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Cited by 152Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease

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Kloske, Courtney M., Wilcock, Donna M.·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.00754PMC PMC7203730
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Abstract

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disease, currently affecting over 5 million Americans with projections expected to rise as the population ages. The hallmark pathologies of AD are Aβ plaques composed of aggregated beta-amyloid (Aβ), and tau tangles composed of hyperphosphorylated, aggregated tau. These pathologies are typically accompanied by an increase in neuroinflammation as an attempt to ameliorate the pathology. This idea has pushed the field toward focusing on mechanisms and the influence neuroinflammation has on disease progression. The vast majority of AD cases are sporadic and therefore, researchers investigate genetic risk factors that could lead to AD. Apolipoprotein E (ApoE) is the largest genetic risk factor for developing AD. ApoE has 3 isoforms-ApoE2, ApoE3, and ApoE4. ApoE4 constitutes an increased risk of AD, with one copy increasing the risk about 4-fold and two copies increasing the risk about 15-fold compared to those with the ApoE3 allele. ApoE4 has been shown to play a role in Aβ deposition, tau tangle formation, neuroinflammation and many subsequent pathways. However, while we know that ApoE4 plays a role in these pathways and virtually all aspects of AD, the exact mechanism of how ApoE4 impacts AD progression is murky at best and therefore the role ApoE4 plays in these pathways needs to be elucidated. This review aims to discuss the current literature regarding the pathways and mechanisms of ApoE4 in AD progression with a focus on its role in neuroinflammation.

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  • Differences in APOE isoform-specific receptor binding affinity and lipid interactions affect neuroinflammation, tau pathology, and amyloid plaque dynamics.

    “Studies indicate that APOE binding is integral to some of these processes [16–20] with differences in APOE isoform-specific receptor binding affinity and lipid interactions affecting neuroinflammation, tau pathology, and amyloid plaque dynamics [21–24].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [23]

    The “ApoE in the Central Nervous System” section (page not provided) describes isoform differences in LDL-receptor affinity and lipid binding. The “ApoE and Aβ” and “ApoE and Tau” sections (pages not provided) report isoform-related differences in plaque formation and tau-associated neuroinflammation, but do not establish that the receptor-binding and lipid interactions cause those outcomes. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • APOE and APOE3Ch influence both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.

    “Collectively, these recent findings underscore the influence of APOE and APOE3Ch on both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [23]

    The “ApoE and Aβ” and “ApoE and Tau” sections describe effects of ApoE isoforms on amyloid pathology and tau-related neuroinflammation. They do not establish the claim about APOE3Ch specifically; a search for APOE3Ch and Christchurch found no passage addressing that variant. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Neuroinflammation is a major pathological feature strongly correlated with Aβ plaque and NFT pathologies and modulates AD progression.

    “Neuroinflammation is another major pathological feature that is strongly corelated with the Aβ plaque and NFT pathologies and modulates AD progression”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Kloske & Wilcock 2020

    The Introduction and “Inflammation in Alzheimer’s Disease” sections describe neuroinflammation as important to AD progression, while the microglia and “ApoE and Tau” sections link inflammatory responses to Aβ plaques and tau pathology (page numbers unavailable). The paper does not establish the claimed strong correlation with both plaque and NFT pathology. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • ApoE4 is associated with decreased ability of astrocytes to maintain Ca2+ and K+ homeostasis.

    “it has been proposed that ApoE4 is associated to a decreased ability of astrocytes to maintain Ca2+ and K+ homeostasis [24]”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [24]

    The “Astrocytes in Neuroinflammation” section says that astrocytes in Alzheimer’s disease can lose their ability to maintain calcium levels and potassium homeostasis. It does not attribute that specific loss to ApoE4, so the ApoE4 association in the citing sentence is not supported by this passage. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ApoE4 is associated with increased levels of neurotoxic and inflammatory cytokines (TNFα, IL-6, IL-1β) and nitric oxide released by microglia and astrocytes in different models of AD.

    “Different studies have showed an association between this ApoE isoform and increased levels of neurotoxic and inflammatory cytokines, such as tumor necrosis factor α (TNFα), Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and nitric oxide released by microglia and astrocytes, in different models of AD [24].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [24]

    In “Early Investigations of ApoE Isoforms’ Role on Inflammation” (page unavailable), the review reports higher brain TNFα and IL-6 in ApoE4 mice and greater nitric oxide release from ApoE4 microglia. “ApoE and Aβ” reports increased glial activity measured by IL-1β in an AD mouse model. The cited passages do not establish that astrocytes release the listed substances, and the TNFα/IL-6 finding comes from LPS-treated mice rather than an identified AD model. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Kloske, C. M., & Wilcock, D. M.
Affiliations
University of Kentucky (US)
Corresponding author
Wilcock, Donna M.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-04-30
Volume
11
Pages
754-754
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.00754
PMC
PMC7203730
OpenAlex
W3021259566
Cited by
152
References
49
Citations by year
2026: 11 · 2025: 22 · 2024: 22 · 2023: 38 · 2022: 25 · 2021: 28 · 2020: 6
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, apolipoprotein E, APOE ε4, neuroinflammation, amyloid plaques, tau tangles, genetic risk factors, APOE isoforms, disease progression
MeSH terms
Alzheimer Disease, Apolipoproteins E, Astrocytes, Autophagy, Blood-Brain Barrier, Humans, Inflammation, Signal Transduction, Amyloid beta-Peptides, tau Proteins

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