TREML2 (triggering receptor expressed on myeloid cells like 2) is a transmembrane immune receptor located on chromosome 6.1 that functions as a cell surface receptor in innate and adaptive immunity 1. The protein acts as a counter-receptor for CD276, enhancing T-cell activation through this interaction. However, evidence for TREML2 interaction with B7-H3 in human systems remains unsupported 2. TREML2 has emerged as a prominent genetic factor in neurodegenerative disease. Multiple variants in TREML2 show differential effects on Alzheimer's disease (AD) pathology: the rs3747742-C variant is protective, while others function as risk factors 3. The protective rs3747742-C allele associates with increased hippocampal CA1 subfield volume in cognitively normal elderly, suggesting enhanced brain reserve as a protective mechanism 4. TREML2 variants also correlate with cerebrospinal fluid tau and amyloid-beta levels, key AD biomarkers 3. Beyond AD, TREML2 expression associates with white matter hyperintensities volume 5. Clinically, genetically predicted decreased TREML2 protein levels associate with increased ankylosing spondylitis risk 6 and ovarian cancer risk 7, positioning TREML2 as a potential therapeutic target across multiple diseases. TREML2 also represents a candidate biomarker in neuropathic pain pathology 8.