Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds

Anthony J. Griswold, Katrina Celis, Parker L. Bussies, Farid Rajabli, Patrice L. Whitehead, Kara L. Hamilton-Nelson, Gary W. Beecham, Derek M. Dykxhoorn, Karen Nuytemans, Liyong Wang, Olivia K. Gardner, Daniel A. Dorfsman, Eileen H. Bigio, Marek Marsel Mesulam, Sandra Weintraub, Changiz Geula, Marla Gearing, Elisa McGrath-Martinez, Clifton L. Dalgard, William K. ScottJonathan L. Haines, Margaret A. Pericak-Vance, Juan I. Young, Jeffery M. Vance*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Introduction: Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences. Methods: Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA. Results: A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44-46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P < 1.8E–317) in 24 of 32 cell clusters. The transcriptome of one astrocyte cluster, with high APOE ε4 expression and specific to ELA, is suggestive of A1 reactive astrocytes. Discussion: AD patients with ELA expressed significantly greater levels of APOE than ALA APOE ε4 carriers. These differences in APOE expression could contribute to the reduced risk for AD seen in African APOE ε4 carriers.

Original languageEnglish
Pages (from-to)1179-1188
Number of pages10
JournalAlzheimer's and Dementia
Issue number7
StatePublished - Jul 2021
Externally publishedYes


  • APOE
  • Alzheimer's disease
  • local ancestry
  • single-nucleus RNA-seq


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