Few studies have investigated whether levels of CSF AD biomarkers differ among patients with different IL-10 -1082G/A, IL-1β -1473C/G, IL-1α -889C/T, 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 (Aβ1-42, t-tau, p-tau181, p-tau199, p-tau231 and VILIP-1) among patients with aforementioned genotypes. This study gave several notable findings. Levels of Aβ1-42 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 significantly increased in patients with CG IL-1β -1473C/G genotype. P-tau levels were significantly 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.
SNPs in genes for IL-1α, IL-1β, IL-6, IL-10 and TNFα can influence transcription and consequently the amount of the produced cytokines [9–11]. Decrease in the amount of anti-inflammatory cytokines and increase in pro- inflammatory cytokines results in increased inflammation, favouring the development of AD . In that way certain genotypes in these SNPs (IL-10 -1082G/A, IL-1β -1473C/G, IL-1α -889C/T, IL-6 -174C/G and TNFα -308A/G) can make some people more vulnerable to the development of neuroinflammation and consequently the development of AD. Given that the production of IL-10 is significantly decreased in carriers of the IL-10 -1082 A genotype [28,29], a decrease in anti-inflammatory cytokine IL-10 levels could result in increased inflammation, favouring the development of AD . It was found that the C IL-6 -174 allele is associated with decrease in IL-6 plasma levels  so this genotype could be protective against AD. TNFα being a main pro-inflammatory cytokine, its higher production is associated with increased inflammation and AD progression. TNFα inhibitors have been suggested as potential therapeutics for AD . The influence 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 [9,31,32], while some studies did not find differences in TNFα protein levels in patients with different TNFα -308 genotypes . Regarding polymorphisms in additional pro-inflammatory 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 . 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 IL-1β, our results differed from aforementioned studies. CSF AD biomarkers did not differ between patients with different IL-1α -889 genotypes, while levels of CSF AD biomarkers were pathological in carriers of G allele in IL-1β -1473 polymorphism.
IL-10 -1082G/A (rs1800896), IL-1β -1473C/G (rs1143623), IL-1α -889C/T (rs1800587), IL-6 -174C/G (rs1800795) and TNFα -308A/G (rs1800629) polymorphisms were previously associated with AD in epidemiological studies. Studies on association of IL-10 -1082G/A polymorphism and AD yielded inconsistent results. Associations between the A allele in IL-10 -1082 polymorphism and increased risk for AD or the G allele and decreased risk for AD have been reported [11,37–43]. However, other investigators found no association between IL-10 -1082 polymorphism and AD [44–52] or showed GG IL-10 -1082 genotype to be significantly increased in AD patients  and AA IL-10 -1082 genotype to decrease the risk for AD . Meta-analyses revealed an association between IL-10 -1082 AA and AG genotype and increased risk for AD , and an association between IL-10 -1082 GG genotype and reduced risk for AD . However, the meta-analysis of Mun et al. found no association between IL-10 -1082 polymorphism and AD risk . Our results agree with studies showing association between IL-10 -1082 A genotype and increased risk for AD [11,37–43].
Cytokine IL-1β is likely involved in cognitive decline related to inflammation . As such, polymorphisms in IL-1β were studied to assess possible association with AD (for example, IL-1β -511, IL-1β -31 and IL-1β +3953 polymorphisms [8,58–60]). Association of IL-1β -1473G/C polymorphism with AD was assessed in only two studies. There was no significant difference in distribution of IL-1β -1473 genotypes between AD patients and controls [61,62]. In contrast to these studies, we observed levels of various CSF AD biomarkers to be altered in subjects with different IL-1β -1473 genotypes. Our results indicate that IL-1β -1473 polymorphism may represent a consistent marker of AD and that the frequency of IL-1β -1473 genotypes should be further tested on larger AD and MCI cohorts.
