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Cited by 84Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

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Gamache, Julia, Yun, Young, Chiba-Falek, Ornit·2020·Disease Models & Mechanisms
DOI 10.1242/dmm.045211PMC PMC7473656
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Abstract

The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in ‘omics’ technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.

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  • Sex differences in AD-related genes are not limited to risk factors like APOE but are pertinent to dominant AD mutations as well.

    “Together with the sex differences in pathology seen in mice transgenically expressing App with the Swedish mutation and presenilin 1 with the A246E mutation37, these data indicate the sex differences in AD-related genes are not limited to risk factors like APOE but pertinent to dominant AD mutations as well (for review, see38).”

    From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [38]

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Authors
Gamache, J., Yun, Y., & Chiba-Falek, O.
Affiliations
  • Duke University (US)
  • Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA
ORCID
Venue
Disease Models & Mechanisms
Publisher
The Company of Biologists
Published
2020-08-01
Volume
13
Issue
8
ISSN
  • 1754-8403 (ISSN-L)
  • 1754-8411
DOI
10.1242/dmm.045211
PMC
PMC7473656
OpenAlex
W3080496437
Cited by
84
References
342
Citations by year
2026: 13 · 2025: 12 · 2024: 16 · 2023: 12 · 2022: 12 · 2021: 17 · 2020: 1
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Disease Models & Mechanisms (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institutes of Health (R01-AG057522-01, R01-AG040370-01A1)
  • National Institute on Aging (R01-AG057522-01, R01-AG040370-01A1)
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
apolipoprotein E, Alzheimer's disease, sex differences, age-related neurodegenerative diseases, sex hormones, neurodegeneration, endophenotypes, rodent models
MeSH terms
Age Factors, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Female, Humans, Male, Nerve Degeneration, Phenotype, Prognosis, Risk Factors, Sex Characteristics, Sex Factors, Genetic Variation, Risk Assessment, Neurodegenerative Diseases, Genetic Predisposition to Disease, Health Status Disparities

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