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INTRODUCTION: Two alleles (ε2 and ε4) in the APOE gene are known to be strongly associated with lipid metabolism disorders, such as dyslipidemia, which are important risk factors for the development of cardiovascular diseases. While prior research has largely centered on adult populations, establishing APOE-lipid associations in infants, children, and adolescents-especially those from historically understudied groups-could inform earlier interventions and treatments.OBJECTIVES: This study aimed to evaluate the dependence of the metabolome on the APOE variants using five diverse cohorts that span infancy through adulthood, comprising a total of over 190,000 individuals.METHODS: We extracted the APOE variants (rs7412 and rs429358) from all cohorts-testing both the ε2 allele (rs7412-T and rs429358-T) and the ε4 allele (rs7412-C and rs429358-C)-and evaluated their associations with the global plasma metabolome which was measured by mass spectrometry-based (Metabolon or Ó³»­´«Ã½) or NMR-based (Nightingale) assays depending on the cohort, using a Bonferroni-corrected significance threshold.RESULTS: Among 589 metabolites tested in our discovery population, only six including sphingomyelins and cholesterol were significantly associated with the rs7412/ε2 allele. Sphingomyelin (d18:1/22:0) and cholesterol were negatively associated with ε2 allele (β-value = -0.54 [-0.76, -0.32] p-value = 1.39 × 10 and - 0.55 [-0.77, -0.33]; p-value = 1.49 × 10, respectively). These relationships were replicated in the four additional cohorts without heterogeneity.CONCLUSION: Our findings support the need for early intervention in lipid levels regardless of age, sex, and ethnicity and further investigations of the APOE variants on risk of various diseases in later life.