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A High-Density Whole-Genome Association Study Reveals That APOE Is the Major Susceptibility Gene for Sporadic Late-Onset Alzheimer's Disease
Abstract
OBJECTIVE: While the apolipoprotein E (APOE) epsilon allele is a well-established risk factor for late-onset Alzheimer's disease (AD), initial genome scans using microsatellite markers in late-onset AD failed to identify this locus on chromosome 19. Recently developed methods for the simultaneous assessment of hundreds of thousands of single nucleotide polymorphisms (SNPs) promise to help more precisely identify loci that contribute to the risk of AD and other common multigenic conditions. We sought here to demonstrate that more precise identification of loci that are associated with complex, multi-genic genetic disorders can be achieved using ultra-high-density whole-genome associations by demonstrating their ability to identify the APOE locus as a major susceptibility gene for late-onset AD, despite the absence of SNPs within the APOE locus itself, as well as to refine odds ratios (ORs) based on gold-standard phenotyping of the study population. METHOD: An individualized genome-wide association study using 502,627 SNPs was performed in 1086 his-topathologically verified AD cases and controls to determine the OR associated with genes predisposing to Alzheimer's disease. RESULTS: As predicted, ultra-high-density SNP genotyping, in contrast to traditional microsatellite-based genome screening approaches, precisely identified the APOE locus as having a significant association with late-onset AD. SNP rs4420638 on chromosome 19, located 14 kilobase pairs distal to the APOE epsilon variant, significantly distinguished between AD cases and controls (Bonferroni corrected p value = 5.30 x 10(-34), OR = 4.01) and was far more strongly associated with the risk of AD than any other SNP of the 502,627 tested. CONCLUSION: This study provides empirical support for the suggestion that the APOE locus is the major susceptibility gene for late-onset AD in the human genome, with an OR significantly greater than any other locus in the human genome. It also supports the feasibility of the ultra-high-density whole-genome association approach to the study of AD and other heritable phenotypes. These whole-genome association studies show great promise to identify additional genes that contribute to the risk of AD.
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In the citing paper
“Also, previous studies of clinically and neuropathologically characterized cases and controls may have been too small to demonstrate that APOE2 homozygotes have an even lower OR than the relatively low-risk APOE2/3 group due to the paucity of APOE2 homozygotes, who comprise <1% of the general population1,4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
In the citing paper
“while the presence of one or two copies of the APOE2 allele is associated with a lower risk of Alzheimer’s dementia and an older mean age at dementia onset1–4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
In the citing paper
“Compared to the most common APOE3/3 genotype, each additional copy of the APOE4 allele is associated with a higher risk of Alzheimer’s dementia and a younger mean age at dementia onset, such that APOE4 homozygotes are at the highest risk”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
In the citing paper
“such that APOE4 homozygotes are at the highest risk”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
In the citing paper
“Apolipoprotein E (APOE), the major susceptibility gene for late-onset Alzheimer’s disease (AD), has three common alleles (APOE2, 3, and 4), giving rise to six genotypes (APOE2/2, 2/3, 3/3, 2/4, 3/4, and 4/4).”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
In the citing paper
“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 [6]
In the citing paper
“The apolipoprotein E4 (APOE4) allele is the most common and important genetic risk factor for late-onset sporadic AD [19–21].”
From 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner (2020) · cites this paper as [19]
In the citing paper
“Apolipoprotein (ApoE) is the major susceptibility gene for the common late-onset form of Alzheimer's disease and the presence of the ε4 allele increases the risk of developing AD [2].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [2]
In the citing paper
“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 [81]
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Genetics, Transcriptomics, and Proteomics of Alzheimers Disease
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Self-citationNeuropathological diagnostic criteria for Alzheimer's disease
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Self-citationThe personal and clinical utility of polygenic risk scores
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Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
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Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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Review Article: Genetics of Alzheimer Disease
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Metadata
- Authors
- Coon, K. D., Myers, A. J., Craig, D. W., Webster, J. A., Pearson, J. V., Lince, D. H., Zismann, V. L., Beach, T. G., Leung, D., Bryden, L., Halperin, R. F., Marlowe, L., Kaleem, M., Walker, D. G., Ravid, R., Heward, C. B., Rogers, J., Papassotiropoulos, A., Reiman, E. M., Hardy, J., & Stephan, D. A.
- Affiliations
- Translational Genomics Research Institute (US)
- University of Miami (US)
- Banner Sun Health Research Institute (US)
- National Institutes of Health (US)
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2007-04-15
- Volume
- 68
- Issue
- 04
- Pages
- 613-618
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2017581860
- Cited by
- 569
- References
- 15
- Citations by year
- 2026: 4 · 2025: 18 · 2024: 15 · 2023: 37 · 2022: 32 · 2021: 26 · 2020: 23 · 2019: 23 · 2018: 28 · 2017: 20 · 2016: 21 · 2015: 22 · 2014: 29 · 2013: 28 · 2012: 42
- FWCI
- 36.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institute on Aging (U01AG016976)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- late-onset Alzheimer's disease, apolipoprotein E, genetic susceptibility, single nucleotide polymorphisms, whole-genome association studies, chromosome 19, odds ratio, genetic susceptibility loci
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Chromosome Mapping, Chromosomes, Human, Pair 19, Female, Humans, Male, Risk Factors, Odds Ratio, Case-Control Studies, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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