Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley, Robert W.; Weisgraber, Karl H.; Huang, Yadong

doi:10.1073/pnas.0600549103

Cited by 912Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsLipoproteins and Cardiovascular Health

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

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Mahley, Robert W., Weisgraber, Karl H., Huang, Yadong·2006·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0600549103PMC PMC1414631

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Abstract

The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synapto-dendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer’s disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid β peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N- and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of “structure correctors” to convert apoE4 to an “apoE3-like” molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and “mitochondrial protectors” to prevent cellular energy disruption.

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APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease.
“Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD)1–3.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [2]
The “ApoE and Neuropathology” section calls apoE4 the major known genetic risk factor for Alzheimer’s disease in many populations. It does not specify late-onset disease, and the citing sentence omits the population qualifier. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Most AD patients have sporadic late-onset AD, in which the APOE gene contains a predominant risk variant.
“Most AD patients have sporadic late-onset AD (LOAD), in which the apolipoprotein E (APOE) gene contains a predominant risk variant6,7.”
From APOE3 - R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [6]
The ‘ApoE and Neuropathology’ section identifies apoE4 as the major known genetic risk factor for AD in many populations. It does not establish that most AD patients have sporadic late-onset AD or specifically tie that risk-factor statement to late-onset disease. (LLM, conf=0.85)
Experimental — accuracy not yet measured
In neurons, apoE4 is associated with impaired mitochondrial respiration.
“In neurons, apoE4 is associated with impaired mitochondrial respiration”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
The section “ApoE4 Neuropathology Independent of Aβ” (page unavailable) associates apoE4 with reduced neuronal glucose utilization and describes mitochondrial dysfunction in cultured neurons. That supports impaired mitochondrial function, but the paper does not specifically establish impaired mitochondrial respiration. (LLM, conf=0.82)
Experimental — accuracy not yet measured
The largest apoE4 fragment, apoE4(1-272), causes mitochondrial fragmentation.
“and cause mitochondrial fragmentation [10, 17, 20]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
In “ApoE4 Neuropathology Independent of Aβ” (page unavailable), the paper says apoE4(1-272) accumulates in mitochondria and describes mitochondrial dysfunction associated with apoE fragments. It does not say that apoE4(1-272) causes mitochondrial fragmentation, a distinct change in mitochondrial structure. (LLM, conf=0.84)
Experimental — accuracy not yet measured
The largest apoE4 fragment, apoE4(1-272), interacts directly with mitochondria to reduce mitochondrial membrane potential.
“The largest apoE4 fragment, apoE4(1–272), interacts directly with mitochondria to reduce mitochondrial membrane potential”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
In “ApoE4 Neuropathology Independent of Aβ” (page unavailable), the paper reports that apoE4(1–272) accumulates in mitochondria and that apoE fragments disrupt mitochondrial electropotential in cultured neurons. It does not establish that apoE4(1–272) directly binds mitochondria: the Mitochondrial Binding subsection says how the fragments associate with mitochondria is unknown and offers direct binding as one possibility. (LLM, conf=0.87)
Experimental — accuracy not yet measured

