Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

Abstract

The noradrenergic and dopaminergic systems are affected in Alzheimer's disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine ␤hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called -1021C/T or -970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau 181 , p-tau 199 , and p-tau 231 ), amyloid-␤ 42 (A␤ 42 ), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in A␤ 42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau 181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. A␤ 42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau 181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

Association of IL-1β, IL-1α and IL-10 single nucleotide polymorphisms with Mini-Mental State Examination and event-related potentials

“…Our results support these studies as MMSE scores were significantly lower in MCI patients with the IL-10 -1082 A genotype. Additionally, these results are in accord with our recent study showing that CSF ptau 181 levels are pathological in patients carrying the AA IL-10 -1082 genotype [18]. However, it should kept in mind that other studies failed to detect an association between the IL-10 -1082 polymorphism and AD [46,72,[79][80][81][82][83][84][85][86] or showed opposite results (association of the G allele in IL-10 -1082 polymorphism with increased risk for AD) [71,74].…”

“…The most important finding of this study is the association of the IL-1β -1473 polymorphism with MMSE scores and P300 ERP. This finding together with our previous results [18] indicates that the IL-1β -1473 polymorphism could be strong genetic biomarker of AD. MMSE scores in all subjects with different IL-1α -889C/T genotypes.…”

“…Our results agree with previous studies showing increased risk of AD in carriers of a T allele in the IL-1α -889 polymorphism [8][9][10][11][12][13][14][15][16][17]46,[50][51][52]. However, due to the facts that many studies did not reveal an association of the IL-1α -889 polymorphism and AD and that our recent study failed to detect an association of this polymorphism with CSF AD biomarkers [18], these results should be validated in larger cohorts.…”

“…+3953, IL-1β -31 and IL-1β -511 polymorphisms were mainly tested [43][44][45][46], although the results of our previous study [18] showed that levels of various cerebrospinal fluid (CSF) biomarkers (amyloid β 1-42 , total tau, phosphorylated tau isoforms and visinin-like protein 1) were pathological in patients carrying a G allele in the IL-1β -1473 polymorphism. The results of the present study are further strengthening the association of IL-1β -1473 polymorphism with AD, as MMSE scores were lower and P300 latencies increased in patients carrying a G allele in the IL-1β -1473 polymorphism.…”

“…As presence of a T allele in the IL-1α -889 polymorphism leads to increase in transcriptional activity of the IL-1α gene [29,30], this could explain why carriers of a T allele in the IL-1α -889 polymorphism have higher risk for AD [8][9][10][11][12][13][14][15][16][17]. Our recent study showed that there is no association between CSF AD biomarkers and IL-1α -889 genotypes [18]. However, the present study indicates that although the IL-1α -889 polymorphism is not suitable as an early genetic biomarker of AD, it could be an index of disease severity as patients carrying the T allele in IL-1α -889 polymorphism have significantly lower MMSE scores.…”