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However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n\u00a0=\u00a01087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n\u00a0=\u00a0819; and the Busselton Health Study [BHS], n\u00a0=\u00a04384), and we defined associations between <jats:italic>APOE<\/jats:italic> \u03b52 and \u03b54 and 569 plasma\/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the <jats:italic>APOE<\/jats:italic> genotype mediated by plasma\/serum lipid species.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 237 and 104 lipid species were associated with <jats:italic>APOE<\/jats:italic> \u03b52 and \u03b54, respectively. Of these 68 (\u03b52) and 24 (\u03b54) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of <jats:italic>APOE<\/jats:italic> genotypes mediated up to 30% and 10% of <jats:italic>APOE<\/jats:italic> \u03b52 and \u03b54 treatment effect, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Plasma lipid species mediate the treatment effect of <jats:italic>APOE<\/jats:italic> genotypes on Alzheimer's disease and as such represent a potential therapeutic target.<\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.12538","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T07:03:42Z","timestamp":1643094222000},"page":"2151-2166","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["<i>APOE<\/i> \u03b52 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort 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