Tau phosphorylation pathway genes and cerebrospinal fluid tau levels in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.

FIG. 1

CSF tau levels in AD compared to Controls. CSF log 10 p-tau levels (Panel A). CSF log 10 t-tau levels (Panel B). CSF log 10 p-tau/t-tau levels (Panel C).

FIG. 2

Beta coefficients for CSF phosphorylation tau and total tau levels in AD and controls for Tau phosphorylation pathway gene collapsed genotypes. The effect of a SNP for each disease group (AD or controls) was analyzed using linear regression, where CSF biomarker level was the outcome variable and the independent variables were age, gender, race, APOE ε4 status, disease status and SNP collapsed genotype (presence or absence of the minor allele; i.e., EF and EE vs. FF). A confidence interval which does not cross the vertical line at zero indicates that the difference in genotypes is significant (P<0.05) before adjustment for multiple comparisons for that group. A beta coefficient (solid square for AD, circle for controls) to the right of the vertical line represents higher CSF biomarker levels for the collapsed genotype group that contains minor alleles (EF, EE). Significant SNP P-values are shown in Table III.

FIG. 3

Beta coefficients for CSF phosphorylation tau relative to total tau levels in AD and controls for tau phosphorylation pathway gene collapsed genotypes. The effect of a SNP for each disease group (AD or controls) was analyzed using linear regression, where CSF biomarker level was the outcome variable and the independent variables were age, gender, race, APOE ε4 status, disease status, SNP collapsed genotype (presence or absence of the minor allele; i.e., EF and EE vs. FF). A confidence interval which does not cross the vertical line at zero indicates that the difference in genotypes is significant (P<0.05) before adjustment for multiple comparisons for that group. A beta coefficient (solid square for AD, circle for controls) to the right of the vertical line represents higher CSF biomarker levels for the collapsed genotype group that contains minor alleles (EF, EE). Significant SNP P-values are shown in Table III.

FIG. 4

CSF tau levels in controls and AD patients stratified by collapsed genotype for SNPs rs 7768046 (FF = AA; EE, EF = GG, AG) (Panel A) and rs913675 (FF = AA; EE, EF = GG, AG) (Panel B). Unadjusted P-values are based on the two-sample t-test while adjusted P-values take into account gender, race, age, and APOE ε4 status (parentheses) are based on a linear model.