these effects are mediated by circulating metabolites. Causal estimates were primarily derived using the inverse-variance weighted method, with robustness evaluated through a series of complementary sensitivity analyses, including Cochran's Q statistic, MR-Egger intercept testing, Radial MR, MR-PRESSO, and leave-one-out analyses. Additional validation was provided by Steiger directionality testing, linkage disequilibrium score regression, multivariable MR analyses, and independent replication, collectively ensuring the reliability of the causal inferences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR analyses showed that PI(18:1\/18:1) and TAG(52:3) were causally associated with a lower risk of AD. Mediation analyses further identified triglyceride levels in low-density lipoproteins (LDL), medium LDL, and small LDL as intermediates, accounting for 17.6%, 22.8%, and 18.1% of the protective effect of PI(18:1\/18:1) on AD risk, respectively. By contrast, the free cholesterol to total lipid ratio in medium high-density lipoproteins (HDL) emerged as a deleterious mediator, explaining 13.0% of the protective association between TAG(52:3) and AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study highlights the importance of PI(18:1\/18:1) and TAG(52:3) in AD development, and suggests that triglyceride levels in LDL, medium LDL, and small LDL, as well as the free cholesterol to total lipids ratio in medium HDL, may act as mediators in this pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/25424823261456655","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T05:33:26Z","timestamp":1781328806000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating metabolites mediate the effects of lipids on Alzheimer's disease: A Mendelian randomization and mediation analysis"],"prefix":"10.1177","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9321-5400","authenticated-orcid":false,"given":"Xinyu","family":"Yang","sequence":"first","affiliation":[{"name":"Henan University of Chinese Medicine"},{"name":"Department of Rehabilitation, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1666-1909","authenticated-orcid":false,"given":"Chang","family":"Chai","sequence":"additional","affiliation":[{"name":"Henan University of Chinese Medicine"},{"name":"Department of Rehabilitation, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Li","sequence":"additional","affiliation":[{"name":"Henan University of Chinese Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4020-6829","authenticated-orcid":false,"given":"Yanjie","family":"Li","sequence":"additional","affiliation":[{"name":"Henan University of Chinese Medicine"},{"name":"Department of Rehabilitation, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_3_3_3_2","unstructured":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. 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