Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease

Topic: Amyloid, tau and blood-test diagnosis

Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

@article{corder1994-7920638,
  author  = {Corder, E. H. and Saunders, A. M. and Risch, N. J. and Strittmatter, W. J. and Schmechel, D. E. and Gaskell, P. C. and Rimmler, J. B. and Locke, P. A. and others},
  title   = {{Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease}},
  journal = {Nature genetics},
  year    = {1994},
  doi     = {10.1038/ng0694-180},
  pmid    = {7920638},
  url     = {https://doi.org/10.1038/ng0694-180}
}

Key findings

• Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60).
• Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families.
• Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD.
• Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele.
• The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

Why it matters

This study found that the APOE epsilon2 allele appears to protect against late-onset Alzheimer's disease, while the epsilon4 allele increases risk, with the two versions acting in opposite directions. It supports the idea that apolipoprotein E is directly involved in the disease, but it does not test any treatment or prevention.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/ng0694-180
• PubMed: 7920638
• Original source →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease Neurology · 1993-08-01 · usefulness score 65/100 · Genetics
• Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease Nature · 1991-02-21 · usefulness score 63/100 · Genetics
• Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families Science · 1993-08-13 · usefulness score 63/100 · Genetics
• Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease Neurology · 1984-07-01 · usefulness score 58/100 · Getting a diagnosis
• Diagnosis of Alzheimer's Disease Archives of Neurology · 1985-11-01 · usefulness score 58/100 · Getting a diagnosis
• Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-03-01 · usefulness score 58/100 · Genetics
• The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease Annals of neurology · 1993-11-01 · usefulness score 55/100 · Disparities
• Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-09-01 · usefulness score 54/100 · Genetics
• Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-10-01 · usefulness score 53/100 · Genetics
• Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype Experimental neurology · 1994-02-01 · usefulness score 50/100 · Brain tissue and pathology
• Apolipoprotein E and Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1995-05-01 · usefulness score 50/100 · Genetics
• Familial Alzheimer Dementia: a prevalent disorder with specific clinical features Psychological Medicine · 1984-02-01 · usefulness score 42/100 · Health systems and care delivery

Later studies that cite this one

115 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing Nature genetics · 2019-02-28 · usefulness score 85/100 · Risk factors
• Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease JAMA · 2023-02-21 · usefulness score 73/100 · Genetics
• APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease New England Journal of Medicine · 2024-06-20 · usefulness score 72/100 · Genetics
• APOE ε4 increases risk for dementia in pure synucleinopathies JAMA neurology · 2013-02-01 · usefulness score 69/100 · Genetics
• Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study Archives of neurology · 1998-07-01 · usefulness score 69/100 · Genetics
• Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals JAMA · 1995-04-01 · usefulness score 68/100 · Getting a diagnosis
• Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease JAMA neurology · 2022-07-01 · usefulness score 67/100 · Genetics
• Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study Neurology · 2007-09-01 · usefulness score 67/100 · Long-term cohort studies

Related studies in Genetics

• Apolipoprotein E, ɛ4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region Human Molecular Genetics · 1994-01-01 · usefulness score 48/100
• Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease JAMA · 1995-03-01 · usefulness score 65/100
• Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease Annals of internal medicine · 2002-08-01 · usefulness score 58/100
• Apolipoprotein E genotype and neurological disease onset in Niemann-Pick disease, type C1 American journal of medical genetics. Part A · 2012-09-28 · usefulness score 54/100
• Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans JAMA · 2013-04-01 · usefulness score 78/100
• Regional cerebral perfusion in patients with Alzheimer's disease and mild cognitive impairment: effect of APOE epsilon4 allele Neuroradiology · 2012-07-25 · usefulness score 38/100

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1,339 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.

• Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature · 2011-08-21 · usefulness score 62/100 · Lewy body dementia
• Clonal hematopoiesis is associated with protection from Alzheimer's disease Nature medicine · 2023-06-15 · usefulness score 80/100 · Inflammation and the immune system
• Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia Neurology · 2010-01-01 · usefulness score 55/100 · Brain scans and imaging

Similar studies

• Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease 1994 · Genetics
• Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions 1993 · Genetics
• Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex 1997 · Genetics
• Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease 1994 · Brain tissue and pathology
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