Lipidomics reveals TREM2-associated dysregulation of plasma lipid metabolism in Alzheimer's disease

Background Triggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid metabolism remains unclear. Objective To investigate the association between plasma sTREM2 and peripheral lipid profiles in AD and to explore the mechanistic role of TREM2 in peripheral lipid regulation. Methods We conducted a cross-sectional study of 59 AD patients and 54 healthy controls and measured plasma biomarkers including sTREM2 as well as performed targeted lipidomics profiling. Mechanistic exploration was performed via plasma and hippocampal lipidomics in Trem2 knockout and APP/PS1 mice. Results Plasma sTREM2 levels were elevated in AD and were negatively correlated with the plasma p-tau217/Aβ 42 ratio and p-tau217. Multivariate analysis revealed a distinct lipidomics signature in AD, in which 30 lipid species were significantly altered. We prioritized significantly altered biomarkers to inform a composite biomarker panel combining sTREM2 with a set of sphingomyelins, phosphatidylinositols, diacylglycerols, fatty acids, and cholesteryl esters, which showed strong discrimination between AD and controls (AUC = 0.93). In a mouse model of APP/PS1, we found that Trem2 knockout partially normalized plasma sphingomyelins and hexosylceramide levels. Finally, cross-tissue comparisons further suggested that TREM2 exerted distinct effects on peripheral sphingolipid metabolism that were less evident in hippocampal tissue. Conclusions Our findings associate TREM2 with lipid dysregulation in AD and support development of a plasma sTREM2–lipid panel for patient classification.