Abstract
Monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in peripheral inflammation, has been shown to modulate established Alzheimer's disease (AD) loci. In this study, we hypothesized that blood MCP-1 levels may impact the associations of other genetic variants with AD risk beyond the well-established AD loci. We performed a genome-wide association study (GWAS) using logistic regression with the generalized estimating equation (GEE) and Cox proportional hazards models to examine the combined effects of single nucleotide polymorphisms (SNPs) and blood MCP-1 levels on AD. Three datasets were used: the Framingham Heart Study (FHS), Religious Orders Study/Memory and Aging Project (ROSMAP), and Alzheimer's Disease Neuroimaging Initiative (ADNI). We identified SNPs in two genes in the meta-analysis, namely, neuron navigator 3 (NAV3, also named unc-53 homolog 3, rs696468) (p < 7.55 × 10(-9)) and the homolog unc-5 netrin receptor c (UNC5C rs72659964) (p < 1.07 × 10(-8)), which are modified by blood MCP-1 concentration for AD risk. Elevated blood MCP-1 concentrations increased AD risk and brain AD pathology in individuals with NAV3 (rs696468-CC) and UNC5C (rs72659964-AT + TT) genotypes. Given that NAV3 and UNC5C are involved in regulating neurite outgrowth and guidance, increased MCP-1 levels may disturb the functions of vulnerable gene carriers to increase AD risk.