Associations between CLU polymorphisms and memory performance: The role of serum lipids in Alzheimer's disease

CLU encoding clusterin, has been reported to associate with Alzherimer's disease (AD) by genome-wide asso-ciation studies (GWAS) based on Caucasian populations. Our previous case-control study has independently confirmed the disease association of CLU in Chinese population. Since little is known about the underlying mechanism of CLU in AD, we have conducted this study to investigate whether the genetic impact of CLU polymorphisms on cognitive functioning is via serum lipid's dysfunction. Three GWAS previously published CLU polymorphisms including rs2279590, rs11136000 and rs9331888, were genotyped in 689 subjects. Serum levels of triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured and tested as mediators. Delayed Word Recall Test (DWRT) was used to evaluate subjects' memory performance. Multiple mediation analysis, a nonparametric procedure to create confidence interval, was performed according to Preacher and Hayes's Bootstrapping method. Our findings suggested significant corre-lation between CLU polymorphism and DWRT scores for rs11136000 (p = 0.045) after adjustment for age, gender, body mass index, and APOE epsilon 4 status, with borderline significant correlation for rs2279590 (p = 0.058). Both T allele of rs11136000 and A allele of rs2279590 were negatively correlated with serum TG levels (p = 0.003; p = 0.001, separately). Moreover, A allele of rs2279590 was positively correlated with serum HDL-C levels (p = 0.015). Consistent with our hypotheses, the genetic impact of CLU polymorphisms on memory performance were partially mediated through TG (rs11136000 95% CI [-0.099,-0.003] and rs2279590 95% CI [-0.104, -0.004]), but not through HDL-C and LDL-C. Our findings indicate CLU polymorphisms may modify AD susceptibility through lipid metabolic pathway.