The DOI matches its Crossref record; 114 of the 114 references it cites were found in a registry or an index.
Apolipoprotein E: Far More Than a Lipid Transport Protein
Abstract
First recognized as a major determinant in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E has emerged as an important molecule in several biological processes not directly related to its lipid transport function, including Alzheimer's disease and cognitive function, immunoregulation, and possibly even infectious diseases. ApoE is a polymorphic protein arising from three alleles at a single gene locus. The three major isoforms, apoE4, apoE3, and apoE2, differ from one another only by single amino acid substitutions, yet these changes have profound functional consequences at both the cellular and molecular levels. ApoE3 seems to be the normal isoform in all known functions, while apoE4 and apoE2 can each be dysfunctional. Isoform (allele)-specific effects include the association of apoE2 with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis and the association of apoE4 with increased risk for both atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth; isoform-specific differences in cellular signaling events may also exist. Functional differences in the apoE isoforms that affect (or did affect) survival before the reproductive years probably account, at least in part, for the allele frequencies of the present day.
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In the citing paper
“Exchangeable apolipoproteins are typically consisting of two functional domains: lipid-binding domain and receptor-binding domain24.”
From Brain-targeted drug delivery by manipulating protein corona functions (2019) · cites this paper as [24]
In the citing paper
“However, these striking vasculotropic effects observed here in APP/ε2 mice may not be robustly seen in human subjects, where ε2 homozygotes constitute only 1% of the population, with less than 10% of them developing type III hyperlipoproteinemia, what is linked to distinctly different contribution of apoE to VLDL formation between humans and mice [62].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [62]
In the citing paper
“By contrast, APOE4 has increased binding affinity (up to two-fold) for heparin and HSPG over APOE3 (refs. 32–35).”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [32]
In the citing paper
“As serum apoE plays its role in lipid metabolism through the LDL receptor, the HSPG and LDL receptor‐related protein (LRP) pathway (Mahley & Rall Jr., 2000), mutations could alter the configuration of the APOE protein and further impact its binding ability to LDL receptor, which could explain the formation of lipoprotein thrombi in the glomerulus.”
From Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations (2020) · cites this paper as Mahley & Rall Jr., 2000
In the citing paper
“Human apoE is a protein consisting of 299 amino acid residues with a molecular weight of 34 kDa8).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [8]
In the citing paper
“ε3 has Cys112 and Arg158, while ε4 (Cys112Arg, p.Cys130Arg) has arginine at both positions and ε2 (Arg158Cys, p.Arg176Cys) has cysteine at both positions (Fig.3)8).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [8]
In the citing paper
“apoE on triglyceride-rich lipoproteins binds to the LDL receptor (LDLR), the LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) ( 3,4 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [4]
In the citing paper
“Despite the presence of several receptors that are capable of internalizing apoE such as low-density lipoprotein receptor (LDLR), LDLR-related protein (LRP), apoER2, and VLDLR, in neurons apoE is mostly imported via the LDLR [12]–[15].”
From LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease (2010) · cites this paper as [13]
In the citing paper
“APOE ε4 (E4) is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD).”
From Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner (2014) · cites this paper as Mahley and Rall, 2000
In the citing paper
“Apolipoprotein E (apoE) is a critical ligand for high-affinity binding of remnant lipoproteins to members of the low density lipoprotein receptor (LDLR) family and HSPG (5–7).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [7]
In the citing paper
“Thus, besides being a risk factor for Alzheimer’s disease, apoE4 is associated with an increased risk for coronary heart disease (7).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [7]
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
Self-citationLIPOPROTEIN METABOLISM IN THE MACROPHAGE: Implications for Cholesterol Deposition in Atherosclerosis
Brown, M. S., & Goldstein, J. L. (1983) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.52.070183.001255 · Cited by 2,300
Apolipoprotein E polymorphism and atherosclerosis.
Davignon, J., Gregg, R. E., & Sing, C. F. (1988) · Arteriosclerosis: An Official Journal of the American Heart Association, Inc. · doi:10.1161/01.atv.8.1.1 · Cited by 1,981
Neurotrophic and Neurotoxic Effects of Amyloid β Protein: Reversal by Tachykinin Neuropeptides
Yankner, B. A., Duffy, L. K., & Kirschner, D. A. (1990) · Science · doi:10.1126/science.2218531 · Cited by 1,975
Fat Transport in Lipoproteins — An Integrated Approach to Mechanisms and Disorders
Fredrickson, D. S., Levy, R. I., & Lees, R. S. (1967) · New England Journal of Medicine · doi:10.1056/nejm196701052760107 · Cited by 1,911
ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.
