The apolipoprotein E (APOE) varepsilon4 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 varepsilon4 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 theGRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entireGAB2gene. SNP rs2373115 (p = 9 × 10-11) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts withAPOEvarepsilon4 to further modify risk.GAB2was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference withGAB2gene expression increased tau phosphorylation. Our findings suggest thatGAB2modifies LOAD risk inAPOEvarepsilon4 carriers and influences Alzheimer's neuropathology.