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Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease
Open accessAbstract
Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
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“The greatest risk factors for late-onset Alzheimer's are older age, 62,63 genetics 64,65 -especially the e4 form of the apolipoprotein E (APOE) gene -and having a family history of Alzheimer's.[66][67][68][69]”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [64]
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In the citing paper
“Between 45% and 50% of AD patients carry at least one APOE4 allele compared to only 15% of age-matched healthy controls.5,11”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The major risk factor for AD is inheritance of the E4 allele of apolipoprotein E (APOE).5,6”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [3]
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“the presence of which dramatically increases risk for developing AD and decreases age of onset by 10 to 15 years”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [3]
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“Variables available from the CCSMA included age of dementia onset, gender, education, and presence of one or two APOE ε4 alleles, determined from buccal DNA.(24)”
From Progression of Cognitive, Functional, and Neuropsychiatric Symptom Domains in a Population Cohort With Alzheimer Dementia: The Cache County Dementia Progression Study (2011) · cites this paper as [24]
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“Among these genes, apolipoprotein E ( APOE ; especially the APOE ε 4 allele) is the highest genetic risk factor for LOAD [23,24].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [23]
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“The three primary APOE isoforms (APOE2, APOE3, and APOE4) have distinct effects on AD onset and age-related progression, with APOE4 increasing susceptibility and APOE2 offering protection (Corder et al., 1993; Saunders et al., 1993; Wolf et al., 2013).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Saunders et al., 1993
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In the citing paper
“the ε4 allele is the strongest genetic risk factor for late-onset AD”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Saunders et al 1993
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In the citing paper
“The risk for AD is 3–4-fold higher in individuals carrying one APOE ε4 allele and about 10–15-fold higher in those carrying two APOE ε4 alleles”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Saunders et al 1993
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“In conclusion, APOE4 is the strongest genetic risk factor for AD with high prevalence (Saunders et al 1993, Sims et al 2020).”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Saunders et al 1993
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The ε-4 isoform of apoE is the strongest molecular risk factor for the development of AD. About 60–80% of AD patients have at least one copy of apoE4 [2], [4], [5] and the risk for AD is increased in an ε-4 allele dose-dependent manner [6].”
From LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease (2010) · cites this paper as [5]
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In the citing paper
“The greatest risk factors for Alzheimer's dementia are older age, 70 , 71 genetics — especially the e4 form of the apolipoprotein E (APOE) gene 72 , 73 — and having a family history of Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [72]
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In the citing paper
“in contrast, the APOE ε2 allele confers protection against developing AD (2-5).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [3]
Experimental — accuracy not yet measuredIn the citing paper
“Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [3]
In the citing paper
“the e4 allele has been associated with an increased risk of Alzheimer's disease, 1-7”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [3]
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Metadata
- Authors
- Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper-MacLachlan, D. R., Alberts, M. J., Hulette, C., Crain, B., Goldgaber, D., & Roses, A. D.
- Affiliations
- Duke University (US)
- Departments of Medicine [Neurology] (Drs. Saunders, Strittmatter, Schmechel, Pericak-Vance, Alberts, and Roses, and S. Joo and B. Rosi), Neurobiology (Drs. Strittmatter, Schmechel, and Roses), and Pathology (Drs. Hulette and Crain), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC; the Department of Medicine [Neurology] (Drs. St. George-Hyslop and Crapper-MacLachlan), Centre for Research in Neurodegenerative Disease, University of Toronto,...
- Venue
- Neurology
- Published
- 1993-08
- Volume
- 43
- Issue
- 8
- Pages
- 1467-1467
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W1999631936
- Cited by
- 3,786
- References
- 29
- Citations by year
- 2026: 46 · 2025: 67 · 2024: 96 · 2023: 75 · 2022: 83 · 2021: 107 · 2020: 101 · 2019: 89 · 2018: 93 · 2017: 74 · 2016: 86 · 2015: 93 · 2014: 102 · 2013: 95 · 2012: 119
- FWCI
- 105.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- American Health Assistance Foundation
- Medical Research Council Canada
- National Institutes of Health (MO1-RR-30)
- Medical Research Council
- National Institute on Aging (NIA AG05128, NIA AG 07922)
- National Institute of Neurological Disorders and Stroke
- National Center for Research Resources (M01 RR 30)
- 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
- apolipoprotein E, APOE ε4, Alzheimer's disease, sporadic Alzheimer's disease, genetic susceptibility, amyloid-beta, APOE isoforms, allele frequency, genetic association
- MeSH terms
- Aged, Alleles, Alzheimer Disease, Apolipoproteins E, Female, Gene Amplification, Gene Frequency, Humans, Male, Middle Aged, Mutation
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