Abstract
BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer’s disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer’s Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsAβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
Highlights
triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system
While tau-related neurodegeneration is associated with an increase in cerebrospinal fluid (CSF) Soluble TREM2 (sTREM2), Amyloid β-peptide (Aβ) pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2
Association of CSF sTREM2 with genetic and demographical data We studied a total of 1027 participants of the Alzheimer’s Disease Imaging Initiative (ADNI) study
Summary
TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Homozygous loss-of-function mutations in TREM2 are sufficient to cause Nasu-Hakola disease (NHD) and FTD-like syndrome [13, 14]. Together, this suggests that abnormal TREM2 function plays an essential role across different neurodegenerative diseases. Homozygous mutations causing NHD or FTD-like syndrome (such as p.T66M) retain misfolded TREM2 in the endoplasmic reticulum, preventing its maturation and its cleavage on the plasma membrane. Patients bearing these mutations have undetectable levels of sTREM2 in CSF and blood [2, 20, 21]
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