Abstract
Background: Both the genetic and pathological studies link Alzheimer’s disease (AD) to the triggering receptor expressed on myeloid cells 2 (TREM2). A large number of studies have explored the value of cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a biomarker for the diagnosis and prediction of AD; however, the findings are inconsistent. We aimed to review the studies that investigated the association of CSF sTREM2 levels and AD risk, and to provide the recommendations for future research.Methods and Results: A systematic literature search was performed using the MEDLINE, EMBASE, and Web of Science (all databases) databases. The meta-analysis for the association between the CSF sTREM2 levels and AD risk included 15 studies (17 comparisons) with a total of 1,153 cases and 1,626 controls. The total results showed that the higher CSF sTREM2 levels and AD risk were associated [standardized mean difference (SMD) = 0.428, 95% CI (0.213, 0.643), I2 = 81.1%]. However, the analysis of the subgroup of “age difference ≤ 2 years” indicated that sTREM2 was not associated with AD [SMD = 0.090, 95% CI (−0.092, 0.272), I2 = 27.4%] and had a significantly lower heterogeneity. Combining the results of the “age difference of 5–10 years” [SMD = 0.497, 95% CI (0.139, 0.855), I2 = 82.5%] and “age difference > 10 years” [SMD = 0.747, 95% CI (0.472, 1.023), I2 = 50.0%] subgroups showed that the difference in CSF sTREM2 between the AD and control groups was positively correlated with the age difference. A meta-regression analysis showed that the age difference can explain 33.4% of the between-study variance. By conducting further subgroup analyses of the five age-matched studies (495 cases and 364 controls) according to the measurement method, and whether inclusion criteria containing the requirement for pathological evidence of AD, no changes were observed in the corresponding pooled SMD or in the significance of the results. The meta-analysis result of “age difference ≤ 2 years” group was robust in the sensitivity analysis.Conclusion: The available high-quality evidence does not yet support an association between the CSF sTREM2 levels and AD risk. Age matching between the patients with AD and cognitively unimpaired controls was a major influencing factor in the results.
Highlights
Alzheimer’s disease (AD), as a clinically heterogeneous and complex neurodegenerative disease, is considered the most common type of dementia and induces a heavy burden to the patients and families
The eligible studies were included in this meta-analysis: (1) investigated the relationship between the cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels and AD risk; (2) included a case group of patients with AD and a group of cognitively unimpaired controls; (3) clinical criteria that used to diagnose AD were qualified; (4) provided data with the mean and SD or median and interquartile range (IQR) or median and the minimum and maximum; (5) the studies performed in humans; (6) full text in English
152 records were excluded based on their title and/or abstract: these were repetitive publications (n = 90), conference abstracts (n = 14), the reports of animal studies (n = 7), the reports of studies that investigated either the outcomes irrelevant to this meta-analysis (n = 18), the markers other than sTREM2 (n = 1), review or meta-analysis (n = 12), protocol (n = 1), the studies of which sTREM2 levels was not measured in CSF (n = 2), the reports of studies that only had triggering receptor expressed on myeloid cells 2 (TREM2) gene information (n = 6), or the studies of which did not have a normal cognitive function group (n = 1)
Summary
Alzheimer’s disease (AD), as a clinically heterogeneous and complex neurodegenerative disease, is considered the most common type of dementia and induces a heavy burden to the patients and families. It is reported that the initial activation of microglia induces phagocytosis of Aβ, prevents oligomer formation, and limits the neurotoxicity of Aβ deposited in plaques; its continuous activation and further inflammatory response might accelerate the neurodegeneration (Nordengen et al, 2019). In contrast to the use of classical fluid biomarkers of Aβ and tau proteins, the reliable inflammatory markers in the diagnosis of AD are lacking. Both the genetic and pathological studies link Alzheimer’s disease (AD) to the triggering receptor expressed on myeloid cells 2 (TREM2). A large number of studies have explored the value of cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a biomarker for the diagnosis and prediction of AD; the findings are inconsistent. We aimed to review the studies that investigated the association of CSF sTREM2 levels and AD risk, and to provide the recommendations for future research
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