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

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 contri...

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Published inAlzheimer's & dementia Vol. 17; no. 7; pp. 1179 - 1188
Main Authors Griswold, Anthony J., Celis, Katrina, Bussies, Parker L., Rajabli, Farid, Whitehead, Patrice L., Hamilton‐Nelson, Kara L., Beecham, Gary W., Dykxhoorn, Derek M., Nuytemans, Karen, Wang, Liyong, Gardner, Olivia K., Dorfsman, Daniel A., Bigio, Eileen H., Mesulam, Marek Marsel, Weintraub, Sandra, Geula, Changiz, Gearing, Marla, McGrath‐Martinez, Elisa, Dalgard, Clifton L., Scott, William K., Haines, Jonathan L., Pericak‐Vance, Margaret A., Young, Juan I., Vance, Jeffery M.
Format Journal Article
LanguageEnglish
Published United States 01.07.2021
Subjects
Aged
Aged, 80 and over
Alleles
Alzheimer Disease - ethnology
Alzheimer Disease - genetics
Alzheimer's disease
APOE
Apolipoprotein E4 - genetics
Black People - genetics
Female
Heterozygote
Humans
local ancestry
Male
Sequence Analysis, RNA
single‐nucleus RNA‐seq
White People - genetics
APOE
single-nucleus RNA-seq
local ancestry
Alzheimer's disease
Online AccessGet full text
ISSN1552-5260
1552-5279
1552-5279
DOI10.1002/alz.12287

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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.
AbstractList 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. Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA. 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 ) 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. 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.
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.
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.INTRODUCTIONApolipoprotein 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.Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA.METHODSSingle-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA.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.RESULTSA 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.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.DISCUSSIONAD 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.
Author Whitehead, Patrice L.
Dalgard, Clifton L.
Dorfsman, Daniel A.
Bigio, Eileen H.
Griswold, Anthony J.
Mesulam, Marek Marsel
Geula, Changiz
Wang, Liyong
Scott, William K.
McGrath‐Martinez, Elisa
Bussies, Parker L.
Dykxhoorn, Derek M.
Hamilton‐Nelson, Kara L.
Haines, Jonathan L.
Gardner, Olivia K.
Pericak‐Vance, Margaret A.
Vance, Jeffery M.
Young, Juan I.
Celis, Katrina
Nuytemans, Karen
Rajabli, Farid
Beecham, Gary W.
Gearing, Marla
Weintraub, Sandra
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single-nucleus RNA-seq
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Notes Anthony J. Griswold, Katrina Celis, Juan I. Young, and Jeffery M. Vance contributed equally to this study.
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Snippet Introduction Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4...
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...
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SubjectTerms Aged
Aged, 80 and over
Alleles
Alzheimer Disease - ethnology
Alzheimer Disease - genetics
Alzheimer's disease
APOE
Apolipoprotein E4 - genetics
Black People - genetics
Female
Heterozygote
Humans
local ancestry
Male
Sequence Analysis, RNA
single‐nucleus RNA‐seq
White People - genetics
Title Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Falz.12287
https://www.ncbi.nlm.nih.gov/pubmed/33522086
https://www.proquest.com/docview/2484157965
Volume 17
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