GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers
Open accessAbstract
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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Prior genome-wide association studies of AD all identified strong evidence for association to APOE but less convincing evidence implicating other genes.
“All have identified strong evidence for association to APOE, but less convincing evidence implicating other genes2 -9 .”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [9]
rs541458 was directly genotyped in the extension sample, the TGEN study and the Li et al. study, with p<0.05 in each, and in meta-analysis it was one of the most significant SNPs (meta-p=8×10-10).
“This SNP is 8kb 5′ to the PICALM gene and was directly genotyped in the extension sample, the TGEN study and the Li et al. study, with p<0.05 in each.Following meta-analysis, this is one of our most significant SNPs (meta-p= 8×10 -10 )”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [9]
The first association studies covering most of the genome were published in 2007.
“The first association studies covering most of the genome were published in 2007 [81, 82].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [82]
GWAS hits for AD include genes Apoe, Ms4a6d, Plcg2 and Gab2.
“GWAS hits for AD included genes that are currently under intense mechanistic investigation, including Apoe , Ms4a6d , Plcg2 and Gab2 (Reiman et al., 2007) (Figure 6B,H).”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Reiman et al., 2007
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- Authors
- Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Huentelman, M. J., Craig, D. W., Coon, K. D., Liang, W. S., Herbert, R. H., Beach, T., Rohrer, K. C., Zhao, A. S., Leung, D., Bryden, L., Marlowe, L., Kaleem, M., Mastroeni, D., Grover, A., Heward, C. B., Ravid, R., Rogers, J., Hutton, M. L., Melquist, S., Petersen, R. C., Alexander, G. E., Caselli, R. J., Kukull, W., Papassotiropoulos, A., & Stephan, D. A.
- Affiliations
- Translational Genomics Research Institute (US)
- National Institutes of Health (US)
- Arizona Alzheimer’s Consortium (US)
- Netherlands Institute for Neuroscience (NL)
- Mayo Clinic (US)
- Mayo Clinic in Arizona (US)
- University of Washington (US)
- Corresponding author
- Reiman, Eric M.
- Stephan, Dietrich A.
- ORCID
- Reiman, Eric M.
- Webster, Jennifer A.
- Myers, Amanda J.
- Hardy, John
- Dunckley, Travis
- Zismann, Victoria L.
- Pearson, John V.
- Huentelman, Matthew J.
- Craig, David W.
- Liang, Winnie S.
- Beach, Thomas
- Zhao, Alice S.
- Leung, Doris
- Mastroeni, Diego
- Melquist, Stacey
- Alexander, Gene E.
- Caselli, Richard J.
- Kukull, Walter
- Papassotiropoulos, Andreas
- Stephan, Dietrich A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 54
- Issue
- 5
- Pages
- 713-720
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2587162
- OpenAlex
- W2008352401
- Cited by
- 487
- References
- 35
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 8 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 4 · 2019: 10 · 2018: 12 · 2017: 14 · 2016: 20 · 2015: 19 · 2014: 34 · 2013: 33 · 2012: 55
- FWCI
- 40.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Mayo Clinic
- National Institutes of Health (1k01ag024079-01a2)
- National Institute on Aging (R01AG023193, P50AG005144, P50 AG17824, P30AG012300, P30AG017824, AG 025688, U01AG016976, K01-AG-024079, P50AG016570, P50AG005128, P30AG010161, P50AG008702, P50AG025711, P50AG005681, P50AG005142, P50AG008671, P30AG019610, P50AG005146, P30AG013846, P50AG005136, P50AG005134, R21AG029576, P50AG025688, P30 AG01542, P50AG016574)
- National Heart, Lung, and Blood Institute (U01HL084744)
- National Institute of Mental Health (R01 MH60451, P50MH060451)
- National Institute of Neurological Disorders and Stroke (U24NS051872, R01 NS39764, P50NS039764)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, late-onset Alzheimer's disease, APOE ε4, Gab2, genetic susceptibility, gene-gene interaction, single nucleotide polymorphisms, haplotypes, tau phosphorylation, neurofibrillary tangles, dystrophic neurites
- MeSH terms
- Alzheimer Disease, Brain, Brain Chemistry, DNA Mutational Analysis, Gene Expression Regulation, Gene Frequency, Genetic Markers, Genetic Testing, Haplotypes, Humans, Mutation, Phosphorylation, Risk Factors, Neurofibrillary Tangles, tau Proteins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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