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A4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphism
Abstract
Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele.
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“Together these data expand previous studies in mouse models of Aβ aggregation suggesting a pathogenic role for C4b and Serpina3n23,24,44,45, as well as genetic studies linking the human homologue SERPINA3 to AD risk46”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [46]
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Self-citation
Metadata
- Authors
- Kamboh, M. I., Sanghera, D. K., Ferrell, R. E., & DeKosky, S. T.
- Venue
- Nature Genetics
- Published
- 1995-08-01
- Volume
- 10
- Issue
- 4
- Pages
- 486-488
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2152410944
- Cited by
- 336
- References
- 26
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 2 · 2012: 7
- FWCI
- 26.07
- Type
- journal article
- Language
- en
- Update notices
- correction (1995-09-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag009202-07)
- National Institute on Aging (AG 05-133, AG 07562, P50AG005133, AG09202, R01AG007562)
- 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
- Alzheimer's disease, APOE ε4, alpha-1-antichymotrypsin, signal peptide, genetic susceptibility, gene dosage effect, genetic modifiers, amyloid-beta, amyloid plaques
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alleles, alpha 1-Antichymotrypsin, Alzheimer Disease, Apolipoproteins E, Base Sequence, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Molecular Sequence Data, Polymorphism, Genetic, Risk Factors, DNA Primers, Genetic Predisposition to Disease
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