For inexperienced drivers, the passenger riding shotgun can affect the safety of the ride. Similarly, seemingly benign genes can modify the risk presented by disease-associated genes. Reiman et al. report a gene that affects susceptibility to late-onset Alzheimer's disease in people carrying a disease-associated allele in a recent article in Neuron.
Late onset Alzheimer's disease affects people older than age 60. Each copy of the ε4 allele of apolipoprotein E (APOE) increases Alzheimer's disease risk and decreases the age of onset. APOE ε4 contributes approximately 65% to disease risk, suggesting that additional genes contribute to or modify susceptibility.
To identify new genes associated with late-onset Alzheimer's disease, the authors genotyped over 500,000 single nucleotide polymorphisms (SNPs) in more than 1400 people. The only allele that was different between people with late-onset Alzheimer's disease and controls was APOE ε4, so the authors divided their dataset into APOE ε4 carriers and noncarriers. Of the 25 SNPs most associated with late-onset Alzheimer's disease in the APOE ε4 carrier group, 10 localized to the scaffolding protein growth factor receptor-bound protein (GRB)-associated binding protein 2 (GAB2).
One haplotype block covered the entire GAB2 gene. APOE ε4 carriers with the GAB2 genotype GG at SNP rs2373115 were more likely to have late-onset Alzheimer's disease relative to those with the genotypes GT or TT. Across all cohorts, the GAB2 haplotype increased Alzheimer's disease risk 4-fold in APOE ε4 carriers.
The hippocampus and posterior cingulate cortex are vulnerable to damage in Alzheimer's disease. These regions showed increased GAB2 expression in people with late-onset Alzheimer's disease relative to controls. In contrast, visual cortex, which is less affected by Alzheimer's disease, showed similar GAB2 expression in people with Alzheimer's disease and controls. In late-onset Alzheimer's disease brains, many of the hippocampal cells that were positive for GAB2 were dystrophic or had inclusions similar to Alzheimer's disease-associated neurofibrillary tangles.
Normal GAB2 activity may protect the brain. GAB2 activates phosphatidylinositol 3-kinase (PI3K), which in turn activates Akt. Akt inactivates glycogen synthase kinase-3 (Gsk3), which, when active, phosphorylates tau. Because hyperphosphorylated tau forms toxic neurofibrillary tangles in Alzheimer's disease brains, the authors hypothesized that GAB2 acts in the healthy brain to block tau phosphorylation. Consistent with their hypothesis, neuroglioma cultures treated with GAB2 siRNA showed increased tau phosphorylation relative to vehicle-treated cultures.
Previous research has shown that people with at least one APOE ε4 allele have an odds risk for late-onset Alzheimer's disease of approximately 4.0. In the current study, people with disease-associated alleles for both APOE and GAB2 had an odds risk of 24.64. How does GAB2 interact with APOE to increase disease risk? In the Alzheimer's brain, APOE localizes to plaques and neurofibrillary tangles and may induce their formation. Perhaps the disease-associated GAB2 allele reduces GAB2 activity, increasing tau phosphorylation and exacerbating tangle formation in APOE ε4 carriers.