IL-1β, IL-6, IL-10, and TNFα single nucleotide polymorphisms are associated with cerebrospinal �uid levels of biomarkers of Alzheimer’s disease

Background Neuroin�ammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-in�ammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNFα) that participate in neuron damage. However, anti-in�ammatory cytokines (such as IL-10), which maintain homeostasis of immune response, are also released. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β -1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896) and TNFα -308A/G (rs1800629) polymorphisms with AD. Methods In this study, we assessed whether people carrying certain genotypes in these polymorphisms are more prone to develop AD-related pathology, re�ected by pathological levels of cerebrospinal �uid (CSF) AD biomarkers including amyloid β1–42 (Aβ1–42), total tau (t ‐ tau), tau phosphorylated at Thr 181 (p ‐ tau181), Ser 199 (p ‐ tau199), and Thr 231 (p ‐ tau231), and visinin ‐ like protein 1 (VILIP ‐ 1). The study included 115 AD patients, 53 patients with mild cognitive impairment (MCI), 11 healthy controls, and 54 patients with other causes of dementia. Results A signi�cant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. T-tau levels were increased while Aβ1-42 levels were decreased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G and GG TNFα -308A/G genotype. Conclusions These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G) and TNFα (-308A/G) could be more vulnerable to development of neuroinglammation, and consequently of AD. IL-6 -174C/G and TNFα -308A/G genotypes that were previously associated with AD [12,13]. We compared the levels of six AD CSF biomarkers (Aβ 1-42 , t-tau, p-tau 181 , p-tau 199 , p-tau 231 and VILIP-1) among patients with aforementioned genotypes. This study gave several notable �ndings. Levels of Aβ 1-42 were decreased, while levels of t-tau were increased in carriers of G allele in IL-1β -1473C/G polymorphism. T-tau levels were also signi�cantly increased in patients with CG IL-1β -1473C/G genotype. P-tau levels were signi�cantly increased in patients with AA IL-10 -1082G/A and GG TNFα -308A/G genotype, and in carriers of G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. Levels of VILIP-1 were increased in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G and GG TNFα -308A/G genotype. in increased in�ammation, favouring the development of AD [27]. It was found that the C IL-6 -174 allele is associated with decrease in IL-6 plasma levels [10] so this genotype could be protective against AD. TNFα being a main pro-in�ammatory cytokine, its higher production is associated with increased in�ammation and AD progression. TNFα inhibitors have been suggested as potential therapeutics for AD [30]. The in�uence of TNFα -308 polymorphism on TNFα protein production remains however unclear. Most studies reported that the A TNFα -308 allele is associated with increased production of TNFα while some studies did not �nd differences in TNFα protein levels in patients with different TNFα -308 genotypes [33]. Regarding polymorphisms in additional pro-in�ammatory cytokines IL-1α and IL-1β that were also tested in this study, it was showed that T allele in the IL-1α -889 polymorphism was associated with increased transcriptional activity in IL-1α gene and overexpression of IL-1α protein [34,35], while G allele in IL-1β -1473 polymorphism was associated with weaker promoter activity [36]. Our results support most of these studies, because we observed pathological levels of CSF AD biomarkers in carriers of A allele in IL-10 -1082 polymorphism, carriers of G allele in IL-6 -174 polymorphism and carriers of A allele in TNFα -308 polymorphism. However, regarding polymorphisms in genes for IL-1α and IL1β, our results studies. CSF AD biomarkers did not differ with IL-1α -889 genotypes, while levels of CSF AD biomarkers pathological G allele in -1473 polymorphism. of the genetic Sarajärvi that A allele carriers are less susceptible for AD than GG homozygotes, their analysis of biomarkers in patients with different TNFα -308 genotypes revealed that levels of Aβ 1-42 were pathological in carriers of an A TNFα -308 allele compared to GG homozygotes This with our study as we detected pathological CSF levels of p-tau 231 and VILIP-1 in GG homozygotes in comparison to carriers of an A TNFα -308 allele, and we found no differences in CSF Aβ 1-42 levels between patients with different TNFα -308 genotype. The �ndings of et al. our results [12]. Although the results of our previous genetic study [128] showed no signi�cant difference in distribution of TNFα -308 genotypes between AD patients and HC, in the present study we detected pathological levels of CSF p-tau 231 and VILIP-1 in AD patients with the GG compared to AG TNFα -308 genotypes. Other groups also did not detect a difference in distribution of TNFα -308 genotypes between AD patients and HC, but observed difference in distribution of haplotypes (that include the TNFα -308 polymorphism) between AD patients and HC [130,133]. Thus, the scope of our next study should be analysis of TNFα haplotypes’ distribution between AD patients and HC. Our study suggest that heterozygosity in TNFα -308 polymorphism could be protective against AD, as pathological levels of CSF AD biomarkers were detected in both AA and GG TNFα -308 homozygotes. This deserves further validation.