Non-white or non-European descent

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Minorities are underrepresented in health studies, most research on APOE-ε4 and Alzheimer’s has been conducted on white subjects of European descent. Further compounding this situation is that much of the research conducted on health conditions that affect ApoE4s: Alzheimer’s, Cardiovascular disease, shortened longevity, etc. often do not stratify by APOE status much less racial/ethnic status. One would think genes are color blind, and yet there are differences in non-European ApoE4s. So what to believe? This wiki is dedicated to sharing what research is available.


According to this article Researchers Explain Why Black Americans Are At Higher Risk For Alzheimer's (Meghan Rabbitt, 24 Jun 2020) less than 5 percent of participants in U.S. health studies are black yet older African Americans are about twice as likely than non-Hispanic white people to develop Alzheimer’s or other dementias.

So is the key to this statistic that they are black, ApoE4, living in the United States, or some combination of all of these? While the answer is not clear, in 2005 this paper APOE ε4 is not associated with Alzheimer's disease in elderly Nigerians (Oye Gureje et al, 22 Dec 2005) was published that found Nigerian APOEε4/4 carriers held a very low incidence of Alzheimer’s, contrary to what is generally considered a very high genetic risk. From the abstract of this paper:

Since 1992, research teams from Indiana University and the University of Ibadan have been collecting and comparing data from two diverse, elderly populations to identify risk factors for dementia and Alzheimer's disease. Apolipoprotein E (APOE) was genotyped in 2,245 Nigerian samples. Of these, 830 had a diagnosis: 459 were normal, and 140 had dementia including 123 diagnosed with Alzheimer's disease. In contrast with other populations, the APOE ε4 allele was not significantly associated with Alzheimer's disease or dementia. This lack of association in the Yoruba might reflect genetic variation, environmental factors, as well as genetic/environmental interactions.

From this Key Alzheimer’s gene acts differently in non-Europeans(LA Bline, 15 Nov 2019):

In this study, individuals with African-derived ancestry in their APOE gene had 39 percent lower odds of Alzheimer’s than did individuals with European-derived APOE.

and from the same study, this article, Research Provides More Clues into APOE Gene’s Protective Factors (Phil Gutis, 13 Nov 2019)

Caribbean Hispanic individuals who inherited their APOE E4 from European ancestors had greater risk of Alzheimer’s disease compared to individuals who inherited APOE E4 from African ancestors, after adjusting for other known risk factors

And from this research article Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds (Anthony J. Griswold et al, 1 Feb 2021)

Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA).

According to the Alzheimer’s Association Alzheimer’s Disease Facts and Figures report, older African Americans are about twice as likely to have Alzheimer’s or other dementias as older whites. So what is driving the higher rate of dementia in African Americans? According to this article, Alzheimer's risk factors may be measurable in adolescents and young adults (Science News, 30 Jul 2020) the risk factors that are disproportionately apparent in African Americans include heart health factors -- such as high blood pressure, high cholesterol and diabetes -- and social factors like education quality. But this is conjecture, as cited above, black Americans are sorely underrepresented in health studies.

Fortunately, there is more all-inclusive research is being conducted. This press release addresses four studies NIH expands nation’s Alzheimer’s and related dementias research capacity (National Institutes of Health, 10 Sep 2020):

To further incentivize innovative ideas and opportunities in Alzheimer's disease and related dementias research, the National Institute on Aging (NIA), part of the National Institutes of Health, has funded four exploratory Alzheimer’s Disease Research Centers (ADRCs). These new centers will broaden current ADRC research initiatives with underrepresented populations such as African Americans, Native Americans, and those in rural communities — all of which have different risk factors for developing these devastating diseases.

Whether these studies will separate APOE genetic status is unknown.

For further exploration:

From Amyloid PET imaging in self-identified non-Hispanic Blacks from the Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study (Kacie Deters et al, 10 Feb 2021)

Results: NHB [Non-Hispanic Blacks] had lower rates of amyloid-positivity and lower continuous amyloid levels compared to NHW [Non-Hispanic Whites]. This race effect on amyloid was strongest in the APOE ε4 group. Within NHB, those with a lower percentage of African ancestry had higher amyloid. A greater proportion of NHB did not pass initial screening compared to NHW, suggesting potential sources of bias related to race in the A4 PET data.

