GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers

Neuron. 2007 Jun 7;54(5):713-20. doi: 10.1016/j.neuron.2007.05.022.

Abstract

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Apolipoprotein E4 / genetics*
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Brain Chemistry / genetics
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Gene Expression Regulation / genetics
  • Gene Frequency
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Haplotypes / genetics
  • Humans
  • Mutation
  • Neurofibrillary Tangles / genetics
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Phosphorylation
  • Polymorphism, Single Nucleotide / genetics*
  • Risk Factors
  • tau Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apolipoprotein E4
  • GAB2 protein, human
  • Genetic Markers
  • tau Proteins

Grant support