ApoE4 lipid-binding region (240-270 aa) in the C-terminal domain is involved in direct interaction with mitochondria and binding to Aβ.
“while the lipid-binding region (240–270 aa) in the C-terminal domain is more likely involved in direct interaction with mitochondria (Figure 1) and binding to Aβ [26].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [26]
The Fig. 4 caption identifies residues 240–270 as a lipid- and Aβ-binding region involved in mitochondrial localization. But the “Mitochondrial Binding” section says the authors do not know how apoE fragments associate with mitochondria: direct lipid binding is one possibility alongside indirect routes. The source therefore does not establish that direct interaction is more likely. Page numbers were not provided in the excerpts. (LLM, conf=0.87)
Experimental — accuracy not yet measured
ApoE4 receptor-binding region (136-150 aa) is required for binding to the LDL receptor and to tau protein.
“Within the N-terminal domain, ApoE4 receptor-binding region (136–150 aa) is required for its binding to the low-density lipoprotein (LDL) receptor and to tau protein”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [26]
The Fig. 4 caption (ApoE4 Neuropathology in the Context of Aβ) says residues 136–150 play a key role in binding to the LDL receptor and tau, and Structural Differences Among the ApoE Isoforms identifies them as the LDL receptor-binding site. But ApoE4 Effects on Tau Phosphorylation says apoE4 does not interact significantly with tau in vitro, unlike apoE3. The source therefore does not establish that this region is required for apoE4 to bind tau. (LLM, conf=0.86)
Experimental — accuracy not yet measured
ApoE4 largest fragment (1-272 aa) directly interacts with mitochondria, leading to decrease in Δψm and mitochondrial fragmentation.
“ApoE4 largest fragment (1–272 aa) was shown to directly interact with mitochondria, which leads to a decrease in Δψm and mitochondrial fragmentation [26,29,73].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [26]
The “ApoE4 Neuropathology Independent of Aβ” section reports that apoE4(1–272) accumulates in mitochondria and that apoE fragments disrupt mitochondrial electropotential in cultured neurons. It does not report mitochondrial fragmentation, and it explicitly says how the fragments associate with mitochondria is unknown, so direct interaction is not established. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The observed difference in Aβ deposition between apoE isoforms cannot be simply attributed to apoE4 levels being lower than apoE3.
“However, the structure of apoE3 and apoE4 differs significantly from each other (Mahley et al., 2006), and the observed difference in Aβ deposition cannot be simply attributed to apoE4 levels being lower than apoE3.”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Mahley et al., 2006
Recently identified functional siRNA sequences target Apolipoprotein E (ApoE), implicated in several neurodegenerative diseases.
“Recently, we identified functional siRNA sequences targeting Apolipoprotein E (ApoE), implicated in several neurodegenerative diseases, including Alzheimer’s disease and Amyotrophic Lateral Sclerosis26–28 (Ferguson et al., manuscript in preparation).”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [27]
Apolipoprotein E is believed to play a critical role in brain function.
“Because apoE is believed to play a critical role in brain function11”
From Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function (2014) · cites this paper as [11]
ApoE4 has been associated with a variety of neuropathological processes, including Alzheimer disease (AD).
“ApoE4 has been associated with a variety of neuropathological processes, including Alzheimer disease (AD) (2).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [2]
ApoE4 lowers the age of onset of Alzheimer's disease.
“lowers the age of onset [4–14]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
In neurons, apoE4 is associated with neurotoxicity.
“and neurotoxicity [10, 17–19, 34, 35]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
In neurons, apoE4 is associated with decreased neurite outgrowth.
“decreased neurite outgrowth”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
ApoE4 increases risk for Alzheimer's disease.
“ApoE4 increases risk for AD”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [10]
Several proteases are suggested to be responsible for ApoE4 cleavage at different sites, including collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D, and HtrA1.
“Several proteases have been suggested to be responsible for ApoE4 cleavage at different sites, including collagenase, matrix metalloproteinas-9 (MMP-9) [25], neuron-specific α-chymotrypsin-like serine protease [26], cathepsin D (the only aspartic protease identified) [27] and high-temperature requirement serine protease A1 (HtrA1) [21].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [26]
The three common apoE isoforms differ by only one or two amino acids at residue 112 or 158, but these differences profoundly alter apoE structure and function.
“Although the three common isoforms differ by only one or two amino-acids at residue 112 or 158, these differences profoundly alter apoE structure and function (Mahley et al., 2006).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mahley et al., 2006
The 29 kDa amino-terminal fragment generated by chymotrypsin-like serine protease has been shown to induce cytoskeletal disruptions and perturb mitochondrial energy balance.
“The 29 kDa amino-terminal fragment generated by chymotrypsin-like serine protease has been shown to induce cytoskeletal disruptions and perturb mitochondrial energy balance.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mahley et al., 2006
Along with Aβ-independent intrinsic toxicities, apoE4 has been shown to exacerbate neurotoxicity triggered by Aβ and other insults.
“Along with Aβ-independent intrinsic toxicities, apoE4 has been shown to exacerbate neurotoxicity triggered by A and other insults (Mahley et al., 2006).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mahley et al., 2006
One of the most extensively investigated direct toxic mechanisms involves the 29 kDa carboxyl-terminal-truncated fragment of apoE4 (amino acid 1-272 residues).
“One of the most extensively investigated direct toxic mechanisms involves the 29 kDa carboxyl-terminal-truncated fragment of apoE4 (amino acid 1–272 residues) (Mahley et al., 2007; Mahley et al., 2006).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mahley et al., 2006
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 [14]

