@article{0f77720f7d57456b88ecd61e6e8b6e90,
title = "Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds",
abstract = "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.",
keywords = "APOE, Alzheimer's disease, local ancestry, single-nucleus RNA-seq",
author = "Griswold, {Anthony J.} and Katrina Celis and Bussies, {Parker L.} and Farid Rajabli and Whitehead, {Patrice L.} and Hamilton-Nelson, {Kara L.} and Beecham, {Gary W.} and Dykxhoorn, {Derek M.} and Karen Nuytemans and Liyong Wang and Gardner, {Olivia K.} and Dorfsman, {Daniel A.} and Bigio, {Eileen H.} and Mesulam, {Marek Marsel} and Sandra Weintraub and Changiz Geula and Marla Gearing and Elisa McGrath-Martinez and Dalgard, {Clifton L.} and Scott, {William K.} and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Young, {Juan I.} and Vance, {Jeffery M.}",
note = "Funding Information: This study was supported by the National Institute on Aging (grant numbers R01‐AG059018, U01‐AG052410, RF1‐AG054074, and U01‐AG057659), and the BrightFocus Foundation, and Alzheimer's Association (grant number A2018425S). The work was also funded by the National Institutes of Health (grant number P50‐AG0256878 and P30‐AG013854) from Emory and from Northwestern, respectively. Funding Information: This study was supported by the National Institute on Aging (grant numbers R01-AG059018, U01-AG052410, RF1-AG054074, and U01-AG057659), and the BrightFocus Foundation, and Alzheimer's Association (grant number A2018425S). The work was also funded by the National Institutes of Health (grant number P50-AG0256878 and P30-AG013854) from Emory and from Northwestern, respectively. Genomic and data analysis was provided by the Center for Genome Technology from the John P. Hussman Institute for Human Genomics from the University of Miami Miller School of Medicine. We thank Dr. Holly Cukier for helpful discussions of the data; Mr. Benjamin Goldstein for data analysis assistance; and the numerous participants, researchers, and staff from many studies who collected and contributed to the data. Publisher Copyright: {\textcopyright} 2021 the Alzheimer's Association",
year = "2021",
month = jul,
doi = "10.1002/alz.12287",
language = "English (US)",
volume = "17",
pages = "1179--1188",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "7",
}
