Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
Abstract
Human apolipoprotein (APO) E has three common isoforms that differentially affect lipid and neuronal homeostasis. APOE4, the major known genetic risk factor for Alzheimer's disease (AD), increases the occurrence and lowers the age of onset of AD. APOE4 carriers account for 65-80% of all AD cases, highlighting the importance of APOE4 in AD pathogenesis. Emerging data suggest that APOE4 contributes to AD through various pathways, some of which are dependent on amyloid-beta (Abeta). Although these Abeta-dependent roles of APOE4 have been widely studied, APOE4 has detrimental effects on neurons independent of Abeta: aberrant proteolysis of APOE4 generates neurotoxic fragments, stimulates Tau phosphorylation, which disrupts the cytoskeleton, and impairs mitochondrial function.
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Astrocytes are the primary source of APOE production in the brain, and disease-related phenotypes are influenced by interactions between astrocyte-secreted APOE and neurons.
“This is significant because astrocytes are the primary source of APOE production in the brain, and disease-related phenotypes are influenced by the interactions between astrocyte-secreted APOE and neurons (Huang, 2010; Huang and Mucke, 2012).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Huang, 2010
APOE4 expression has deleterious effects on numerous Aβ-independent pathways, including lipid metabolism, tau pathology, bioenergetics, neuronal development, synaptic plasticity, the neuro-vasculature, and neuro-inflammation.
“APOE4 expression has also been shown to have deleterious effects on numerous Aβ-independent pathways, including lipid metabolism, tau pathology, bioenergetics, neuronal development, synaptic plasticity, the neuro-vasculature, and neuro-inflammation”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [14]
The apoE4 domain interaction renders apoE4 more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments.
“Importantly, this domain interaction renders apoE4 to be more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments [20–22].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [21]
ApoE plays major roles in Alzheimer's disease pathogenesis in both an amyloid-β-dependent and independent manner.
“Overall, it has been demonstrated, both in vivo and in vitro, that apoE plays major roles in AD pathogenesis in both an Aβ-dependent and independent manner, and different cellular sources of apoE4 may contribute in distinct ways to AD pathogenesis [4–8, 12–14, 21, 22].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [21]
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References 125 · Cited by 170
- Authors
- Huang, Y.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Huang, Yadong
- ORCID
- Huang, Yadong
- Venue
- Trends in Molecular Medicine
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 16
- Issue
- 6
- Pages
- 287-294
- ISSN
- 1471-4914 (ISSN-L)
- OpenAlex
- W2047167072
- Cited by
- 170
- References
- 125
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 9 · 2023: 2 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 9 · 2017: 16 · 2016: 14 · 2015: 8 · 2014: 13 · 2013: 12 · 2012: 20
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P01AG022074)
- 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
- APOE ε4, Alzheimer's disease pathogenesis, tau phosphorylation, cytoskeleton disruption, mitochondrial dysfunction, APOE isoforms, genetic risk factors
- MeSH terms
- Alzheimer Disease, Animals, Humans, Models, Biological, Neurons, Amyloid beta-Peptides, Apolipoprotein E4
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