The association of IL-6 -174C/G polymorphism with AD is ambiguous. Some studies found an association between a C allele in IL-6 -174 polymorphism and decreased risk for AD [63–70], while others found no association between the IL-6 -174 polymorphism and AD [47,48,52,54,71–80]. Additionally, some studies found the C allele in the IL-6 -174 polymorphism to be associated with increased risk for AD [38,41,81–83]. Meta-analyses testing association of IL-6 -174 polymorphism with AD also returned inconsistent results. Dai et al.  and Qi et al.  showed the CC IL-6 -174 genotype to be associated with decreased risk for AD, while Mun et al. showed that the IL-6 -174 polymorphism is not associated with AD . Our results support studies showing that the CC IL-6 -174 genotype is associated with a decreased risk for AD [63–70,84,85].
Studies on association of pro-inflammatory IL-1α cytokine brain overexpression with AD  showed that the presence of a T allele in the IL-1α -889 polymorphism is associated with an increased risk for AD [87–96]. Other studies however did not report an association between this polymorphism and AD [48,53,54,97–116]. Yet, meta-analyses demonstrated that an association between the IL-1α -889 polymorphism and AD exists [8,117–119]. Our study found no association between this polymorphism and CSF biomarkers in any of the analyzed groups.
Variable results were also obtained from investigations of the association between the TNFα -308A/G polymorphism and AD. Several confirmed that presence of the A allele in the TNFα -308 polymorphism increases the risk for AD [46,120–122], while others found no association between this polymorphism and AD [12,33,47,70,123–128]. Other authors suggested that the A allele in the TNFα -308 polymorphism is protective against AD [13,129,130]. Meta-analyses also gave inconsistent results. Furthermore, Di Bona et al.  did not confirm the association between TNFα -308 polymorphism and AD. The meta-analysis of Lee et al.  showed that the A allele in the TNFα -308 polymorphism may be a risk factor for AD in East Asians, but not in Middle Easterners and Europeans. Wang  confirmed that the A allele increases risk for AD in Asians but decreases risk in Northern Europeans. Our study included only three AD patients with the AA TNFα -308 genotype. These three patients had pathological levels of all examined CSF AD biomarkers, except for Aβ1-42 (Table 2). This result remains however inconclusive due to the small sample. We also detected pathological levels of CSF AD biomarkers in patients with the GG TNFα -308 genotype The levels of CSF AD biomarkers in patients with different TNFα -308 genotypes were also investigated by Sarajärvi et al.  and Laws et al.  Although the genetic analysis of Sarajärvi et al.  showed 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 Aβ1-42 were pathological in carriers of an A TNFα -308 allele compared to GG homozygotes . This contrasts with our study as we detected pathological CSF levels of p-tau231 and VILIP-1 in GG homozygotes in comparison to carriers of an A TNFα -308 allele, and we found no differences in CSF Aβ1-42 levels between patients with different TNFα -308 genotype. The findings of Laws et al. support our results . Although the results of our previous genetic study  showed no significant difference in distribution of TNFα -308 genotypes between AD patients and HC, in the present study we detected pathological levels of CSF p-tau231 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.
IL-1α, IL-1β, IL-6, IL-10 and TNFα were also studied as potential biomarkers of AD. However, the results on measurement of these and other inflammatory markers in body fluids were inconsistent . Thus, recently a lot of meta-analyses were conducted with purpose to determine the potential of inflammatory markers as biomarkers of AD. The increase in IL-6 was associated with all-cause dementia, but not AD in meta-analyses of Darewwsh et al.  and Koyama et al.  Additional meta-analyses observed increase in peripheral IL-6, IL-1β [137–139] and TNF-α  in AD patients compared to HC. However, meta-analyses of Saleem et al.  and Su et al.  observed no significant difference in inflammatory markers between MCI patients and HC. Brosseron et al.  divided inflammatory markers measured in body fluids into three groups by involvement in the disease; 1) cytokines unchanged during disease (like IL-1α), 2) cytokines that increase slightly but steadily during disease (like IL-1β, IL-6, and TNF-α) and 3) cytokines that have a peak when MCI converses to AD.