Assessing the Clinical Relevance of Blood Soluble Triggering Receptor Expressed on Myeloid Cells 2 in Neurological Diseases.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial and peripheral myeloid cell function, with its soluble form (sTREM2) emerging as a biomarker of neuroinflammation. Although cerebrospinal fluid (CSF) sTREM2 is consistently elevated in neurodegenerative diseases, the clinical relevance of blood sTREM2 remains unclear. We performed a retrospective observational study including 547 individuals: Alzheimer's disease (AD, n = 142), mild cognitive impairment (MCI, n = 42), multiple sclerosis (MS, n = 105), hereditary transthyretin amyloidosis with polyneuropathy (ATTR-PN, n = 23), asymptomatic ATTR mutation carriers (n = 25), and controls (n = 210). Plasma sTREM2 concentrations were measured using Lumipulse automated chemiluminescent enzyme immunoassay platform (Fujirebio, Tokyo, Japan). Age-adjusted multivariate analysis was performed to compare disease groups with controls. In controls, plasma sTREM2 levels increased with age, with a significant breakpoint at 68 years, after which the rate of increase markedly accelerated. Across diagnostic groups, AD, MCI, and MS patients exhibited significantly lower plasma sTREM2 levels (11%-18% reduction) compared to controls (p < 0.05), independent of age. No significant differences were observed in ATTR-PN patients or asymptomatic carriers. Age remained a strong positive predictor of sTREM2 levels across all groups. In conclusions, plasma sTREM2 levels are reduced in AD, MCI, and MS despite known elevations in CSF, indicating a divergence between peripheral and central TREM2 biology. The lack of alteration in ATTR-PN suggests tissue-specific regulation of sTREM2. These findings highlight that blood sTREM2 does not directly mirror central nervous system microglial activation but may reflect peripheral immune dynamics, warranting further investigation into its role as a biomarker of systemic immune dysfunction in neurodegenerative diseases.