Figure 1.
Rs1868402 is associated with CSF ptau181 levels, PPP3R1 mRNA expression levels and tangle counts.
A. Association of rs1868402 with CSF ptau181 levels (WU-ADRC-CSF n = 353) was tested by an Analyses of Covariance (ANCOVA) including CDR, age and APOE genotype as covariates. B: Minor allele carriers of rs1868402 have significantly lower PPP3R1 mRNA levels in individuals with AD pathology (n = 82). C: Minor allele carriers of rs1868402 have significantly higher numbers of tangles (n = 82). D: PPP3R1 mRNA expression correlates with tangle counts in individuals with AD pathological changes (n = 82). The p-value is for the correlation between mRNA levels and genotypes.
Table 1.
Summary of sample characteristics.
Table 2.
Summary of biomarker characteristics.
Table 3.
SNPs associated with CSF ptau181 levels in the initial series, the replication series and the combined dataset.
Table 4.
Rs 1868402 is associated with CSF ptau181 levels in individuals with Aβ deposition.
Figure 2.
Survival curves comparing age at onset of LOAD between the different genotypes of rs1868402.
Survival fractions were calculated using the Kaplan-Meier method and significant differences were calculated by Log-rank test. Association with age at onset was calculated in a combined series with samples from WU-ADRC-CC, ADNI-CC and MRC.
Table 5.
Rs1868402 is not associated with risk for AD.
Figure 3.
Genetic variants associated with CSF ptau181 levels are also associated with rate of progression of AD.
Rate of progression is defined as the change in the Clinical Dementia Rating sum of boxes (SB-CDR) score per year. Association of SNPs with progression was calculated using a mixed linear model (PROC MIXED) after controlling for age, sex, APOE, initial CDR, CSF ptau181 and Aβ42 levels. A. Minor allele carriers of rs1868402, are associated with higher CSF ptau181 levels, and show a 6 fold faster progression than homozygotes for the major allele (CDR-SB/year: 0.58 vs 0.09; p = 0.0026) in individuals from the WU-ADRC-CSF with low CSF Aβ42 levels (<500pg/ml). For this SNP the dominant model was used because it showed the best fit in all the analyses. B. rs3785883 genotypes do not have significantly different progression rates P = 0.057. The genotype frequency distribution for rs3785883 with disease progression is most likely not significant due to the low statistical power. AA carriers show a CDR-SB of 1.01, AG of 0.47 and GG 0.26 (p = 0.057). The additive model was used because it showed the best fit. C. Rs1868402 and rs3785883 show an epistatic interaction. Carriers of the alleles associated with higher CSF ptau181 levels (CT+CC for rs1868402 and AA for 3785883) showed a CDR-SB/year of 1.02 vs −0.006 for carriers of alleles associated with lowest CSF ptau181 levels. LP indicates lumbar puncture.
Table 6.
Association with rate of disease progression.
Table 7.
Variants that modify CSF Aβ42 levels affect risk for AD, whereas variants associated with CSF ptau181 levels affect rate of progression.