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Cited by 87Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Griswold, Anthony J., Celis, Katrina, Bussies, Parker L., Rajabli, Farid, Whitehead, Patrice L., Hamilton‐Nelson, Kara L., Beecham, Gary W., Dykxhoorn, Derek M. +16 more·2021·Alzheimer's & Dementia
DOI 10.1002/alz.12287PMC PMC8843031
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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.

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  • The degree of risk and protection afforded by E4 and E2 respectively vary according to ancestry.

    “First, the degree of risk and protection afforded by E4 and E2 respectively vary according to ancestry1,59–62.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [59]

    The Introduction (page unavailable) states that Alzheimer’s disease risk associated with APOE ε4 varies by ancestral background, including a comparison of risk across three populations. It does not address whether the protection afforded by ε2 varies by ancestry; a search for ε2 found no relevant passage. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • APOE mRNA expression levels seem to be higher in astrocytes from APOEε4 homozygous individuals with European versus African local ancestry.

    “Interestingly, APOE mRNA expression levels seem to be higher in astrocytes from APOEε4 homozygous individuals with European versus African local ancestry14; this observation could be owing to substantial differences in the frequency of certain SNPs that impact the regulation of the APOE gene expression15.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [14]

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Authors
Griswold, A. J., Celis, K., Bussies, P. L., Rajabli, F., Whitehead, P. L., Hamilton‐Nelson, K. L., Beecham, G. W., Dykxhoorn, D. M., Nuytemans, K., Wang, L., Gardner, O. K., Dorfsman, D. A., Bigio, E. H., Mesulam, M. M., Weintraub, S., Geula, C., Gearing, M., McGrath‐Martinez, E., Dalgard, C. L., Scott, W. K., Haines, J. L., Pericak‐Vance, M. A., Young, J. I., & Vance, J. M.
Affiliations
  • University of Miami (US)
  • Northwestern University (US)
  • Northwestern ADC Neuropathology Core Northwestern University Feinberg School of Medicine Chicago Illinois USA
  • Emory University (US)
  • The American Genome Center Uniformed Services University Bethesda Maryland USA
  • Henry M. Jackson Foundation (US)
  • Case Western Reserve University (US)
Corresponding author
Vance, Jeffery M.
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2021-02
Volume
17
Issue
7
Pages
1179-1188
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.12287
PMC
PMC8843031
OpenAlex
W3127093013
Cited by
87
References
43
Citations by year
2026: 19 · 2025: 22 · 2024: 15 · 2023: 16 · 2022: 13 · 2021: 2
FWCI
7.23
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Alzheimer s & Dementia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01‐AG059018, U01‐AG052410, RF1‐AG054074, U01‐AG057659)
  • BrightFocus Foundation
  • Alzheimer's Association (A2018425S)
  • National Institutes of Health (P50‐AG0256878, P30‐AG013854)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, APOE ε4
MeSH terms
Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Female, Heterozygote, Humans, Male, Sequence Analysis, RNA, Black People, White People, Apolipoprotein E4

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