Interrogating the protective effect of African APOE alleles on Alzheimer's disease risk through pleiotropy

Project Summary/Abstract
Alzheimer’s disease (AD) is a highly heritable trait, where much of the phenotypic variation is explained
by genetic variation. A significant proportion of AD risk is explained by ancestry and APOE genotype. We and
others have shown that ancestry differences across the genome (global ancestry) and at the APOE locus (local
ancestry) are significantly associated with risk of AD in admixed populations. African-derived APOE alleles
are associated with reduced risk of AD after controlling for global ancestry and APOE ε2/ε3/ε4 genotype in
African American, Caribbean Hispanic, and Puerto Rican samples. This local ancestry effect may be driven by
variants on African-derived haplotypes, European-derived haplotypes, or both. The focus of this study is to
determine which variants on these haplotypes may explain the association between African-derived APOE
alleles and reduced risk of AD and to characterize their potential consequences at the cellular level.
APOE is involved in many pathways relevant to AD, including lipid biosynthesis and two ends of the
efferocytosis pathway: recognition/engulfment and adaptation. This may explain why the ε2 and ε4 alleles
associated with AD risk are associated with many phenotypes, including peripheral lipid traits (lipids) and
inflammatory markers like C-reactive protein (CRP). Both ε2 and ε4 are associated with unfavorable lipid and
CRP profiles that are themselves associated with AD risk, AD biomarkers, and other causes of morbidity and
mortality. As with AD, the strength of association between ε2 and ε4 and both lipids and CRP vary with
ancestry. Joint consideration of AD with lipid and inflammation-related traits is expected to reveal additional
pathophysiological information not identifiable in separate analyses.
Therefore, we propose to investigate local ancestry effects at APOE and AD risk within the Alzheimer’s
Disease Sequencing Project (ADSP) whole genome sequence (WGS) data, along with their effects on
harmonized lipid traits and CRP levels paired with WGS data from the Trans-Omics for Precision Medicine
(TOPMed) project among admixed participants who were not ascertained for AD. We will estimate local
ancestry probabilities, then test for association between global (across the genome) and local (at APOE)
ancestry using two alternative approaches. Contrasting ancestry-specific APOE haplotypes within and
between these studies will allow us to nominate variants with pleiotropic vs. trait-specific effects. Our
bioinformatics pipeline will link variants to their potential consequences using gene expression and regulatory
data tailored to AD, prioritizing the appropriate model systems for future studies. This work will facilitate
therapeutic target selection that avoids negative effects on lipid and inflammatory phenotypes associated with
significant morbidity and mortality.

Grant Number: 5R21AG089267-02
NIH Institute/Center: NIH
Principal Investigator: ELIZABETH BLUE