The alleles associated with lower tau and ptau levels (which would be considered protective) are associated with lower risk for AD, lower tangle counts and slower memory decline. As in the previously published GWAS for CSF tau/ptau levels, we found that the APOE locus was the strongest signal for CSF tau and ptau ( Han et al., 2010; Kim et al., 2011; Table 2). SNPs in this locus explain between 0.25% and 0.29% of the variability in CSF tau and ptau levels ( Table 3). APOE is a known genetic risk factor for AD and most functional studies have focused on Aβ-dependent mechanisms. To determine

whether or not Ibrutinib price the association of APOE SNPs with CSF tau and ptau levels was dependent of Aβ pathology we performed analyses including CSF Aβ42 levels as a covariate. We also stratified our samples by case control status and by low or high CSF Aβ42 levels. In all of these analyses, we PI3K activation found that the association between APOE SNPs and tau or ptau levels remained significant ( Table 4 and S2), suggesting that APOE may also affect tau pathology via an Aβ-independent mechanism. Several other studies support this hypothesis. APOE shows isoform specific differences in its interaction with tau in vitro ( Gibb et al., 2000; Zhou et al., 2006), and in transgenic mice neuron-specific differences

in APOE isoform proteolysis are associated with increased tau phosphorylation ( Brecht et al., 2004) and pathology ( Andrews-Zwilling et al., 2010). These data see more provide additional evidence that APOE could also influence risk for AD through a tau-dependent

mechanism, independent of effects on Aβ. When APOE genotype was included as a covariate, some SNPs in the APOE locus showed a moderate association with CSF tau/ptau levels (rs769449; p = 9.07 × 10−03), indicating that most of the association is driven by APOE genotype, but suggesting that there may be additional variants in this region that modify CSF tau levels and risk for AD, independently of APOE genotype. SNPs within the 3q28 locus showed association with CSF tau/ptau levels and a range of AD phenotypes including AD risk in the case control data set, tangle pathology, and rate of cognitive decline providing four independent sources of evidence that variants in this region influence risk for AD through a tau-dependent mechanism. Bioinformatic analysis did not reveal any strong putative functional SNP. However, the genes located in this region (GEMC1, OSTN and the noncoding RNA SNAR-I, IL6RAP, UTS2D, and CCDC50) are highly expressed in brain and involved in neuronal synaptogenesis ( Yoshida et al., 2012). The most significant SNP in this locus and 33 SNPs in LD with rs9877502 are located in transcription factor binding sites and some of these SNPs are also part of a transcription factor matrix (additional information on https://hopecenter.wustl.