Dataset Information

Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans.

ABSTRACT:

Background

The APOE?4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOE?4 to AD risk could be population-specific, with ?4 conferring a lower risk to Blacks or African Americans.

Objective

To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).

Methods

We selected data from 1) the National Alzheimer's Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N?=?7,997, 60% female) with genotypes from the Alzheimer's Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N?=?1,248, 60% female). Using ?3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU.

Results

In both cohorts, we find no difference in the odds or age of onset of AD among the ?4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE?4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ?4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification.

Conclusion

Our study finds similar effects of the ?4-linked haplotypes defined by rs769449 on AD as compared to ?3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.

SUBMITTER: Mezlini AM

PROVIDER: S-EPMC7774865 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans.

Mezlini Aziz M AM Magdamo Colin C Merrill Emily E Chibnik Lori B LB Blacker Deborah L DL Hyman Bradley T BT Das Sudeshna S

Journal of Alzheimer's disease : JAD 20200101 1

<h4>Background</h4>The APOEɛ4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOEɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans.<h4>Objective</h4>To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).<h4>Methods</h4>We selected data from 1) the National Alzheimer's Coo ...[more]

PMID: 33016904

Similar Datasets

Project description:BACKGROUND:Genetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer's disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recent studies have found evidence that DNA methylation may contribute to the pathogenesis of dementia, but its association with cognitive function in populations without dementia remains unclear. METHODS:We assessed DNA methylation levels of 48 CpG sites in the APOE genomic region in peripheral blood leukocytes collected from 289 African Americans (mean age?=?67 years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Using linear regression, we examined the relationship between methylation in the APOE genomic region and multiple cognitive measures including learning, memory, processing speed, concentration, language and global cognitive function. RESULTS:We identified eight CpG sites in three genes (PVRL2, TOMM40, and APOE) that showed an inverse association between methylation level and delayed recall, a measure of memory, after adjusting for age and sex (False Discovery Rate q-value?<?0.1). All eight CpGs are located in either CpG islands (CGIs) or CGI shelves, and six of them are in promoter regions. Education and APOE ?4 carrier status significantly modified the effect of methylation in cg08583001 (PVRL2) and cg22024783 (TOMM40), respectively. Together, methylation of the eight CpGs explained an additional 8.7% of the variance in delayed recall, after adjustment for age, sex, education, and APOE ?4 carrier status. Methylation was not significantly associated with any other cognitive measures. CONCLUSIONS:Our results suggest that methylation levels at multiple CpGs in the APOE genomic region are inversely associated with delayed recall during normal cognitive aging, even after accounting for known genetic predictors for cognition. Our findings highlight the important role of epigenetic mechanisms in influencing cognitive performance, and suggest that changes in blood methylation may be an early indicator of individuals at risk for dementia as well as potential targets for intervention in asymptomatic populations.

Dataset Information

Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans.

Background

Objective

Methods

Results

Conclusion

Publications

Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans.

Similar Datasets

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