APOE ε4 and Alzheimer's disease risk in Vietnamese populations

Abstract

APOE ε4 is the most significant genetic risk factor for Alzheimer's disease (AD), but this risk varies with ancestry. Little is known about the APOE ε4-AD risk in Vietnamese populations. We found two Vietnamese-language articles that included full APOE genotype data in Vietnamese AD dementia participants (N = 60) and controls (N = 30). APOE ε4/ε3 versus ε3/ε3 was associated with an odds ratio of 8.96 (95% confidence interval: 2.87–32.4) for AD dementia. Despite wide confidence intervals, the APOE ε4-AD odds ratio in Vietnamese populations appears similar to Korean and Japanese populations, who have the highest known APOE ε4-AD odds ratio.

Keywords

Alzheimer's disease global health Vietnam

Introduction

APOE has three common alleles (ε2, ε3, and ε4), and APOE ε4 is the most significant genetic risk factor for Alzheimer's disease (AD).¹ For an individual with European ancestry, carrying one or two copies of the APOE ε4 allele increases the odds of developing AD 3- and 14-fold, respectively, whereas the APOE ε3 or ε2 alleles are neutral or protective, respectively.^1,2 Converging evidence demonstrates that ancestry significantly influences APOE ε4's associated risk of AD. In African Americans or Hispanics, the APOE ε4-AD risk is attenuated, and in Nigerian Yoruban individuals, there is no discernable increased risk.^2–6 Korean and Japanese populations have some of the highest known impact of APOE ε4 on AD risk: carrying two copies of APOE ε4 increases the odds of AD up to 26-fold.³ While the cause of this APOE ε4 ancestry-dependent risk on AD is still a matter of active research, early evidence suggests that genetic ancestry near the APOE locus, which may involve a variant in the APOE ε4 promoter region or other SNP variants in linkage disequilibrium with APOE ε4,^7–9 is what primarily drives the ancestry-dependent APOE ε4-AD association, although other medical, environmental and socioeconomic risk factors may also play important roles.^5,10,11

Little is known regarding the APOE ε4-AD risk in Vietnamese individuals. This is a problem because knowledge of how APOE ε4 impacts AD is increasingly part of AD personalized medicine: APOE testing is built into new blood-test algorithms for AD, some of which are already commercially available.^12,13 Direct-to-consumer genetic tests for APOE provide an explanation of a person's lifetime risk for AD.¹⁴ APOE is crucial to determine an individual's predicted risk/benefit of new anti-amyloid drugs for AD.¹⁵ APOE ε4 carriers are eligible for new gene therapy trials.¹⁶ Thus, AD diagnostics, predictive medicine, and therapeutics increasingly rely upon APOE status. The present study aims to review the literature on the APOE ε4-AD risk in Vietnamese individuals.

Methods

Standard protocol approvals, registrations, and patient consents

The current genetic association study followed the Strengthening the Reporting of Genetic Association Studies (STREGA) reporting guideline. Participants or their caregivers provided written informed consent in the original studies. The current study protocol was granted an exemption by the University of Minnesota Institutional Review Board because the analyses were carried out on already-published and de-identified patient data.

Search strategy

For the online literature review, our goal was to find articles with information regarding the odds of AD associated with APOE ε4 in Vietnamese individuals. We used PubMed MeSH terms [Alzheimer's disease AND Vietnam], yielding eight studies. Zero included APOE data. PubMed was searched using MeSH terms [Apolipoproteins E AND Vietnam], which yielded four articles. Each was excluded due to their focus on Vietnam-era non-Vietnamese adults or Vietnamese children. We searched [Apolipoproteins E AND Asian People / genetics], which yielded 273 articles. We manually screened their abstracts and methodologies, but none included Vietnamese populations. Another PubMed MeSH search using the terms [Alzheimer Disease/genetics AND Asian People/genetics], yielded 344 articles. Screening their abstracts and methodologies, one article examined genetic risk factors in Vietnamese patients with early-onset AD.¹⁷ This study was initially included. Web of Science and Embase were searched using the combined terms “APOE” and “Vietnam,” which yielded 34 and 28 studies, respectively. No new articles were found.

The abstracts and methodologies of Vietnamese-language online and print-only medical journals discussing APOE ε4 in AD were individually screened by native Vietnamese-speaking co-authors. This search resulted in two print-only and one print and online available articles.^18–20 One of the three articles had substantial overlap with the article found as part of the first search of English-language literature.^17,20 In particular, both reports had a control and early-onset AD group with identical recruitment locations, numbers of participants, and APOE ε4 frequencies. However, the Vietnamese language report had a late-onset AD group that was not present in the English language report.²⁰ Because of the high probability of overlapping data, we decided to omit the smaller English-language study and retain the larger Vietnamese-language study. Based on a review of the study date, location, sequencing techniques, and investigators, the remaining two studies did not involve overlapping participants.^18,19 No articles were excluded based on missing data, diagnostic criteria employed, genotyping method, or recruitment method of participants.

