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Cited by 202Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Cell type‐specific roles of APOE4 in Alzheimer disease

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Blumenfeld, Jessica, Yip, Oscar, Kim, Min Joo, Huang, Yadong·2024·Nature Reviews Neuroscience
DOI 10.1038/s41583-023-00776-9PMC PMC11073858
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Abstract

The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before. In particular, cutting-edge omics studies have enabled APOE4 to be studied at the single-cell level and have allowed the identification of critical APOE4 effects in AD-vulnerable cellular subtypes. Through these studies, it has become evident that APOE4 produced in various types of CNS cell - including astrocytes, neurons, microglia, oligodendrocytes and vascular cells - has diverse roles in AD pathogenesis. Here, we review these scientific advances and propose a cell type-specific APOE4 cascade model of AD. In this model, neuronal APOE4 emerges as a crucial pathological initiator and driver of AD pathogenesis, instigating glial responses and, ultimately, neurodegeneration. In addition, we provide perspectives on future directions for APOE4 research and related therapeutic developments in the context of AD.

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  • The proportion of inhibitory interneurons could be correlated with AD disease progression.

    “However, it has been shown that inhibitory neurons express higher levels of APOE4, and the proportion of inhibitory interneurons could be correlated with AD disease progression [4,34,48]”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [4]

    The ‘APOE4 in Disease-associated neuronal subtypes’ section reports that AD progression was related to the proportion of neurons—especially inhibitory interneurons—expressing high levels of APOE. The claim omits that expression qualifier: the passage does not establish a correlation with the proportion of all inhibitory interneurons. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In the brain, APOE is mainly produced by astrocytes, which generate up to 80% of total brain APOE.

    “In the brain, APOE is mainly produced by astrocytes, which generate up to 80% of total brain APOE (Blumenfeld et al., 2024).”

    From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Blumenfeld et al., 2024

    The 'Expression and regulation of astrocytic APOE' section says astrocytes produce most CNS APOE and contribute approximately 75–80% of total APOE in the mouse brain. The citing sentence applies the 80% figure to the brain generally, without the mouse qualifier. No page number is provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • apoE facilitates cholesterol transport, extracellular amyloid beta clearance, synaptic pruning, and blood-brain barrier integrity.

    “apolipoprotein E (apoE), a lipid‐binding protein expressed by astrocytes, which facilitates cholesterol transport, extracellular amyloid beta (Aβ) clearance, synaptic pruning, and blood–brain barrier (BBB) integrity.”

    From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [2]

  • Astrocytes are critical for maintaining CNS homeostasis, playing essential roles in lipid metabolism and clearance of toxic protein aggregates.

    “Astrocytes are critical for maintaining central nervous system (CNS) homeostasis, playing essential roles in lipid metabolism and the clearance of toxic protein aggregates.”

    From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [2]

  • APOE is primarily expressed by astrocytes in the brain, but neurons have also been shown as a source for APOE.

    “Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [4]

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Authors
Blumenfeld, J., Yip, O., Kim, M. J., & Huang, Y.
Affiliations
Gladstone Institutes (US)
Corresponding author
Huang, Yadong
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2024-01-08
Volume
25
Issue
2
Pages
91-110
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-023-00776-9
PMC
PMC11073858
OpenAlex
W4390673474
Cited by
202
References
209
Citations by year
2026: 80 · 2025: 81 · 2024: 41
FWCI
10.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (RF1AG076647, R01AG065540, R01AG071697, P01AG073082)
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
APOE ε4, apolipoprotein E, Alzheimer's disease, late-onset Alzheimer's disease, genetic risk factors, astrocytes, microglia, oligodendrocytes, vascular cells, neurodegeneration, glial response, single-cell omics, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Neuroglia, Neurons, Apolipoprotein E4

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