APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer’s Disease Risk in a Multiracial Sample
Open accessAbstract
Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer’s disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10−94; GT: OR = 15.87, p = 2.62 × 10−9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10−108; GT: OR = 12.63, p = 3.44 × 10−64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.
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The degree of risk and protection afforded by E4 and E2 respectively vary according to ancestry.
“First, the degree of risk and protection afforded by E4 and E2 respectively vary according to ancestry1,59–62.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [61]
Results §3.1 reports that the Alzheimer’s disease risk associated with ε4 differs across ethnic groups. But the Introduction explicitly says the protective effect of ε2 does not vary by ethnicity, contrary to that part of the claim. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe frequency of rs405509 genotypes in the APOE promoter differs between East Asian and European populations, with the T/T genotype significantly more frequent in East Asians.
“The frequency of the rs405509 genotypes in the promoter region of APOE are different between East Asian and European populations with the frequency of the T/T genotype being significantly higher in East Asians.”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [17]
Results §3.2 reports that the rs405509 T allele is more frequent in East Asians than in people of European ancestry (0.739 versus 0.528), and the Discussion describes large differences in rs405509 genotype frequencies across ethnic groups. Our copy does not specifically report a statistical comparison showing that the T/T genotype is significantly more frequent in East Asians. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe odds ratio for Alzheimer's disease with the APOE ε4 allele is higher in East Asians than in Europeans.
“We have previously reported that the odds ratio for AD with the ε4 allele is higher in East Asians than in Europeans [17].”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [17]
The East Asian population has a higher risk of Alzheimer's disease associated with the APOE ε4 allele.
“with the East Asian population having a higher risk of AD associated with the APOE ε4 allele”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [17]
The T genotype at rs405509 results in lower expression of APOE.
“Functional experiments using a reporter assay have demonstrated that the T genotype at rs405509 resulted in lower expression of APOE [17].”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [17]
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Self-citationApolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
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Self-citationA missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
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APOE‐ε4 carriership and dementia risk over 10 years among Asian American and White older adults
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The Association Between APOE Genotype, Race, and Dementia
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Self-citation
- Authors
- Choi, K., Lee, J., Gunasekaran, T., Kang, S., Lee, W., Jeong, J., Lim, H., Zhang, X., Zhu, C., Won, S.-Y., Choi, Y., Seo, E., Lee, S., Gim, J., Chung, J., Chong, A., Byun, M., Seo, S., Ko, P.-W., Han, J.-W., McLean, C., Farrell, J., Lunetta, K., Miyashita, A., Hara, N., Won, S., Choi, S.-M., Ha, J.-M., Jeong, J., Kuwano, R., Song, M., An, S., Lee, Y., Park, K., Lee, H.-W., Choi, S., Rhee, S., Song, W., Lee, J., Mayeux, R., Haines, J., Pericak-Vance, M., Choo, I., Nho, K., Kim, K.-W., Lee, D., Kim, S., Kim, B., Kim, H., Jun, G., Schellenberg, G., Ikeuchi, T., Farrer, L., Lee, K., & Initative, A. D. N.
- Affiliations
- Chosun University (KR)
- Ewha Womans University (KR)
- Boston University (US)
- Seoul National University (KR)
- Seoul National University Hospital (KR)
- Kyungpook National University (KR)
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 13620, Korea
- The Alfred Hospital (AU)
- Brain Research Institute, Niigata University (JP)
- Chonnam National University (KR)
- Gachon University (KR)
- Pusan National University (KR)
- Dong-A University (KR)
- Chung-Ang University (KR)
- Gwangju Institute of Science and Technology (KR)
- Columbia University (US)
- Case Western Reserve University (US)
- Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33101, USA
- Indiana University Indianapolis (US)
- Seoul National University Bundang Hospital (KR)
- University of Pennsylvania (US)
- Corresponding author
- Lee, Kun
- ORCID
- Lee, Jang
- Gunasekaran, Tamil
- Kang, Sarang
- Lee, Wooje
- Lim, Ho
- Zhang, Xiaoling
- Zhu, Congcong
- Won, So-Yoon
- Lee, Seok
- Gim, Jungsoo
- Chong, Ari
- Seo, Sujin
- Ko, Pan-Woo
- McLean, Catriona
- Farrell, John
- Lunetta, Kathryn
- Miyashita, Akinori
- Hara, Norikazu
- Won, Sungho
- Choi, Seong-Min
- Ha, Jung-Min
- Jeong, Jee
- Song, Min
- An, Seong
- Lee, Young
- Park, Kyung
- Lee, Ho-Won
- Choi, Seong
- Rhee, Sangmyung
- Song, Woo
- Lee, Jung
- Mayeux, Richard
- Haines, Jonathan
- Choo, IL
- Nho, Kwangsik
- Lee, Dong
- Kim, SangYun
- Kim, Byeong
- Kim, Hoowon
- Jun, Gyungah
- Schellenberg, Gerard
- Ikeuchi, Takeshi
- Farrer, Lindsay
- Lee, Kun
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2019-08-16
- Volume
- 8
- Issue
- 8
- Pages
- 1236
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC6723529
- OpenAlex
- W2968596792
- Cited by
- 72
- References
- 79
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 13 · 2020: 8
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- PMC
- Funders
- National Research Foundation of Korea (NRF-2014M3C7A1046041)
- National Institute on Aging (R01-AG048927; P30-AG13846; U01-AG032984; RF1-AG057519)
- Japan Agency for Medical Research and Development (JP18kk0205009)
- 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
- Alzheimer's disease, APOE ε4, APOE promoter polymorphisms, gene-environment interaction, effect modification, ethnic differences, East Asian populations, cortical atrophy, disease risk, age of onset
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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