Blood levels of MCP‐1 modulate the genetic risks of Alzheimer's disease mediated by HLA‐DRB1 and APOE for Alzheimer's disease

Introduction C‐Reactive protein (CRP) and monocyte chemoattractant protein‐1 (MCP‐1) are both implicated in the peripheral proinflammatory cascade and blood‒brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP‐1 level exerts different effects on the AD risk depending on the genotypes. Methods Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed. Results An elevated blood MCP‐1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA‐DRB1) rs9271192‐AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50–6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59–6.53, p = 0.001). In contrast, among HLA‐DRB1 rs9271192‐AA and APOE ε4 noncarriers, blood MCP‐1 levels were not associated with these phenotypes. Discussion Since HLA‐DRB1 and APOE are expressed in the BBB, blood MCP‐1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA‐DRB1 rs9271192‐AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways.