This multicenter ROC analysis validated SPTLC2 (AUC = 0.804), AMD1 (AUC = 0.769), and IGSF3 (AUC = 0.768) as effective diagnostic biomarkers for distinguishing AD subtypes (95% CIs ≥ 0.75), while establishing clinical-grade cutoff values targeting immune-metabolic pathway abnormalities to enable translational research standards for targeted interventions. Here, SPTLC2 is linked to Alzheimer disease.