rs7101429 — GAB2 GAB2 Alzheimer's risk modifier

Intronic variant in GAB2 that modulates late-onset Alzheimer's disease risk; the minor G allele is protective

See your personal result for GAB2

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

GAB2 — A Signal Transduction Scaffold That Modifies Alzheimer's Risk

GAB2 (GRB2-associated-binding protein 2)11 GAB2 (GRB2-associated-binding protein 2)
a scaffolding adapter protein that coordinates intracellular signaling downstream of growth factor and cytokine receptors encodes a key node in the PI3K/AKT signaling cascade. In neurons, this pathway regulates the activity of GSK-3β (glycogen synthase kinase-3 beta)22 GSK-3β (glycogen synthase kinase-3 beta)
an enzyme that phosphorylates tau protein; excess tau phosphorylation leads to neurofibrillary tangles, a hallmark of Alzheimer's disease. The rs7101429 variant sits deep within an intron of GAB2. The minor G allele at this locus is protective.

The Mechanism

GAB2 functions by recruiting and activating PI3K after receptor stimulation, leading to AKT phosphorylation and the consequent inhibition of GSK-3β. When GSK-3β activity is suppressed, tau remains in its normal, soluble, microtubule-stabilizing form. When GAB2 expression or function is reduced, PI3K/AKT signaling is weaker, GSK-3β is less inhibited, and tau hyperphosphorylation becomes more likely.

Reiman et al. demonstrated that interfering with GAB2 expression directly increased tau phosphorylation in cell models33 Reiman et al. demonstrated that interfering with GAB2 expression directly increased tau phosphorylation in cell models
providing the mechanistic basis for the genetic association. This biologically grounded mechanism distinguishes GAB2 from many GWAS-identified loci whose function remains unclear.

The Evidence

Reiman et al. (2007) conducted a genome-wide SNP survey across neuropathologically verified AD cases and controls44 Reiman et al. (2007) conducted a genome-wide SNP survey across neuropathologically verified AD cases and controls
n=1,411 across three cohorts, published in Neuron, identifying a GAB2 haplotype strongly associated with AD protection in APOE ε4 carriers (lead variant rs2373115, OR=4.06). The rs7101429 variant was among the haplotype-tagging SNPs.

Schjeide et al. (2009) attempted replication in more than 4,000 DNA samples from approximately 1,300 AD families55 Schjeide et al. (2009) attempted replication in more than 4,000 DNA samples from approximately 1,300 AD families
published in Archives of Neurology and found that rs7101429 was the only GAB2 variant to yield consistent significant association (P=0.002), with minor allele (G) carriers showing approximately 30% reduced AD risk. Crucially, the protective direction matched the original GWA study.

Zou et al. (2013) performed a meta-analysis across four North American case-control series (2,316 LOAD cases, 2,538 controls), combined with all previously published data66 Zou et al. (2013) performed a meta-analysis across four North American case-control series (2,316 LOAD cases, 2,538 controls), combined with all previously published data
up to 22,253 total samples. After pooling, protective GAB2 variants showed odds ratios of 0.82–0.88 (all p<0.04). Higher GAB2 mRNA levels in postmortem brain tissue correlated with fewer neurofibrillary tangles (r=−0.34, p=0.0006) and fewer senile plaques (r=−0.32, p=0.001) in 102 individuals.

Liang et al. (2011) extended the evidence using FDG-PET brain imaging77 Liang et al. (2011) extended the evidence using FDG-PET brain imaging
published in NeuroImage, showing that carriers of the protective GAB2 haplotype maintained higher glucose metabolism in bilateral temporal, parietal, and occipital regions — precisely the areas that deteriorate earliest in Alzheimer's disease. This metabolic preservation was detectable decades before any clinical symptoms.

Replication is mixed: Chapuis et al. (2008) found only a marginal trend across 3,155 participants88 Chapuis et al. (2008) found only a marginal trend across 3,155 participants
Neurobiology of Disease, and a Japanese cohort showed no association at all. The overall evidence places GAB2 rs7101429 as a moderate-evidence risk modifier99 moderate-evidence risk modifier
consistent direction in larger meta-analyses, but not uniformly replicated across all populations.

Practical Implications

Unlike pharmacogenomic variants with direct drug-dosing implications, rs7101429 informs risk stratification rather than a specific therapeutic target.

Monitoring for early cognitive changes — particularly episodic memory and executive function — enables earlier intervention if needed.

Interactions

The most clinically significant interaction is with APOE ε4 status (determined by rs429358 and rs7412). Reiman et al.'s original finding was specifically in APOE ε4 carriers1010 Reiman et al.'s original finding was specifically in APOE ε4 carriers
where the GAB2 haplotype modified risk substantially, and Ikram et al.'s meta-analysis (PMID 19118819) showed pooled ORs specifically in ε4 carriers. Individuals who carry both the A risk genotype at rs7101429 and APOE ε4 may face compounded risk.

rs2373115 (the original lead GAB2 variant from the Reiman 2007 GWAS) and rs4945261 (a second independently associated GAB2 variant) are in partial linkage disequilibrium with rs7101429 and define the extended protective haplotype. Users who are heterozygous at rs7101429 may benefit from inspecting their rs2373115 result, as the two-SNP haplotype carries more information than either alone.

Genotype Interpretations

What each possible genotype means for this variant.

GG Beneficial

Full GAB2 neuroprotective effect; both copies of the protective G allele

You carry two copies of the protective G allele at rs7101429, present in roughly 2.5% of Europeans but about 16% of East Asians. Meta-analyses estimate GG carriers have lower odds of developing late-onset Alzheimer's disease compared to AA homozygotes.

AG Intermediate

Partial GAB2 protection; one copy of the neuroprotective G allele

You carry one copy of the protective G allele at rs7101429, present in about 26% of people globally. Compared to AA homozygotes, G-allele carriers have reduced odds of developing late-onset Alzheimer's disease, based on meta-analyses.

AA High Risk

Higher GAB2-associated Alzheimer's risk; reduced neuroprotective signaling

The AA genotype represents the baseline risk state for this locus — not a rare or extreme variant, but the common one.

The evidence is clearest in APOE ε4 carriers, where GAB2 variants modify risk substantially (the original Reiman 2007 GWAS was conducted in this subgroup). In non-ε4 carriers, the effect of rs7101429 is smaller and less consistently detected. Still, the Zou 2013 meta-analysis of up to 22,253 samples found a protective OR of 0.82–0.88 for G-allele carriers, implying that AA homozygotes bear the higher-risk end of this distribution.