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Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease
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Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease
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Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.
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Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury
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In VivoDelivery of a Bcl-xL Fusion Protein Containing the TAT Protein Transduction Domain Protects against Ischemic Brain Injury and Neuronal Apoptosis
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Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice
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Molecular docking to ensembles of protein structures 1 1Edited by B. Honig
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Apolipoprotein E
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Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females
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Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe−/−Mice: Isoform-Specific Effects on Neurodegeneration
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Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line.
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Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice
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Human apolipoprotein E: the Alzheimer's disease connection
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Human apolipoprotein E: Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms
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Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity
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Human Apolipoprotein E4 Domain Interaction
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Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation
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Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth
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Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112
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New optimization method for conformational energy calculations on polypeptides: Conformational space annealing
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Cognitive change and the APOE ɛ4 allele
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ApoE genotype and survival from intracerebral haemorrhage
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The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization
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Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target
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APOE genotype as a risk factor for ischemic cerebrovascular disease
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Expression of Human Apolipoprotein E4 in Neurons Causes Hyperphosphorylation of Protein Tau in the Brains of Transgenic Mice
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Unique Lipoproteins Secreted by Primary Astrocytes From Wild Type, apoE (−/−), and Human apoE Transgenic Mice
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APOE genotype influences acquisition and recall following traumatic brain injury
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Apolipoprotein E4 Forms a Molten Globule
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Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study
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Introduction of human apolipoprotein E4 “domain interaction” into mouse apolipoprotein E
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Lysosomal Membrane Damage in Soluble Aβ-Mediated Cell Death in Alzheimer's Disease
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Androgens Protect against Apolipoprotein E4-Induced Cognitive Deficits
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Apolipoprotein E ε4 is associated with rapid progression of multiple sclerosis
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Targeting of Hepatitis C Virus Core Protein to Mitochondria through a Novel C-Terminal Localization Motif
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Emerging classes of protein–protein interaction inhibitors and new tools for their development
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Interdomain Communication in Hepatitis C Virus Polymerase Abolished by Small Molecule Inhibitors Bound to a Novel Allosteric Site
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Apolipoprotein E modulates Alzheimer’s Aβ(1–42)-induced oxidative damage to synaptosomes in an allele-specific manner
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Reactivity of Apolipoprotein E4 and Amyloid β Peptide
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A Minimally Lipidated Form of Cell-derived Apolipoprotein E Exhibits Isoform-specific Stimulation of Neurite Outgrowth in the Absence of Exogenous Lipids or Lipoproteins
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Neurotoxicity of the 22 kDa Thrombin-Cleavage Fragment of Apolipoprotein E and Related Synthetic Peptides Is Receptor-Mediated
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Fluctuations caught in the act
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A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity
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Amyloid β‐Protein, APOE Genotype and Head Injury
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Nerve Regeneration Occurs in the Absence of Apolipoprotein E in Mice
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APOE: A potential marker of disease progression in ALS
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Regionally specific neuronal expression of human APOE gene in transgenic mice
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Authors: Mahley, R. W., Weisgraber, K. H., & Huang, Y.
Affiliations: Gladstone Institutes (US)
ORCID: Mahley, Robert W.
Huang, Yadong
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2006-04-11
Volume: 103
Issue: 15
Pages: 5644-5651
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0600549103
PMC: PMC1414631
OpenAlex: W2061916198
Cited by: 912
References: 166
Citations by year: 2026: 11 · 2025: 20 · 2024: 33 · 2023: 27 · 2022: 36 · 2021: 38 · 2020: 38 · 2019: 41 · 2018: 28 · 2017: 44 · 2016: 44 · 2015: 49 · 2014: 50 · 2013: 69 · 2012: 62
FWCI: 7.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (AG‐022074)
National Institute on Aging (P01AG022074)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords: APOE ε4, Alzheimer's disease, neuropathology, lipid homeostasis, amyloid-beta, oxidative stress, ischemia, neuroinflammation, traumatic brain injury, molten globule, cytoskeleton disruption, protease inhibitors, therapeutic target
MeSH terms: Alzheimer Disease, Apolipoproteins E, Humans, Lysosomes, Models, Neurological, Nervous System Diseases, Risk Factors, Amyloid beta-Peptides, Apoptosis, Apolipoprotein E4

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Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

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