Alzheimer's disease risk variants show association with cerebrospinal fluid amyloid beta

The use of quantitative endophenotypes in genetic studies may provide greater power, allowing for the use of powerful statistical methods and a biological model for the effects of the disease-associated genetic variation. Cerebrospinal fluid (CSF) amyloid beta (A beta) levels are promising endophenotypes for late-onset Alzheimer's disease (LOAD) and show correlation with LOAD status and A beta deposition. In this study, we investigated 29 single nucleotide polymorphisms (SNPs) positive in Alz-Gene (http://www.alzgene.org) meta-analyses, for association with CSF A beta levels in 313 individuals. This study design makes it possible to replicate reported LOAD risk alleles while contributing novel information about the mechanism by which they might affect that risk. Alleles in ACE, APOE, BDNF, DAPK1, and TF are significantly associated with CSF A beta levels. In vitro analysis of the TF SNP showed a change in secreted A beta consistent with the CSF phenotype and known Alzheimer's disease variants, demonstrating the utility of this approach in identifying NPs that influence risk for disease via an A beta-related mechanism.