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Cited by 336Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.

A4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphism

Kamboh, M. Ilyas, Sanghera, Dharambir K., Ferrell, Robert E., DeKosky, Steven T.·1995·Nature Genetics
DOI 10.1038/ng0895-486
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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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  1. DeKosky, S.T. et al. Alzheimer's disease and related dementias: report of follow-up on the first 1,000 cases from Pittsburgh. Neurology 44, A354–355 (1994).

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Metadata

Authors
Kamboh, M. I., Sanghera, D. K., Ferrell, R. E., & DeKosky, S. T.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
1995-08-01
Volume
10
Issue
4
Pages
486-488
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng0895-486
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
Licence
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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