CSF sTREM2 has opposite association with brain structural damage rate at early and late stage of Alzheimer’s disease

Abstract

AbstractBackgroundThe role of neuroinflammation in the pathogenesis of Alzheimer’s disease (AD) is still controversial. Recent studies proposed that microglial response may have a stage‐dependent effect on disease progression. Considering the CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has emerged as a promising marker of microglial activation, we aimed to further test this hypothesis by studying the association between baseline sTREM2 with dynamic brain structural changes in different stage of AD.Method22 amyloid‐positive (A+) and tau‐positive (T+) AD patients and 24 A+T+ MCI patients were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The patients had baseline measurements of CSF A‐beta, P‐Tau, sTREM2, baseline and follow‐up T1‐weighted and diffusion tensor imaging (DTI) scans, and were followed up for at least one year. Voxel‐based morphometry (VBM) analysis was performed to assess grey matter volumetric change, while fractional anisotropy (FA) and mean diffusivity (MD) were derived from DTI scans to evaluate white matter microstructural integrity. Linear mixed effect models were then applied to model the longitudinal change of grey and white matter integrity, and to analyze the influence of baseline sTREM2 on the rate of brain structural changes.ResultIn A+T+ AD patients, baseline CSF sTREM2 was associated with faster FA decline and MD increase in association fibers including corpus callosum, inferior longitudinal fasciculus, cingulum, inferior fronto‐occipital fasciculus, and superior longitudinal fasciculus. In A+T+ MCI patients, baseline CSF sTREM2 was associated slower grey matter volumetric loss in regions including Alzheimer’s signature cortices such as angular gyrus and precuneus, while mixed findings were found regarding white matter integrity, with a protective effect with regard to MD but a potential negative effect against FA values in association fibers.ConclusionThe current study suggests that microglial activation at early AD stage might have a protective effect against neurodegeneration, while at late stage, it might facilitate neurodegenerative process. These observations support the hypotheses that microglial response is an active factor in the process of Alzheimer’s pathogenesis, and that it has stage‐dependent effects on disease progression. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.