Genetic associations with human longevity at the APOE and ACE loci
Abstract
In an effort to dissect the genetic components of longevity, we have undertaken case-control studies of populations of centenarians (n = 338) and adults aged 20-70 years at several polymorphic candidate gene loci. Here we report results on two genes, chosen for their impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin-converting enzyme (ACE). We find that the epsilon 4 allele of APOE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p < 0.001), while the frequency of the epsilon 2 allele, associated previously with type III and IV hyperlipidemia, is significantly increased (p < 0.01). A variant of ACE which predisposes to coronary heart disease is surprisingly more frequent in centenarians, with a significant increase of the homozygous genotype (p < 0.01). These associations provide examples of genetic influences on differential survival and may point to pleiotropic age-dependent effects on longevity.
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APOE2 affords protection against Alzheimer's disease.
“The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for AD and dementia with Lewy bodies (DLB) (1, 5, 6), whereas APOE2, a well-established longevity determinant, affords protection against the disease (7, 8).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [7]
ApoE4 was the first genetic variation to be associated with decreased longevity.
“ApoE4 was the first genetic variation to be associated with decreased longevity [72].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [72]
The e4 allele is associated with decreased longevity.
“and decreased longevity. 41,44,45”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [45]
The e2 allele is associated with increased longevity.
“and increased longevity.41,44,45”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [45]
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- Authors
- Schächter, F., Faure-Delanef, L., Guénot, F., Rouger, H., Froguel, P., Lesueur-Ginot, L., & Cohen, D.
- Affiliations
- Fondation Jean Dausset-CEPH (FR)
- Venue
- Nature Genetics
- Published
- 1994-01
- Volume
- 6
- Issue
- 1
- Pages
- 29-32
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2069863984
- Cited by
- 1,095
- References
- 36
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 17 · 2023: 14 · 2022: 22 · 2021: 18 · 2020: 26 · 2019: 30 · 2018: 22 · 2017: 29 · 2016: 33 · 2015: 28 · 2014: 33 · 2013: 27 · 2012: 33
- FWCI
- 39.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- human longevity, centenarians, apolipoprotein E, APOE ε4, angiotensin-converting enzyme, ACE I/D polymorphism, genetic association, atherosclerosis, coronary artery disease, cardiovascular risk, hyperlipidemia, pleiotropy, differential survival
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alleles, Apolipoproteins E, Base Sequence, Female, France, Gene Frequency, Genotype, Humans, Peptidyl-Dipeptidase A, Longevity, Male, Middle Aged, Molecular Sequence Data, Polymorphism, Genetic, Sex Characteristics, Case-Control Studies
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