Cerebrospinal fluid and serum d‐serine levels in patients with alzheimer’s disease: A systematic review and meta‐analysis

Abstract

Objective: Alzheimer’s disease (AD) is a complex and severe neurodegenerative disease and still lacks effective methods of diagnosis. Dysfunction of the N‐methyl‐D‐aspartate receptor (NMDAR) has been found to be involved in synapse dysfunction and neurotoxicity of AD mechanisms. D‐Serine, an NMDAR receptor coagonist, is reported as a potential new biomarker for AD. However, the results of serum and cerebrospinal fluid (CSF) D‐serine levels are conflicting. We conducted a meta‐analysis to investigate the serum and CSF D‐serine levels in patients with AD. Methods: We searched PubMed, the Cochrane central register of controlled trials, and the Cochrane database of systematic reviews for trials that measured D‐serine levels both in patients with AD and in controls. We included controlled trials that analyzed D‐serine levels in human samples (e.g., serum and CSF). Studies were pooled using a random‐effect model for comparisons between AD and control group. We used effect size (ES; expressed as D‐serine levels) in each selected meta-analysis to calculate standardized mean difference (SMD). Positive values indicated increased D‐ serine levels in AD group. We presented results with 95% confidence intervals (CIs). The heterogeneity of the included trials was evaluated through visually inspecting funnel plots and using the I2 statistic. Moderators of effects were explored using metaregression. Results: Seven trials with more than 1186 participants were included in this meta‐analysis. D‐serine levels in patients with AD were significantly higher than those in controls (SMD = 0.679, 95% CI = 0.335 to 1.022, p < 0.001). Subgroup analyses showed that the AD group had significantly higher D‐serine levels in serum and CSF compared with the control group (SMD = 0.566 (serum) and 1.008 (CSF); 95% CI = 0.183 to 0.948 (serum) and 0.168 to 1.849 (CSF)). Moreover, a metaregression revealed a significant negative association between ES and mean mini‐mental state examination score in AD group (slope = −0.1203, p = 0.0004). Conclusions: Our results revealed higher D‐serine levels in the serum and CSF of patients with AD relative to the controls. Further studies with a larger sample size and longer follow‐up are recommended to clarify this association.