The most significant SNPs in this locus are located in intron 7 of GLIS3, a gene which is highly expressed in brain. However, these SNPs (rs514716) are not associated with GLIS3 expression in our relatively small series of brain samples (82 AD cases and 39 nondemented individuals). Both common and rare variants in this gene have been associated with risk for diabetes ( Barker et al., 2011; Dimitri et al., 2011). There are several studies linking AD with glucose Anti-diabetic Compound Library order metabolism and diabetes ( Accardi et al., 2012). In fact, a meta-analysis combining data from eight studies, observed an association between

diabetes mellitus and increased risk for AD (OR: 1.51, 95%; CI = 1.31–1.73) ( Bertram et al., 2013). In addition, our pathway analysis IWR-1 cell line independently identified a diabetes pathway (path: hsa04930, p value for ptau = 6.60 × 10−03, and tau = 8.00 × 10−04; Table S6), because of an enrichment of significant SNPs in MAPK9, IRS2, and MAPK1. Two independent analyses in this study therefore suggest that diabetes-related genes may influence CSF tau and ptau levels, and ultimately risk for AD. These data all provide supportive evidence for common variants in this locus that influence

AD pathogenesis. Finally, because SNPs identified in this study were associated with CSF tau/ptau levels, we tested whether these SNPs are also associated with MAPT gene expression. None of the genome-wide significant SNPs showed association with MAPT expression in the brain and MAPT expression was not associated with case-control status in our brain series, the GSE15222, or any other published work on gene expression

in brain ( Webster et al., 2009; Zou et al., 2012). These results suggest that the SNPs identified in this study influence CSF tau/ptau protein levels posttranscriptional mechanism. Tau protein undergoes not several posttranslational modifications including acetylation, glycosylation; and phosphorylation. These changes are thought to play an important role in tau-related pathogenesis ( Farías et al., 2011; Marcus and Schachter, 2011). It is possible that the genes identified in this study modify tau protein levels through posttranslational modification rather than gene expression. Together these results clearly demonstrate the utility of using these endophenotypes to identify AD risk variants and variants associated with the rate of decline in symptomatic AD cases. The use of these endophenotype allowed us to identify risk variants that were not identified by GWAS because either those variants did not pass the stringent multiple test correction applied in the GWAS or were not covered in the earlier studies, because of their relatively low MAF. A second advantage of this approach is that in contrast to GWAS hits from case control studies the endophenotype predicts a specific biological hypothesis for the pathogenic effect, which can be directly tested.