ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions
Open accessAbstract
Significance: It has been proposed that differential physical interactions of apolipoprotein E (apoE) isoforms with soluble amyloid-β (Aβ) in brain fluids influence the metabolism of Aβ, providing a major mechanism to account for how APOE influences Alzheimer’s disease risk. The current study challenges this proposal and clearly shows that lipoproteins containing apoE isoforms are unlikely to play a significant role in Aβ metabolism by binding directly to Aβ in physiological fluids such as cerebrospinal fluid or interstitial fluid. Our in vitro and in vivo results suggest that apoE isoforms influence Aβ metabolism by competing for the same clearance pathways within the brain.
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The loss in binding is thought to contribute to a decrease in the clearance of Aβ and thus is part of the mechanism for the increased risk of apoE ɛ4 allele carriers to develop AD.
“The loss in binding is thought to contribute to a decrease in the clearance of Aβ and thus is part of the mechanism for the increased risk of apoE ɛ4 allele carriers to develop AD [13–15].”
From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [15]
The paper supports the background link between apoE4, impaired Aβ clearance, and increased AD risk. But its Discussion says direct apoE/Aβ binding is unlikely to explain clearance differences and proposes receptor- or transporter-mediated effects instead. That contradicts the claimed mechanism in which a loss of binding reduces clearance. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe bulk of soluble Aβ is cleared through its direct interaction with the LDL receptor family expressed by brain capillary endothelium, neurons, and astrocytes.
“Several studies have shown that the bulk of soluble Aβ is cleared through its direct interaction with the LDL receptor family expressed by brain capillary endothelium [37], neurons [24,38], and astrocytes [39,40], therefore pharmacological disruption of the apoE/Aβ binding is unlikely to impair this process.”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [40]
The Discussion (page unavailable in our copy) says astrocytes are a major Aβ-clearance cell type and suggests that soluble Aβ can bind directly to receptors such as LDLR for clearance without apoE. It does not establish that the bulk of soluble Aβ is cleared by direct receptor binding; it also describes multiple clearance pathways and says LRP1 can act directly or indirectly. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPOE is known to affect many functional aspects of astrocytes, including uptake of glutamate and uptake and degradation of Aβ, as shown in mouse models.
“APOE is known to affect many functional aspects of astrocytes, including, but not limited to, homeostatic support such as uptake of glutamate as well as uptake and degradation of Aβ, as shown in mouse models (Verghese et al., 2013).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Verghese et al., 2013
The Significance section (page not provided) states that apoE isoforms affect Aβ uptake and subsequent degradation in astrocytes, and reports Aβ-clearance findings in a mouse model. The cited paper does not address astrocytic glutamate uptake, so it supports only the Aβ portion of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredapoE can indirectly modulate Aβ clearance through competing with Aβ for the same receptors.
“It has been also proposed that apoE can indirectly modulate Aβ clearance through competing with Aβ for the same receptors [40].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [40]
Position 222 is at a flexible loop region of apoE, corresponding to the shoulder of a domain (residues 244-272) hypothesized to bind Aβ and involved in lipid binding.
“Structurally, position 222 is at a flexible loop region of apoE, corresponding to the shoulder of a domain (residues 244–272) hypothesized to bind Aβ [15] and involved in lipid binding [33].”
From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [15]
The cited paper’s Significance and Discussion sections address apoE–Aβ binding generally, but do not identify residues 244–272 as a hypothesized Aβ-binding domain. Searches for residues 244–272, position 222, and a C-terminal binding site found no passage addressing that structural claim. The separate lipid-binding statement is attached to citation [33], not this source. (LLM, conf=0.74)
Experimental — accuracy not yet measured
APOE, the strongest genetic risk factor for LOAD, largely increases risk by influencing Aβ seeding and clearance.
“In addition, the strongest genetic risk factor for LOAD, apolipoprotein E, APOE, in large part appears to increase risk via influencing Aβ seeding and clearance”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Verghese et al., 2013
ApoE regulates clearance of Aβ by competitively binding to Aβ receptors such as LRP1 on astrocytes, blocking Aβ uptake.
“Instead, ApoE regulates clearance of Aβ by competitively binding to Aβ receptors, such as LDLR-related protein 1 (LRP1) on the surface of astrocytes, and blocking Aβ uptake.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Verghese et al., 2013
Multiple studies suggest that lowering ApoE levels reduces relevant pathology in both amyloidosis and tauopathy mouse models.
“Multiple studies employing ApoE genetic deletion (Bales et al., 1999; Verghese et al., 2013), conditional expression of ApoE isoforms (Liu et al., 2017) or ASO-mediated knockdown of ApoE expression (Huynh et al., 2017b) suggest that lowering ApoE levels reduces relevant pathology in both amyloidosis and tauopathy mouse models (Shi et al., 2017).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Verghese et al., 2013
Several genes encoding proteins intimately associated with the endothelium and Aβ clearance are highly validated AD risk factors, such as APOEε4, PICALM, and CLU.
“Several genes encoding proteins intimately associated with the endothelium and Aβ clearance are highly validated AD risk factors, such as APOEε4, PICALM, and CLU [50, 51].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [50]
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“However, some recent controversial reports indicate that ApoE does not bind Aβ but competes with Aβ for binding to LRP-1 in astrocytes, and this could impact Aβ clearance by glia and across the blood–brain barrier (BBB) (Verghese et al., 2013).”
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Microglial phagocytosis in Alzheimer disease
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“This could be the consequence of ApoE competition with A β for binding LRP1, which might forbid LRP1-dependent metabolism of soluble A β [88].”
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- Authors
- Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Hope Center for Neurological Disorders (US)
- Mayo Clinic in Florida (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-04-25
- Volume
- 110
- Issue
- 19
- Pages
- E1807-16
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3651443
- OpenAlex
- W2161925307
- Cited by
- 556
- References
- 81
- Citations by year
- 2026: 25 · 2025: 45 · 2024: 51 · 2023: 51 · 2022: 43 · 2021: 42 · 2020: 44 · 2019: 43 · 2018: 31 · 2017: 43 · 2016: 40 · 2015: 38 · 2014: 48 · 2013: 12
- FWCI
- 31.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- American Health Assistance Foundation
- Eli Lilly and Company
- National Institutes of Health (AG13956, AG027924, AG 03991, NS074969)
- Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
- National Institute on Aging (P01AG030128, AG03991, R01AG027924, R01AG013956, AG027924, F31AG034004, AG056810, AG034004, AG026276, P50AG005681, P01AG003991, RF1AG046205, R37AG013956, AG13956, R01AG035355, P01AG026276)
- National Institute of Neurological Disorders and Stroke (NS074969, P01NS074969)
- 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
- apolipoprotein E, amyloid-beta clearance, Alzheimer's disease risk, APOE isoforms, APOE3, APOE ε4, soluble amyloid-beta, astrocytes, LRP1, amyloid-beta uptake, cerebrospinal fluid, brain interstitial fluid, receptor competition
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Cell Line, Cholesterol, Gene Expression Regulation, Humans, Protein Binding, Time Factors, Amyloid beta-Peptides, Mice, Knockout, Neurodegenerative Diseases, Protein Isoforms, Mice
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