There is substantial evidence that cerebrospinal fluid (CSF) levels of both Aβ42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Aβ and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau ( MAPT ) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Aβ42 levels were used to stratify the sample into those with and without likely Aβ deposition in the brain the association was only observed in individuals with evidence of Aβ deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Aβ deposition. This endophenotype-based approach provides evidence for a gene ( MAPT SNPs)–physiological environment (Aβ deposition) interaction that places changes in CSF tau after Aβ deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.