Statistical analysis

Data were analyzed between March-July 2024. All statistical analyses were conducted using R, version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria). Odds ratios for the association between AD and APOE ε4/ε3 vs ε3/ε3 genotype or between AD and APOE ε4 heterozygotes vs non-carriers were estimated using logistic regression models with 95% profile-likelihood confidence intervals (CIs) and p-values from likelihood ratio tests. Odds ratios were similarly estimated using the pooled data with covariate adjustment for the study included in the model. Participant level demographic and medical covariates were not included due to lack of individual-level data within any of the articles.

Results

Summary of included studies

Three case-control studies were included (Table 1).^18–20 Participants were evaluated in Hanoi or Ho Chi Minh City, Vietnam. Participants were evaluated during the year preceding the publication date (i.e., August 2008 – June 2009¹⁸ and January 2014 – June 2014¹⁹). The time period for participant evaluations is not specified in the third report; however, the corresponding author was contacted and reported that participants were interviewed between May 2019 – April 2020.²⁰ Participants were evaluated at the corresponding author's associated medical center. The recruitment methodology was not described in any report. All three corresponding authors replied to our request for more information and reported that AD participants were recruited from their respective department's associated clinic, whereas controls were the cognitively unaffected spouses or caregivers of AD patients. Controls had no self-reported cognitive impairment or impairment in instrumental activities of daily living. One study did not include details regarding the sex or age of the control group.²⁰ However, the corresponding author replied to our inquiry and provided age and sex data (Table 1). One study tested participants for autosomal dominant mutations in APP, PSEN1, and PSEN2, finding 6 participants carrying a known pathogenic variant.²⁰ To study APOE in isolation of known autosomal dominant AD variants, we excluded these 6 participants from the present report. While not specified in any of the three publications, participants were presumably of the ethnic majority Kinh (86% of the population of Vietnam), given that individuals belonging to ethnic minorities in Vietnam mostly reside in non-metro and mountainous regions.²¹ In total, 155 AD cases and 58 controls were included. One study employed PCR amplification of the APOE gene fragment with Hhal restriction,¹⁹ while the other two studies employed sequencing technology.^18,20

Table 1.

Individual study characteristics of the three case-control studies included in our review.

Study	N (AD cases, controls)	Age (AD cases age-of-onset, control age at recruitment)^a	Sex (% female, AD cases, controls)	APOE genotype technique	Diagnostic criteria employed	Recruitment site	APOE ε2 allele frequency (AD cases, controls)	APOE ε4 allele frequency (AD cases, controls)	Odds ratio APOE4 status and AD
Nguyen et al., 2015¹⁹	30, 15	70.3 ± 7.5, 71 ± 8.7	50, 47	PCR amplification/Hhal restriction	DSM-IV-TR	Clinic based; Hanoi	5%, 3.3%	47%, 27%	22.0 (p < 0.001)^a
Nguyen et al., 2009¹⁸	30, 15	71.5 ± 9.1, 69.7 ± 8.5	70, 53	DNA sequencer ABI 3130 xl	DSM-IV-TR	Clinic based; Hanoi	3.3%, 10%	43%, 20%	3.56 (p = 0.10)^a
Nguyen et al., 2021²⁰	95, 28	66.0 ± 9.1, 55.4 ± 3.0	63, 52	Illumina Next generation sequencing	DSM-V	Clinic based; Ho Chi Minh City	N/A	31%, 11%	2.08 (p = 0.14)^a

Nguyen et al. (2015)¹⁹ and Nguyen et al. (2009)¹⁸ odds ratios are calculated based on APOE ε4/ε3 versus ε3/ε3, whereas Nguyen et al. (2021)²⁰ odds ratio is for APOE ε4 heterozygote versus non-carrier (due to missing complete genotype information for Nguyen et al. (2021)²⁰).

