Abstract
European local ancestry (ELA) surroundingapolipoprotein E (APOE) ε4confershigher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higherAPOE ε4 expression in ELA versus ALA in AD brains fromAPOE ε4/ε4carriers. Chromatin accessibility differences could contribute to theseexpression changes. We performed single nuclei assays for transposase accessible chromatinsequencing fromthe frontal cortex of six ALA and six ELA AD brains,homozygous for local ancestry andAPOE ε4. Our results showed an increased chromatin accessibility at theAPOE ε4 promoter areain ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide.Genes with increased accessibilityin ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Our results suggest that increased chromatin accessibility ofAPOE ε4 inELA astrocytescontributes to the observed elevatedAPOE ε4 expression, corresponding to the increased AD risk in ELA versus ALAAPOE ε4/ε4 carriers.
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