Nakashima, Y., Plump, A. S., Raines, E. W., Breslow, J. L., & Ross, R. (1994) · Arteriosclerosis and Thrombosis: A Journal of Vascular Biology · doi:10.1161/01.atv.14.1.133 · Cited by 1,693
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., & Herz, J. (1999) · Neuron · doi:10.1016/s0896-6273(00)80861-2 · Cited by 916
Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871
Research works printed but not linked: 10
- Boerwinkle E, 1991, Am. J. Hum. Genet., 49, 1145
- Harmony JAK, Akeson AL, McCarthy BM, Morris RE, Scupham DW, Grupp SA. 1986. Immunoregulation by plasma lipoproteins. In Biochemistry and Biology of Plasma Lipoproteins , ed. AM Scanu, AA Spector, pp. 403–52. New York: Marcel Dekker
- Mahley RW. 1997. Apolipoprotein E: structure and function in lipid metabolism and neurobiology. In The Molecular and Genetic Basis of Neurological Disease , ed. RN Rosenberg, SB Prusiner, S DiMauro, RL Barchi, pp. 1037–49. Boston: Butterworth–Heinemann. 2nd ed.
- Mahley RW, Rall SCJr . 1995. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In The Metabolic and Molecular Bases of Inherited Disease , ed. CR Scriver, AL Beaudet, WS Sly, D Valle, pp. 1953–80. New York: McGraw-Hill. 7th ed.
- Sing CF, 1985, Am. J. Hum. Genet., 37, 268
- 10.1001/jama.1997.03540340052032 · DOI
- Utermann G. 1985. Genetic polymorphism of apolipoprotein E—impact on plasma lipoprotein metabolism. In Diabetes, Obesity and Hyperlipidemias –III, ed. G Crepaldi, A Tiengo, G Baggio, pp. 1–28. Amsterdam: Elsevier Science
- Utermann G, 1980, Am. J. Hum. Genet., 32, 339
- Wisniewski T, 1994, Am. J. Pathol., 145, 1030
- Zannis VI, 1981, Am. J. Hum. Genet., 33, 11
Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
2018 Alzheimer's disease facts and figures
Alzheimer's Association (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.001 · Cited by 1,912
Lipids and Lipid-Based Formulations: Optimizing the Oral Delivery of Lipophilic Drugs
Porter, C. J. H., Trevaskis, N. L., & Charman, W. N. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2197 · Cited by 1,824
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Distinct patterns of brain activity in young carriers of the APOE -ε4 allele
Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., Matthews, P. M., Beckmann, C. F., & Mackay, C. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811879106 · Cited by 1,613
Metadata
- Authors
- Mahley, R. W., & Rall, S. C.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Mahley, Robert W.
- Venue
- Annual Review of Genomics and Human Genetics
- Publisher
- Annual Reviews
- Published
- 2000-09
- Volume
- 1
- Issue
- 1
- Pages
- 507-537
- ISSN
- 1527-8204 (ISSN-L)
- 1545-293X
- OpenAlex
- W2121101037
- Cited by
- 1,836
- References
- 114
- Citations by year
- 2026: 54 · 2025: 85 · 2024: 71 · 2023: 55 · 2022: 95 · 2021: 103 · 2020: 70 · 2019: 79 · 2018: 64 · 2017: 80 · 2016: 86 · 2015: 75 · 2014: 100 · 2013: 80 · 2012: 83
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Genomics and Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01hl047660-10)
- National Heart, Lung, and Blood Institute (HL-47660)
- National Institute of Allergy and Infectious Diseases (R37AI020565)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, apolipoprotein E isoforms, APOE ε4, APOE3, APOE2, APOE polymorphism, Alzheimer's disease, cognitive function, immune regulation, infectious diseases, type III hyperlipoproteinemia, atherosclerosis, cardiovascular disease, neurite outgrowth, allele frequency
- MeSH terms
- Alleles, Animals, Apolipoproteins E, Arteriosclerosis, Biological Transport, Active, Communicable Diseases, Female, Heart Diseases, Humans, Hyperlipoproteinemia Type III, Immunity, Lipoproteins, Male, Models, Molecular, Neurobiology, Phenotype, Polymorphism, Genetic, Reproduction, Risk Factors, Protein Isoforms, Lipid Metabolism
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