From Racial Differences in Dietary Relations to Cognitive Decline and Alzheimer’s Disease Risk: Do We Know Enough? (Puja Agarwal et al, 3 Sep 2020):

In the past few decades, diet has been identified as an important modifiable risk factor for cognitive decline and Alzheimer’s disease. Some studies report poor diet quality among African American and Hispanic older adult populations compared to their white counterparts. We have a limited understanding of how diet affects brain health in different racial-ethnic groups. One primary reason for our lack of knowledge is that most cohort studies are of majority non-Hispanic white participants. Moreover, those that do include minority participants do not publish their findings stratified by racial-ethnic groups, and likely have a less accurate measurement of dietary intake among minority groups. In this review, we summarize the current, albeit limited, literature on racial/ethnic differences in dietary relations to dementia outcomes. We will also discuss methodological issues in conducting nutrition studies in diverse cultures, and suggestions for future research directions. Overcoming the gaps will make it possible to make dietary recommendations for Alzheimer’s prevention that are more relevant for different racial/ethnic groups and set us on a faster track to reduce health disparities.” (Bold font added to quote for emphasis).

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel (Brian W. Kunkle et al, 19 Oct 2020):

Findings: In this genome-wide association meta-analysis of 2748 individuals with Alzheimer disease and 5222 controls, several novel genetic loci and pathways associated with Alzheimer disease in African American individuals were identified.
Meaning: While the major pathways involved in Alzheimer disease etiology in African American individuals are largely similar to those in non-Hispanic White individuals, many of the disease-associated loci within these pathways differ.

Assessment of Racial Disparities in Biomarkers for Alzheimer Disease (John C. Morris et al, 7 Jan 2019)

Conclusions and Relevance: The results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.

Some insight may also be gained by reviewing the below section on the Hispanics as some population have more African ancestry and differences were found in those Hispanics with African ancestry vs European ancestry.

Hispanic, Latino, etc.

Apolipoprotein E ε4 Allele-Based Differences in Brain Volumes Are Largely Uniform Across Late Middle Aged and Older Hispanic/Latino- and Non-Hispanic/Latino Whites Without Dementia (Ariana M. Stickel et al, 26 Feb 2021)

Hispanics/Latinos are at an equal or a greater risk for Alzheimer's disease (AD), yet risk factors remain more poorly characterized as compared to non-Hispanic/Latino Whites. Among non-Hispanic/Latino White cohorts, the apolipoprotein E (APOE) ε4 allele is one of the strongest risk factors for AD with subtle declines in episodic memory and brain volumes detectable in the preclinical stages. We examined whether the APOE ε4 status had a differential impact on cognition and brain volumes among cognitively healthy and mild cognitively impaired Hispanics/Latinos (n = 86; ε4 n = 23) compared to a well-matched group of non-Hispanic/Latino Whites (n = 92; ε4 n = 29). Neither the APOE ε4 status nor the interaction between the ε4 status and ethnicity was associated with cognitive performance. The APOE ε4 status was associated with white matter and not with gray matter volumes. APOE ε4 carriers had a significantly smaller total brain white matter volumes, as well as smaller right middle temporal and left superior temporal volumes. The Hispanics/Latinos had significantly smaller left middle frontal gray matter volumes, yet marginally larger overall white matter volumes, than the non-Hispanic/Latino Whites. Exploratory analysis within the Hispanic/Latino sample found that those people whose primary language was Spanish had larger total brain white matter volumes compared primarily to the English speakers. Importantly, primary language differences only held for Hispanic/Latino ε4 carriers and did not differentiate Hispanic/Latino non-carriers, underscoring the need for further investigation into the impacts of language and acculturation on cognitive aging among the fastest growing ethnic minority group in the United States.

Association between ApoE ε4 Carrier Status and Cardiovascular Risk Factors on Mild Cognitive Impairment among Mexican Older Adults (Sara G. Aguilar-Navarro et al, 14 Nov 2020)

-Cardiovascular risk factors (CVRF), such as hypertension, diabetes, or dyslipidemia, and the presence of the Apolipoprotein E ε4 (ApoE ε4) polymorphism have been associated with an increased risk of developing Alzheimer’s disease (AD) and other dementias but the relationship is inconsistent worldwide. We aimed to establish the association between the ApoE ε4 carrier status and CVRF on MCI [Mild Cognitive Impairment] subtypes (amnestic and non-amnestic) in Mexican older adults.Bulleted list item
-ApoE ε4 carrier status was present in 28.8% participants. The models showed that ApoE ε4 carrier status was not associated neither aMCI [amnesic Mild Cognitive Impairment] nor naMCI [non-amnesic Mild Cognitive Impairment] condition. The interaction term ApoE ε4 × CVRF was not statistically significant for both types of MCI. However, CVRF were associated with both types of MCI and the association remained statistically significant after adjustment by sex, age, and education level. The carrier status of the ApoE genotype does not contribute to this risk.

