Genome-Wide Association Analyses Using Cerebrospinal Fluid Tau and Phospho-Tau Levels As An Endophenotype for Alzheimer’s Disease

Cerebrospinal fluid (CSF) Aß42, tau and tau phosphorylated at threonine 181 (ptau) are promising biomarkers for Alzheimer's Disease. Using a candidate gene approach we have previously identified genetic factors associated with CSF Aß42, and p tau that are also associated with risk for AD, age at onset or disease progression. In this study we have performed a genome-wide association study using CSF tau and p tau levels as an endophenotype to identify additional genetic factors implicated in AD pathogenesis. CSF tau and p tau were measured in 957 European American samples. 356 samples were enrolled in longitudinal studies at the WU-ADRC, 391 in ADNI and 210 in studies at the University of Washington. The samples were genotyped using Illumina chips. The1000 genome data and MACH software were used to impute additional SNPs. The normalized CSF tau and p tau values were tested for association using an additive model in PLINK. Age, gender, site, and/or APOE genotype and CSF Aß42 were included as covariates. Only SNPs in the APOE-TOMM40 region showed genome-wide significant association with tau/p tau levels (rs2075650; p = 1x10−9). This association disappeared when APOE genotype was included as a covariate, indicating that APOE genotype is driving the association (rs2075650; p = 0.33). On the other hand, rs2075650 still showed strong association when CSF Aß42 levels but not APOE genotype were included as a covariate (p = 1.34x10−7). Thirty-seven SNPs outside the APOE-TOMM40 region showed a p-value lower than 10−5. Only 26 were expected by chance. This result may indicate that APOE genotype or other SNPs in LD could affect tau pathology independently of the Aß pathology. The fact that we found more SNPs in the 10−5 range than expected by chance may indicate that additional genetic variants may influence CSF tau levels.