IntroductionEuropean local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4  expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes.MethodsWe 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 ε4.ResultsOur results showed an increased chromatin accessibility at the APOE ε4  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.DiscussionOur results suggest that increased chromatin accessibility of APOE ε4  in ELA astrocytes contributes to the observed elevated APOE ε4  expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

Background: European local ancestry (ELA) surrounding APOE4 is associated with a higher risk for Alzheimer Disease (AD) compared to African local ancestry (ALA). We previously demonstrated significantly higher APOE4 expression in ELA vs ALA in the frontal cortex of APOE4/4 AD patients. Differences in chromatin accessibility could contribute to these differences in APOE4 expression. Methods: We performed single nuclei Assays for Transposase Accessible Chromatin sequencing (snATAC-seq) and single nuclei RNA sequencing (snRNA-seq) from frozen frontal cortex of six ALA and six ELA AD patients, all homozygous for local ancestry and APOE4. Results: We demonstrated that APOE4, including its promoter area, has greater chromatin accessibility in ELA vs ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility and expression in ELA in astrocytes were enriched for synaptic function, cholesterol processing and astrocyte reactivity. Conclusion: Our results suggest that increased chromatin accessibility of APOE4 in astrocyte with the ELA contributes to the observed elevated APOE4 expression, corresponding to the increased AD risk in ELA vs ALA APOE4/4 carriers.