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Cited by 206Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

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Rajabli, Farid, Feliciano, Briseida E., Celis, Katrina, Hamilton-Nelson, Kara L., Whitehead, Patrice L., Adams, Larry D., Bussies, Parker L., Manrique, Clara P. +20 more·2018·PLOS Genetics
DOI 10.1371/journal.pgen.1007791PMC PMC6281216
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Abstract

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.

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  • Large population differences in disease risk for well-known alleles such as APOE-ɛ4 in Alzheimer disease highlight the challenge of determining how population differences in effect size might be affected by interaction effects.

    “Large population differences in disease risk for well-known alleles such as APOE-ɛ4 in Alzheimer disease [29, 30] highlight the challenge of determining how population differences in effect size might be affected by interaction effects.”

    From Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences (2019) · cites this paper as [30]

  • The association between APOEε4 and Alzheimer's disease is weaker among African-American and Hispanic individuals and nonexistent among Nigerian individuals.

    “the association between ε4 and disease is reported to be weaker among African-American and Hispanic individuals [58, 61, 62] and nonexistent among Nigerian individuals [63].”

    From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [62]

  • Individuals who inherited the APOEε4 allele from an African ancestor had a lower risk of developing Alzheimer's disease than an individual who inherited APOEε4 from a European ancestor.

    “individuals that inherited the APOEε4 allele (and surrounding region) from an African ancestor had a lower risk of developing AD than an individual who inherited APOEε4 from a European ancestor [62, 102].”

    From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [62]

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References 46 · Cited by 206

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Authors
Rajabli, F., Feliciano, B. E., Celis, K., Hamilton-Nelson, K. L., Whitehead, P. L., Adams, L. D., Bussies, P. L., Manrique, C. P., Rodriguez, A., Rodriguez, V., Starks, T., Byfield, G. E., Sierra Lopez, C. B., McCauley, J. L., Acosta, H., Chinea, A., Kunkle, B. W., Reitz, C., Farrer, L. A., Schellenberg, G. D., Vardarajan, B. N., Vance, J. M., Cuccaro, M. L., Martin, E. R., Haines, J. L., Byrd, G. S., Beecham, G. W., & Pericak-Vance, M. A.
Affiliations
  • University of Miami (US)
  • North Carolina Agricultural and Technical State University (US)
  • Central University of the Caribbean (PR)
  • Columbia University (US)
  • Boston University (US)
  • University of Pennsylvania (US)
  • Case Western Reserve University (US)
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2018-12-05
Volume
14
Issue
12
Pages
e1007791
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1007791
PMC
PMC6281216
OpenAlex
W2902965768
Cited by
206
References
46
Citations by year
2026: 36 · 2025: 27 · 2024: 21 · 2023: 28 · 2022: 24 · 2021: 29 · 2020: 27 · 2019: 13 · 2018: 1
FWCI
12.03
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Columbia Academic Commons (Columbia University)
Funders
National Institute on Aging (RF1-AG054074, U01-AG032984, U01-AG052410)
Topics
  • Health Sciences › Medicine › Physiology › 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
APOE ε4, Alzheimer's disease, late-onset Alzheimer's disease, genetic risk, local ancestry, African American population, Puerto Rican population
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Black or African American, Female, Gene Frequency, Genetics, Population, Hispanic or Latino, Humans, Male, Puerto Rico, Risk Factors, Genetic Variation, Case-Control Studies, Apolipoprotein E4, Genome-Wide Association Study

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