title: Genetic variation modifies risk for neurodegeneration based on biomarker status.
abstract: BACKGROUND
  While a great deal of work has gone into understanding the relationship between Cerebrospinal fluid (CSF) biomarkers, brain atrophy, and disease progression, less work has attempted to investigate how genetic variation modifies these relationships. The goal of this study was two-fold. First, we sought to identify high-risk vs. low-risk individuals based on their CSF tau and Aβ load and characterize these individuals with regard to brain atrophy in an AD-relevant region of interest. Next, we sought to identify genetic variants that modified the relationship between biomarker classification and neurodegeneration.
  
  
  METHODS
  Participants were categorized based on established cut-points for biomarker positivity. Mixed model regression was used to quantify longitudinal change in the left inferior lateral ventricle. Interaction analyses between single nucleotide polymorphisms (SNPs) and biomarker group status were performed using a genome wide association study (GWAS) approach. Correction for multiple comparisons was performed using the Bonferroni procedure.
  
  
  RESULTS
  One intergenic SNP (rs4866650) and one SNP within the SPTLC1 gene (rs7849530) modified the association between amyloid positivity and neurodegeneration. A transcript variant of WDR11-AS1 gene (rs12261764) modified the association between tau positivity and neurodegeneration. These effects were consistent across the two sub-datasets and explained approximately 3% of variance in ventricular dilation. One additional SNP (rs6887649) modified the association between amyloid positivity and baseline ventricular volume, but was not observed consistently across the sub-datasets.
  
  
  CONCLUSIONS
  Genetic variation modifies the association between AD biomarkers and neurodegeneration. Genes that regulate the molecular response in the brain to oxidative stress may be particularly relevant to neural vulnerability to the damaging effects of amyloid-β.
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics and Research, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hohman
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics and Research, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Mary Ellen I
authors.initials: ME
authors.lastname: Koran
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics and Research, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
keywords: Alzheimer's disease (AD); CSF biomarkers; MRI; amyloid; gene-environment interaction; genomics; tau proteins