Different splice isoforms of peripheral TREM2 mRNA expressions are associated with cognitive decline in mild dementia due to Alzheimer’s disease and reflect central microglia activation

Abstract

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) is upregulated in activated microglia and may be related to cognitive decline in patients with Alzheimer’s disease (AD). There is conflicting evidence regarding the association of peripheral levels of TREM2 mRNA expression and soluble TREM2 (the extracellular domain of TREM2) with cognitive function in patients with AD. The correlation between peripheral TREM2 mRNA expression and neuroinflammation is unclear. Methods We recruited subjects with mild dementia due to AD (clinical dementia rating = 0.5 or 1) and healthy controls. Quantitative real-time polymerase chain reaction analysis was performed using two types of primers. One detects all peripheral TREM2 mRNA isoforms, and the other is specific for TREM2alt. In a subgroup of patients with AD, magnetic resonance spectroscopy (MRS) was used to measure the myo-inositol (mI) level in the posterior cingulate cortex, which is considered a marker for microglial activation. We analyzed the difference in mRNA expression between the two groups and the association between mRNA expression and cognition and mI levels. Results We recruited 61 patients with AD and 51 healthy controls. A one-way analysis of covariance adjusted for covariates showed higher TREM2 and TREM2alt mRNA expression levels in the AD group than in the control group (p = 0.013 and p = 0.001, respectively). Correlation analysis and linear regression examining the association between the mRNA expression levels and mini-mental state examination score showed a positive correlation in patients with AD (TREM2, rs = 0.305, p = 0.017, adjusted p = 0.001; TREM2alt, rs = 0.302, p = 0.018, adjusted p = 0.009) but not in the control group. Subgroup analysis of 25 AD patients with MRS showed a negative correlation between mRNA expression and mI levels (TREM2, rs = -0.426, p = 0.034, adjusted p = 0.032; TREM2alt, rs = -0.447, p = 0.025, adjusted p = 0.028). Conclusions Increased TREM2 and TREM2alt mRNA expression is associated with AD pathogenesis at the mild dementia stage, thereby serving as a potential biomarker for the early symptomatic stage of AD. TREM2 may exert protective effects on both cognition and microglia-mediated neuroinflammation.