Interleukin-18 gene polymorphisms predict risk and outcome of Alzheimer's disease

Inflammation has been extensively implicated in Alzheimer's disease (AD) pathogenesis. Although there is evidence of a key role for cytokines in neuroinflammation processes, so far the proinflammatory cytokine IL-18 has not yet been associated to AD. This study was aimed to investigate the impact of two polymorphisms of human IL-18 gene promoter at positions -607 (C/A) and -137 (G/C) on both susceptibility to and progression of AD. The results revealed that the genotype distribution of -607 (C/A) polymorphism was different between AD patients and control subjects (χ2=7.99, df= 2, p=0.0184). In particular, carriers of CC genotype were at increased risk of developing AD (OR=2.33; 95% CI=1.29-4.22; p=0.0052). The observed genotypes were in Hardy-Weinberg equilibrium as for -607 polymorphism, whereas the -137 polymorphism appeared in Hardy-Weinberg disequilibrium only in patient group (p=0.0061). Finally, in a two year follow up study, the -137 CC genotype was strongly and specifically associated with a faster cognitive decline (F=4.024; df=4,192; p=0.0037 for time by IL-18 -137 G/C group interaction) with no interaction effect with the ApoE ε4/non ε4 allele presence. Since IL-18 cytokine promoter gene polymorphisms have been previously described to have functional consequences on IL-18 expression, it is possible that individuals with a prevalent IL-18 gene variant have a dysregulated immune response, suggesting that IL-18 mediated immune mechanisms may play a crucial role in AD.