APOE ε4 and AD risk in Vietnam

Figure 1 includes two of the three studies (total AD cases: 60; total controls 30)^18,19 and demonstrates an odds ratio of 8.96 of AD associated with APOE ε4/ε3 genotype (AD cases: 34; controls: 6) versus APOE ε3/ε3 (AD cases: 12; controls: 17) in Vietnam (95% CI: 2.87–32.4). Figure 1 compares this odds ratio to the largest racial and ethnic meta-analysis of APOE ε4's association with AD by Belloy et al.³ Figure 1 includes only participants with complete APOE genotype information available (i.e., status of ε2, ε3, or ε4) and does not contain data from the study by Nguyen et al.,²⁰ which only included data on the number of APOE ε4 alleles (i.e., 0, 1, or 2). The individual odds ratios for each study included in Figure 1 are in Table 1 and Supplemental Table 1. Figure 2 compares all three Vietnamese studies and compares participants with one (AD cases: 65, controls: 14) versus zero APOE ε4 alleles (AD cases: 66, controls: 41). The odds ratio of AD associated with one APOE ε4 allele versus zero is 3.59 (95% CI: 1.73–7.90). Because the Nguyen L et al. study only specifies the number of APOE ε4 alleles, we do not have information regarding contributions from APOE ε3 and ε2. For the two studies that contained ε2, ε3, or ε4 genotype data,^18,19 low sample size precluded the measurement of the odds ratio of AD associated with APOE ε2: APOE ε2/ε2 (AD cases: 0, controls: 0), APOE ε2/ε3 (AD cases: 3, controls: 2), and APOE ε2/ε4 (AD cases: 2, controls: 2). The odds ratio for AD associated with APOE ε4 homozygosity (AD cases: 9; controls: 3) versus APOE ε3/ε3 (AD cases: 12; controls: 17) was 4.43 (95% CI: 0.99–25.7), which comes from the two studies that have data regarding non-APOE ε4 genotypes.^18,19 The odds ratio for AD associated with APOE ε4 homozygosity (AD cases: 24; controls: 3) versus no APOE ε4 alleles (AD cases: 66; controls 41) was 6.90 (95% CI: 2.05–33.0).

Figure 1.

The odds ratios of Alzheimer's disease (AD) for those with an APOE ε4/ε3 vs. APOE ε3/ε3 genotypes in different races/ethnicities, with 95% confidence intervals shown. Odds ratios for the association between AD and APOE ε4/ε3 vs ε3/ε3 genotype were estimated using logistic regression models with 95% profile likelihood confidence intervals (CIs) and p-values from likelihood ratio tests. Odds ratios were similarly estimated using the pooled data with covariate adjustment for the study included in the model.

Figure 2.

The odds ratios of Alzheimer's disease (AD) for those with one APOE ε4 allele vs. none, with 95% confidence intervals shown. Odds ratios for the association between AD and APOE ε4 heterozygotes vs non-carriers were estimated using logistic regression models with 95% profile likelihood confidence intervals (CIs) and p-values from likelihood ratio tests. Odds ratios were similarly estimated using the pooled data with covariate adjustment for the study included in the model.

Discussion

Our main finding was that APOE ε4 significantly increases the odds of AD in Vietnamese populations studied thus far: APOE ε4/ε3 increases the odds of AD by 8.96 compared to APOE ε3/ε3. While inter-study variation and wide confidence intervals prevent a conclusive estimation, the odds of AD associated with APOE ε4 are similar, and may even be greater, in Vietnamese populations compared to Korean and Japanese populations, who have the highest known APOE ε4-AD risk of any population studied to date.³

There are limitations to the present report to acknowledge. Firstly, substantial inter-study variation and wide confidence intervals prevent a precise estimate of the APOE ε4 – AD association. Part of this inter-study variability stems from differing study designs. In particular, the Nguyen et al.²⁰ study focused on early-onset AD, which has a different genetic architecture than late-onset AD,²² and included a control group with a mean age of 55 years (over a decade younger than the AD participant group and approximately 15 years younger than the two other included studies’ control groups).^18,19 The Nguyen et al. study thus includes a genetically dissimilar subtype of AD and a control group that is likely too young to demonstrate symptoms of AD, which would bias this study towards underestimating APOE ε4's association with AD. A second limitation is that the ascertainment of AD versus controls was established according to the Diagnostics and Statistical Manual of Mental Disorders, Fourth or Fifth edition (DSM-IV or V) criteria, which do not involve biomarker confirmation and may be susceptible to misdiagnosis.^23,24 This is a particular problem when isolating APOE ε4's risk of AD because APOE ε4 also increases the risk of other neurodegenerative diseases that mimic or co-occur with AD.¹ Thus, whether APOE ε4 increases the odds of AD or clinically similar neurodegenerative diseases is unclear. A third limitation is that all participants were evaluated at tertiary referral centers, which may introduce selection bias that precludes generalizations across all Vietnamese populations. A fourth limitation is the lack of information on environmental factors that may impact the APOE ε4 – AD relationship. For instance, both Hanoi and Ho Chi Minh City suffer from elevated air pollution,^25,26 and Agent Orange and other herbicides were used in massive quantities most notably in South Vietnam during the Vietnam War.²⁷ While air quality and other environmental exposures have been increasingly linked to AD risk, whether they magnify the risk of APOE ε4 on AD is still largely unknown.²⁸ A final limitation inherent to any research using a country as a proxy for genetic ancestry is the substantial intra-country ancestral heterogeneity: Vietnam is home to 54 state-recognized ethnic groups. While the Kinh represent approximately 86% of the total population and are concentrated in cities and coastal regions, other minority groups, who primarily reside in mountainous regions, have distinct ancestries that likely affect this relationship between APOE ε4 and AD.^21,29

