GAB2 Alleles Modify Alzheimer's Risk in APOE Epsilon4 Carriers

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2007 Jun 8

PMID 17553421

Citations 229

Authors

Eric M Reiman

Jennifer A Webster

Amanda J Myers

John Hardy

Travis Dunckley

Victoria L Zismann

Keta D Joshipura

John V Pearson

Diane Hu-Lince

Matthew J Huentelman

David W Craig

Keith D Coon

Winnie S Liang

RiLee H Herbert

Thomas Beach

Kristen C Rohrer

Alice S Zhao

Doris Leung

Leslie Bryden

Lauren Marlowe

Mona Kaleem

Diego Mastroeni

Andrew Grover

Christopher B Heward

Rivka Ravid

Joseph Rogers

Michael L Hutton

Stacey Melquist

Ron C Petersen

Gene E Alexander

Richard J Caselli

Walter Kukull

Andreas Papassotiropoulos

Dietrich A Stephan

Affiliations

Soon will be listed here.

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.

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