Blood and CSF chemokines in Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis

Abstract

Objective: Chemokines, which are chemotactic inflammatory mediators involved in controlling the migration and residence of all immune cells, are closely associated with brain inflammation, recognized as one of the potential processes/mechanisms associated with cognitive impairment. We aim to determine the chemokines which are significantly altered in Alzheimer's disease (AD) and mild cognitive impairment (MCI), as well as the respective effect sizes, by performing a meta-analysis of chemokines in cerebrospinal fluid (CSF) and blood (plasma or serum).

Methods: We searched three databases (Pubmed, EMBASE and Cochrane library) for studies regarding chemokines. The three pairwise comparisons were as follows: AD vs HC, MCI vs healthy controls (HC), and AD vs MCI. The fold-change was calculated using the ratio of mean (RoM) chemokine concentration for every study. Subgroup analyses were performed for exploring the source of heterogeneity.

Results: Of 2338 records identified from the databases, 61 articles comprising a total of 3937 patients with AD, 1459 with MCI, and 4434 healthy controls were included. The following chemokines were strongly associated with AD compared with HC: blood CXCL10 (RoM, 1.92, p = 0.039), blood CXCL9 (RoM, 1.78, p < 0.001), blood CCL27 (RoM, 1.34, p < 0.001), blood CCL15 (RoM, 1.29, p = 0.003), as well as CSF CCL2 (RoM, 1.19, p < 0.001). In the comparison of AD with MCI, there was significance for blood CXCL9 (RoM, 2.29, p < 0.001), blood CX3CL1 (RoM, 0.77, p = 0.017), and blood CCL1 (RoM, 1.37, p < 0.001). Of the chemokines tested, blood CX3CL1 (RoM, 2.02, p < 0.001) and CSF CCL2 (RoM, 1.16, p = 0.004) were significant for the comparison of MCI with healthy controls.

Conclusions: Chemokines CCL1, CCL2, CCL15, CCL27, CXCL9, CXCL10, and CX3CL1 might be most promising to serve as key molecular markers of cognitive impairment, although more cohort studies with larger populations are needed.

Keywords: Alzheimer’s disease; Chemokine; Meta-analysis; Mild cognitive impairment.

Fig. 1

PRISMA diagram of study flow

Fig. 2

The performance of serum/plasma chemokines in differentiating Alzheimer’s disease from healthy controls. Based on average AD to control ratios, head-to-head chemokine performance in serum/plasma. An asterisk indicates significance, p < 0.05

Fig. 3

The performance of serum/plasma chemokines in differentiating MCI from healthy individuals and AD from MCI. The average ratios of MCI to controls and AD to MCI were used to compare chemokine performance in serum or plasma. An asterisk indicates significance, p < 0.05

Fig. 4

The ability of CSF chemokines to distinguish AD from MCI. Average AD to MCI ratios were used to compare CSF chemokine performance. An asterisk indicates significance, p < 0.05

Fig. 5

The performance of the chemokines CCL1, CCL15, CCL27, CXCL9, CXCL10, and CX3CL1 in the serum/plasma in the three pairwise comparisons. An asterisk indicates significance, p < 0.05