Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk

Introduction: European local ancestry (ELA) surrounding apolipoprotein E (APOE) epsilon 4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE epsilon 4 expression in ELA versus ALA in AD brains from APOE epsilon 4/epsilon 4 carriers. Chromatin accessibility differences could contribute to these expression changes. Methods: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE epsilon 4. Results: Our results showed an increased chromatin accessibility at the APOE epsilon 4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Discussion: Our results suggest that increased chromatin accessibility of APOE epsilon 4 in ELA astrocytes contributes to the observed elevated APOE epsilon 4 expression, corresponding to the increased AD risk in ELA versus ALA APOE epsilon 4/epsilon 4 carriers.