Elevated plasma sTREM2 reflects microglial activation but lacks diagnostic and clinical relevance in amyotrophic lateral sclerosis

: Microglial activation contributes to the neuroinflammatory response in amyotrophic lateral sclerosis. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects microglial activity in several neurodegenerative disorders, but its role in amyotrophic lateral sclerosis remains unclear. We evaluated plasma sTREM2 as a marker of microglial activation in amyotrophic lateral sclerosis (ALS) and compared its diagnostic performance with established blood biomarkers of neurodegeneration. Plasma sTREM2, neurofilament light chain (NfL), phosphorylated tau181 (Ptau181), and glial fibrillary acidic protein (GFAP) were measured in 100 patients with ALS, 30 healthy controls, and 30 disease mimics. Group differences were assessed using general linear models adjusted for age and sex. Associations with clinical variables and inflammatory markers were tested using Spearman correlation, and diagnostic performance was evaluated using receiver operating characteristic curves. Plasma sTREM2 differed across groups (p = 0.016), with higher levels in ALS compared with healthy controls (p = 0.013) and in mimics compared with healthy controls (p = 0.007), but no difference between ALS and mimics (p = 0.394). Discrimination between ALS and controls was modest (area under the curve 0.677), with no discrimination between ALS and mimics (area under the curve 0.512). No association was found between sTREM2 and disease severity or inflammatory markers (all p > 0.10). Plasma sTREM2 increases in ALS but lacks diagnostic specificity and clinical associations, supporting its role as a nonspecific marker of neuroimmune activation rather than a biomarker of disease-related neurodegeneration.