In conclusion, the current review highlights the large role APOE ε4 likely plays in the development of AD in Vietnam. For APOE ε4-based AD diagnostics and therapeutics to be equally beneficial, better knowledge of APOE ε4 in the Vietnamese context is required. Larger studies accounting for ancestral heterogeneity and environmental risk factors, employing biomarkers, utilizing more specific diagnostic criteria for AD, and examining APOE ε4's risk on non-AD pathologies will greatly accelerate our understanding of APOE ε4 and its link to neurodegeneration.

Supplemental Material

sj-docx-1-alr-10.1177_25424823251331000 - Supplemental material for APOE ε4 and Alzheimer's disease risk in Vietnamese populations

Supplemental material, sj-docx-1-alr-10.1177_25424823251331000 for APOE ε4 and Alzheimer's disease risk in Vietnamese populations by Adam D Block, Ashley Petersen, Adam Hansen, Matti Matheson, Phuong Anh Thi Nguyen, Viet Luc Tran, Binh Thanh Nguyen, Binh Thanh Nguyen, Binh Thanh Thi Nguyen, Huong Thanh Tran, Trung-Anh Nguyen, Thang Pham, Ladson Hinton, Huong Nguyen and William G Mantyh in Journal of Alzheimer's Disease Reports

Footnotes

Acknowledgments

We thank the Vietnamese Ministry of Health, the staff at the National Geriatric Hospital, and the participants who contributed to this work for making this study possible.

ORCID iD

William G Mantyh

Ethical considerations

The current study protocol was granted an exemption by the University of Minnesota Institutional Review Board because the analyses were carried out on already-published and de-identified patient data.

Author contributions/CRediT

Adam D Block: Data curation; Formal analysis; Investigation; Writing – original draft; Writing – review & editing.

Ashley Petersen: Formal analysis; Visualization; Writing – original draft; Writing – review & editing.

Adam Hansen: Project administration; Writing – review & editing.

Matti Matheson: Project administration; Writing – review & editing.

Phuong Anh Thi Nguyen: Investigation; Project administration; Writing – review & editing.

Viet Luc Tran: Data curation; Investigation; Resources; Writing – review & editing.

Binh Thanh D Nguyen: Data curation; Investigation; Resources; Writing – review & editing.

Binh Thanh C Nguyen: Data curation; Investigation; Resources; Writing – review & editing.

Binh Thanh Thi Nguyen: Data curation; Investigation; Resources; Writing – review & editing.

Huong Thanh Tran: Data curation; Investigation; Resources; Writing – review & editing.

Trung-Anh Nguyen: Data curation; Formal analysis; Investigation; Resources; Supervision; Writing – review & editing.

Thang Pham: Data curation; Formal analysis; Investigation; Resources; Supervision; Writing – review & editing.

Ladson Hinton: Conceptualization; Methodology; Resources; Writing – review & editing.

Huong Nguyen: Conceptualization; Methodology; Resources; Writing – review & editing.

William G Mantyh: Conceptualization; Formal analysis; Methodology; Supervision; Writing – original draft; Writing – review & editing.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was funded by NIH R01AG080806 (William G. Mantyh, MD); the Robert Katzman Clinical Research Training Fellowship (William G. Mantyh, MD), a grant mutually funded by the Alzheimer's Association, the American Academy of Neurology and the American Brain Foundation; the Wallin Foundation (William G. Mantyh, MD); and the Fesler-Lampert Chair of Aging Studies (William G. Mantyh, MD). The funding sources had no role in the study design, collection, analysis, or interpretation of data.

Conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: William G. Mantyh: Personal compensation for consulting with Gerstman-Lehrman Group (current); Honoraria for Northwest Portland Area Indian Health Board (past activity: August 2024); Honoraria for NIH Neuroscience Grand Rounds (past activity: June 2024); Personal compensation as moderator of Regional Clinical Advisory Board meeting for gantenerumab with Genentech/Roche (past activity: November 2022); Personal compensation for educational videos Roon.com (past activity: May 2023).

Data availability

The data supporting the findings of this study are available within the article, within the Vietnamese-language literature (however, the two articles are print-only and found in the Hanoi Medical University Library) and/or its .

Supplemental material

Supplemental material for this article is available online.

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