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

Katrina Celis, Maria D.M.Muniz Moreno, Farid Rajabli, Patrice Whitehead, Kara Hamilton-Nelson, Derek M. Dykxhoorn, Karen Nuytemans, Liyong Wang, Margaret Flanagan, Sandra Weintraub, Changiz Geula, Marla Gearing, Clifton L. Dalgard, Fulai Jin, David A. Bennett, Theresa Schuck, Margaret A. Pericak-Vance, Anthony J. Griswold, Juan I. Young, Jeffery M. Vance

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Introduction: European 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. 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 ε4. Results: Our 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. Discussion: Our 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.

Original languageEnglish (US)
Pages (from-to)3902-3915
Number of pages14
JournalAlzheimer's and Dementia
Volume19
Issue number9
DOIs
StatePublished - Sep 2023
Externally publishedYes

Keywords

  • African
  • Alzheimer's disease
  • European
  • ancestry
  • apolipoprotein E ε4
  • chromatin accessibility
  • gene expression
  • single nuclei assay for transposase accessible chromatin followed by sequencing
  • single nucleus RNA sequencing

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Health Policy
  • Developmental Neuroscience
  • Epidemiology

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