When the sample was stratified by clinical status, rs769449 showed a strong and similar effect size in both cases (n = 519; Beta: 0.067; p = 3.38 × 10−6) and in controls (n = 687; Beta: 0.075, p = 1.54 × 106) with CSF

ptau levels ( Table S2). Several studies have suggested that up to 30% Hydroxychloroquine manufacturer of elderly nondemented control samples meet neuropathological criteria for AD ( Price and Morris, 1999; Schneider et al., 2009). It has also been shown that individuals with CSF Aβ42 levels less than 500 pg/ml in the Knight-ADRC-CSF, and 192 pg/ml in the ADNI series have evidence of Aβ deposition in the brain, as detected by PET-PIB ( Fagan et al., 2006; Jagust et al., 2009). Individuals with CSF Aβ42 levels below these thresholds could be classified as preclinical AD cases with the presumption that some evidence of fibrillar Aβ deposits would be detected ( Fagan et al., 2006; Jagust et al., 2009). When we used these thresholds, rs769449 showed a significant association with CSF tau and ptau in both strata, although the effect size was almost two-fold higher in individuals with high Aβ42 levels (n = 416; Beta: 0.072; p = 6.58 × 10−5, for CSF tau levels) than in individuals with low Aβ42 levels (n = 478; Beta: 0.035; p = 1.83 × 10−2, for CSF tau levels; Table S2). These results indicate that the residual association of SNPs in the SB203580 molecular weight APOE region is

not dependent on clinical status or the presence of fibrillar Aβ pathology and clearly suggests that DNA variants in the APOE gene region influence tau pathology independently of Aβ or AD disease status. To analyze whether there is more than one independent signal in the APOE gene region, APOE genotype was included in the model as a covariate ( Table 4; additional figures on https://hopecenter.wustl.edu/data/Cruchaga_Neuron_2013). The association for the SNPs located in the APOE region was reduced drastically

(p values between 0.02 and 0.008), suggesting that most of the association in this locus is driven by APOE genotype. Outside the APOE region, we detected genome-wide significant association with three loci for CSF tau, ptau, or both at 3q28, 9p24.2, and 6p21.1. Dichloromethane dehalogenase Several SNPs in each locus showed highly significant p values ( Figure 1). For all loci, at least one SNP was directly genotyped ( Table 2) and each of the data sets contributed to the signal, showing similar effect sizes and direction ( Table S3), suggesting that these are real signals and unlikely to be the result of type I error. The strongest association for CSF tau, after APOE, is rs9877502 (p = 4.98 × 10−09), located on 3q28 between GEMC1 and OSTN and the noncoding RNA SNAR-I ( Figures 1 and 2). Fifty-five intragenic SNPs located between SNAR-I and OSTN, showed a p value lower than 9.00 × 10−05 (additional information on https://hopecenter.wustl.edu/data/Cruchaga_Neuron_2013).