Discovery of lipid biomarkers for idiopathic Parkinson’s disease in red blood cells and plasma

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and lipid-rich Lewy bodies containing misfolded alpha-synuclein, implicating lipid dysregulation in pathogenesis. We performed comprehensive lipidomic profiling using liquid chromatography-ion mobility mass spectrometry on paired red blood cell (RBC) and plasma samples from idiopathic PD (iPD) patients (n = 156) and cognitively normal controls (n = 155). We identified significant alterations in 240 RBC and 113 plasma lipids, with elevated sphingomyelins, ceramides, and phosphatidylcholines in RBCs and decreased triacylglycerols, phosphatidylcholines, and phosphatidylinositols in plasma. Multivariate modeling identified an RBC lipid biomarker panel that achieved a discovery-cohort discriminatory AUC of 0.834. Weighted gene co-expression network analysis revealed lipid modules associated with ferroptosis, necroptosis, and sphingolipid and glycerophospholipid signaling, mechanisms converging on alpha-synuclein toxicity and neurodegeneration. This blood-based lipid biomarker panel represents a promising peripheral candidate for iPD detection while providing mechanistic insights into lipid-mediated neurodegeneration.