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Cited by 316Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias

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Martens, Yuka A., Zhao, Na, Liu, Chia-Chen, Kanekiyo, Takahisa, Yang, Austin J., Goate, Alison M., Holtzman, David M., Bu, Guojun·2022·Neuron
DOI 10.1016/j.neuron.2022.03.004PMC PMC9035117
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Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.

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  • Glial cells show APOE4-associated transcriptomic changes in both human E4+ brains and E4-TR mice.

    “Across multiple studies, glial cells show APOE4-associated transcriptomic changes in both human E4+ brains and E4-TR mice5.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [5]

    In “ApoE and intracellular trafficking dysregulation” (page unavailable), the review reports transcriptomic differences between apoE4-TR and apoE3-TR mouse brains. Its References also list a study of APOE4-associated transcriptomic changes in primary mouse microglia. Our copy does not establish the corresponding claim about glial transcriptomic changes in human E4+ brains. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Reducing ApoE levels is generally protective in AD models.

    “Reducing ApoE levels is generally protective in AD models1,4–6.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [1]

    The Phenotypic phase section reports that apoE deficiency in mice greatly reduces amyloid plaques and cerebral amyloid angiopathy. But the Targeting apoE-initiated cascade events section says that increasing or decreasing apoE protein levels may be appropriate depending on the isoform. The source therefore supports protection in some AD models, not a general protective effect of reducing apoE levels. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ApoE has been implicated in various cellular pathways linked to AD pathogenesis, including amyloid-β (Aβ) clearance and aggregation, tau pathology, metabolism, endolysosomal trafficking, and neuroinflammation.

    “Apolipoprotein E (ApoE) has been implicated in various cellular pathways linked to AD pathogenesis, including amyloid-β (Aβ) clearance and aggregation, tau pathology, metabolism, endolysosomal trafficking, and neuroinflammation1–3.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [1]

    The Phenotypic phase links apoE to Aβ aggregation, tau pathology, and neuroinflammation; the Cellular phase describes apoE4-related endosomal trafficking dysregulation, and the Concluding remarks identify lipid metabolism as another apoE pathway. The passages found do not establish the specific claim about Aβ clearance. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Poorly lipidated ApoE may seed Aβ due to its propensity to aggregate, and lipidated ApoE is protective in AD models.

    “Studies suggest poorly lipidated ApoE may seed Aβ due to its propensity to aggregate and that lipidated ApoE is protective in AD models1.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [1]

    The ‘ApoE oligomerization’ section says lipid-free apoE is prone to self-aggregation and that lipidation hinders aggregation. The ‘Phenotypic phase’ section reports that apoE promotes Aβ aggregation in mice and that increased apoE lipidation reduces Aβ deposition. These passages support the protective-lipidation point, but do not establish the specific proposed mechanism that poorly lipidated apoE seeds Aβ because it aggregates. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • APOE has a known key role in AD-related processes including amyloid-β clearance and aggregation, the immune response to pathology, tau pathology development, and the maintenance of cerebrovascular homeostasis.

    “APOE has a known key role in AD-related processes including amyloid-β clearance and aggregation, the immune response to pathology, tau pathology development, and the maintenance of cerebrovascular homeostasis [44].”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [44]

    The Phenotypic phase section says apoE promotes Aβ aggregation and fibrillization, affects tau pathology and AD-related immune responses, and is associated with cerebrovascular dysfunction (page not available in our copy). These passages support most of the sentence, but the paper’s discussion does not establish the specifically attributed role in Aβ clearance; clearance appears in a reference title, not as a finding stated in the text. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Martens, Y. A., Zhao, N., Liu, C.-C., Kanekiyo, T., Yang, A. J., Goate, A. M., Holtzman, D. M., & Bu, G.
Affiliations
  • Mayo Clinic in Florida (US)
  • National Institutes of Health (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Washington University in St. Louis (US)
  • Mayo Clinic (US)
Corresponding author
Bu, Guojun
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2022-04
Volume
110
Issue
8
Pages
1304-1317
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2022.03.004
PMC
PMC9035117
OpenAlex
W4220763938
Cited by
316
References
161
Citations by year
2026: 52 · 2025: 75 · 2024: 80 · 2023: 93 · 2022: 16
FWCI
9.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
National Institute on Aging (U01AG058635, R37AG027924, RF1AG057181, RF1AG046205, U19AG069701)
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, APOE ε4, Alzheimer's disease, dementia with Lewy bodies, APOE isoforms, age-related cognitive decline, genetic risk factors, aging
MeSH terms
Alzheimer Disease, Amino Acids, Apolipoproteins E, Humans, Protein Isoforms, Apolipoprotein E4, Apolipoprotein E2

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