8 June 2007. The apolipoprotein E4 allele (ApoE4) is the most prominent genetic risk factor for late-onset Alzheimer disease (LOAD), but it is not the whole story. The strong contribution of E4 to AD risk has made it difficult to find additional weaker, but nonetheless important genes that help determine when, or if, a person will get AD. Using an optimized genome-wide survey paradigm, a collaborative group led by Dietrich Stephan at the Translational Genomics Research Institute and the Banner Alzheimer’s Institute in Phoenix, Arizona, have succeeded in picking out a gene that acts with E4 to further elevate the risk of late-onset Alzheimer disease. One common allele of the gene, GRB-associated binding protein 2 (GAB2), quadrupled the odds of having AD in ApoE4-positive people.
The work, published in the June 7 Neuron, also links GAB2 expression to pathological changes in AD brain and tau phosphorylation.
To find contributions to late-onset AD, the Stephan group performed a whole-genome single nucleotide polymorphism (SNP) association, with some enhancements to increase the ability to detect weak genetic interactions. The geneticists pushed the density of SNP markers up to more than 500,000 per genome. They then analyzed 1,411 LOAD cases and controls, collected from 20 AD research centers (ADRCs) throughout the U.S. and one in the Netherlands. The subjects fell into distinct cohorts. This enabled the scientists to identify SNP associations in one autopsy-verified cohort comprising brain donors, and to confirm them in another, similar group. A third cohort of clinically diagnosed people who are still alive helped make sure that the results were not skewed by selection bias with the brain donors. Previous work on this sample group confirmed ApoE4 as the predominant genetic risk factor for late-onset AD (see ARF related news story). In that study, people with two copies of the ApoE4 risk allele had 25 times higher risk of disease compared to those without an E4 allele. That’s an even higher risk elevation than is typically seen in ApoE4 homozygote people (usually this number is a 10- to 15-fold risk increase), but no other SNPs showed a significant association with AD risk.
In the new study, first authors Eric Reiman and Jennifer Webster in Phoenix, Arizona, and Amanda Myers of the University of Miami in Florida analyzed the SNP associations for ApoE4 carriers and non-carriers separately. By this approach, they hoped to find genes that interact with E4 and to detect weaker associations that might be obscured by the strength of the E4 effect.
Their strategy paid off: ten of the 25 SNPs with the most significant association to LOAD in the E4 carriers lay within one gene, the GRB-associated binding protein 2 (GAB2) gene on chromosome 11q14.1. Six of them were associated with LOAD in all three cohorts. They lay on one haplotype block that encompassed the entire GAB2 gene, making a strong case for the association between GAB2 and LOAD.
Haplotype mapping identified three common forms of GAB2. One common haplotype contained six SNPs associated with increased risk of AD, one with decreased risk, and one that had no effect. The GAB2 SNP with the strongest association showed a significantly increased risk for AD (odds ratio 4.06, 95 percent confidence interval, 2.81-14.69). By contrast, non-ApoE4 carriers with the same GAB2 SNP showed no elevated risk over non-carriers without it.
To provide biological support for the role of GAB2, the researchers measured gene expression in brain tissue from AD cases and controls. They found LOAD-related increases in GAB2 expression in non-tangle-bearing neurons in some brain areas affected by AD. GAB2 message was increased in the hippocampus and posterior cingular cortex, but was unchanged in four other regions including the entorhinal cortex, middle temporal gyrus, and superior frontal gyrus. In the hippocampus and posterior cingular cortex, GAB2 immunohistochemistry revealed protein in dystrophic neurons and neurites, and in cells with neurofibrillary tangles. In the cortex, the protein was also present in some normal neurons.
GAB2 is a central activator of the PI3 kinase signaling pathway, which affects tau phosphorylation via the regulation of the AKT/GSK3β kinase cascade. The investigators hypothesized that GAB2 might protect cells by blocking tau phosphorylation. Consistent with this idea, downregulating GAB2 expression using siRNA in glioblastoma cells resulted in enhanced phosphorylation of tau at serine 262, a site elevated in AD.
Taken together, the results suggest that GAB2 modifies AD risk in ApoE4 carriers and influences neuropathology. The findings open another small window on the pathogenesis of late-onset AD, but the story is far from finished. To move it along, the authors will make their extensive SNP dataset publicly available for further studies on this gene and others.—Pat McCaffrey.
Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA. GAB2 Alleles Modify Alzheimer's Risk in APOE epsilon4 Carriers.
Neuron. 2007 Jun 7;54(5):713-720. Abstract