APOE alleles’ association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos‐investigation of neurocognitive aging (HCHS/SOL) (Einat Granot‐Hershkovitz et al, 6 Nov 2020) This research took on six Latino subgroups as they differ based on what proportion of their genes trace back to African, European, and Amerindian (indigenous American) ancestries. Cuban individuals have the lowest proportion of Amerindian ancestry of the six groups and a relatively higher proportion of European ancestry.

Results: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P‐value = 0.03), with the strongest association in Cubans (OR = 1.46, P‐value = 0.007). APOE‐ε2 was associated with decreased risk of MCI (OR = 0.37, P‐value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline.
Discussion: Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics (Elizabeth E. Blue, et al. 9 Oct 2019) The study looked at the relationship between APOE and Alzheimer's between 3,067 Caribbean Hispanics and 3,028 individuals of European descent. They found that individuals with African-derived ancestry in their APOE gene had 39 percent lower odds of Alzheimer's than individuals with European-derived APOE.

Results: Among the Caribbean Hispanics, individuals with African‐derived ancestry at APOE had 39% lower odds of AD than individuals with European‐derived APOE, after adjusting for APOE genotype, age, and genome‐wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals.
Discussion: These results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.

Genetics of cognitive trajectory in Brazilians: 15 years of follow-up from the Bambuí-Epigen Cohort Study of Aging (Mateus H. Gouveia et al, 2 Dec 2019) Latin American populations have some of the highest prevalence rates of dementia in the world, but are under-studied. Recognizing that most genetic risk factors for Age-related Cognitive Decline (ACD) come from European populations, this research focused on Latin American population, examining genetic factors of 1,407 older Brazilians over 15 years.

Abstract: Age-related cognitive decline (ACD) is the gradual process of decreasing of cognitive function over age. Most genetic risk factors for ACD have been identified in European populations and there are no reports in admixed Latin American individuals. We performed admixture mapping, genome-wide association analysis (GWAS), and fine-mapping to examine genetic factors associated with 15-year cognitive trajectory in 1,407 Brazilian older adults, comprising 14,956 Mini-Mental State Examination measures. Participants were enrolled as part of the Bambuí-Epigen Cohort Study of Aging. Our admixture mapping analysis identified a genomic region (3p24.2) in which increased Native American ancestry was significantly associated with faster ACD. Fine-mapping of this region identified a single nucleotide polymorphism (SNP) rs142380904 (β = −0.044, SE = 0.01, p = 7.5 × 10−5) associated with ACD. In addition, our GWAS identified 24 associated SNPs, most in genes previously reported to influence cognitive function. The top six associated SNPs accounted for 18.5% of the ACD variance in our data. Furthermore, our longitudinal study replicated previous GWAS hits for cognitive decline and Alzheimer’s disease. Our 15-year longitudinal study identified both ancestry-specific and cosmopolitan genetic variants associated with ACD in Brazilians, highlighting the need for more trans-ancestry genomic studies, especially in underrepresented ethnic groups.

Native American

Given that some Hispanic populations hold a considerable percentage of Native American ancestry, review of the above discussion may be of interest.

(Research on APOEε4 allele among Native Americans needs to go here.)

This press release addresses four studies NIH expands nation’s Alzheimer’s and related dementias research capacity (National Institutes of Health, 10 Sep 2020):

To further incentivize innovative ideas and opportunities in Alzheimer's disease and related dementias research, the National Institute on Aging (NIA), part of the National Institutes of Health, has funded four exploratory Alzheimer’s Disease Research Centers (ADRCs). These new centers will broaden current ADRC research initiatives with underrepresented populations such as African Americans, Native Americans, and those in rural communities — all of which have different risk factors for developing these devastating diseases.

Whether these studies will separate APOE genetic status is unknown


Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk (Daichi Shigemizu et al, 3 Mar 2021)

Abstract: Alzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations. (bold font added for emphasis)

APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline (Steve R Makkar et al, Oct 2020) Participants included 19,225 individuals aged 54–103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years.

APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

APOE gene polymorphism in long-lived individuals from a central China population (Guodong Liu et al, 12 Jun 2017) Holding the ApoEε4 allele is typically negatively correlated with longevity, however this paper has found that carriage of ε4 in central China is associated with longevity. In southern and eastern China, this correlation does not hold up.


Epidemiology of Alzheimer’s Disease and Dementia in Arab Countries: A Systematic Review (Ashraf El-Metwally et al, 2019) Researchers looked at many studies and factors that influence dementia, including ApoE geneotypes. The researchers found that there was a greater prevalence of Alzheimer’s in ε4 carriers, but “The major risk factor that exacerbates dementia among the Arab countries is age and illiteracy.