Our objective was to determine the effects of lipids and complement proteins on early and intermediate age-related macular degeneration (AMD) stages using machine learning models by integrating metabolomics and proteomic data.Nested case-control study.The analyses were performed in a subset of the Singapore Indian Chinese Cohort (SICC) Eye Study. Among the 6753 participants, we randomly selected 155 Indian and 155 Chinese cases of AMD and matched them with 310 controls on age, sex, and ethnicity.We measured 35 complement proteins and 56 lipids using mass spectrometry and nuclear magnetic resonance, respectively. We first selected the most contributing lipids and complement proteins to early and intermediate AMD using random forest models. Then, we estimated their effects using a multinomial model adjusted for potential confounders.Age-related macular degeneration was classified using the Beckman classification system.Among the 310 individuals with AMD, 166 (53.5%) had early AMD, and 144 (46.5%) had intermediate AMD. First, high-density lipoprotein (HDL) particle diameter was positively associated with both early and intermediate AMD (odds ratio [OR]early = 1.69; 95% confidence interval [CI],1.11-2.55 and ORintermediate = 1.72; 95% CI, 1.11-2.66 per 1-standard deviation increase in HDL diameter). Second, complement protein 2 (C2), complement C1 inhibitor (IC1), complement protein 6 (C6), complement protein 1QC (C1QC) and complement factor H-related protein 1 (FHR1), were associated with AMD. C2 was positively associated with both early and intermediate AMD (ORearly = 1.58; 95% CI, 1.08-2.30 and ORintermediate = 1.56; 95% CI, 1.04-2.34). C6 was positively (ORearly = 1.41; 95% CI, 1.03-1.93) associated with early AMD. However, IC1 was negatively associated with early AMD (ORearly = 0.62; 95% CI, 0.38-0.99), whereas C1QC (ORintermediate = 0.63; 95% CI, 0.42-0.93) and FHR1 (ORintermediate = 0.73; 95% CI, 0.54-0.98) were both negatively associated with intermediate AMD.Although both HDL diameter and C2 levels show associations with both early and intermediate AMD, dysregulations of IC1, C6, C1QC, and FHR1 are only observed at specific stages of AMD. These findings underscore the complexity of complement system dysregulation in AMD, which appears to vary depending on the disease severity.The authors have no proprietary or commercial interest in any materials discussed in this article.© 2024 by the American Academy of Ophthalmology.