Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders
Open accessAbstract
Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer's disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12-29 kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders.
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APOE variants modulate other inflammation-associated pathologies, including atherosclerosis.
“In addition, APOE variants modulate other inflammation-associated pathologies, including atherosclerosis3.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [3]
The “ApoE and cardiovascular disease” sections on ApoE2 and ApoE4 state that these variants increase the risk of atherosclerosis. The passages explain this through lipoprotein and cholesterol metabolism; they do not address the claim’s characterization of atherosclerosis or other pathologies as inflammation-associated. (LLM, conf=0.82)
Experimental — accuracy not yet measuredApoE is classically considered to play a critical role in cardiovascular and neurodegenerative disorders.
“ApoE is classically considered to play a critical role in cardiovascular and neurodegenerative disorders [63, 64];”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [63]
The apoE3 and apoE4 amino acid sequences differ only at position 112, where apoE4 has an arginine instead of a cysteine.
“The apoE3 and apoE4 amino acid sequences differ only at position 112 where apoE4 has an Arg instead of a Cys.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [13]
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 [13]
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Kemp, S. B., Carpenter, E. S., Steele, N. G., Donahue, K. L., Nwosu, Z. C., Pacheco, A., Velez-Delgado, A., Menjivar, R. E., Lima, F., The, S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3929 · Cited by 197 · see citing works
Nelson, M. R., Liu, P., Agrawal, A., Yip, O., Blumenfeld, J., Traglia, M., Kim, M. J., Koutsodendris, N., Rao, A., Grone, B., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01480-8 · Cited by 118 · see citing works
Self-citationApolipoprotein E4 genotype compromises brain exosome production
Peng, K. Y., Pérez-González, R., Alldred, M. J., Goulbourne, C. N., Morales-Corraliza, J., Saito, M., Saito, M., Ginsberg, S. D., Mathews, P. M., & Levy, E. (2019) · Brain · doi:10.1093/brain/awy289 · Cited by 109 · see citing works
Thedrez, A., Blom, D. J., Ramin-Mangata, S., Blanchard, V., Croyal, M., Chemello, K., Nativel, B., Pichelin, M., Cariou, B., Bourane, S., et al. (2018) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.117.310217 · Cited by 105 · see citing works
Common germline variants of the human APOE gene modulate melanoma progression and survival
Ostendorf, B. N., Bilanovic, J., Adaku, N., Tafreshian, K. N., Tavora, B., Vaughan, R. D., & Tavazoie, S. F. (2020) · Nature Medicine · doi:10.1038/s41591-020-0879-3 · Cited by 108 · see citing works
On the origin of proteins in human drusen: The meet, greet and stick hypothesis
Bergen, A. A., Arya, S., Koster, C., Pilgrim, M. G., Wiatrek-Moumoulidis, D., van der Spek, P. J., Hauck, S. M., Boon, C. J. F., Emri, E., Stewart, A. J., et al. (2019) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.12.003 · Cited by 101 · see citing works
ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance
Ramms, B., Patel, S., Nora, C., Pessentheiner, A. R., Chang, M. W., Green, C. R., Golden, G. J., Secrest, P., Krauss, R. M., Metallo, C. M., et al. (2019) · Journal of Lipid Research · doi:10.1194/jlr.m093740 · Cited by 59 · see citing works
Kinetics of plasma apolipoprotein E isoforms by LC-MS/MS: a pilot study
Blanchard, V., Ramin-Mangata, S., Billon-Crossouard, S., Aguesse, A., Durand, M., Chemello, K., Nativel, B., Flet, L., Chétiveaux, M., Jacobi, D., et al. (2018) · Journal of Lipid Research · doi:10.1194/jlr.p083576 · Cited by 43 · see citing works
Huang, Y., Xie, Y., Zhang, Y., Liu, Z., Jiang, W., Ye, Y., Tang, J., Li, Z., Yin, Z., & Lin, X.-J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02370-2 · Cited by 41 · see citing works
Aslam, M. M., Fan, K.-H., Lawrence, E., Bedison, M. A., Snitz, B. E., DeKosky, S. T., Lopez, O. L., Feingold, E., & Kamboh, M. I. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02170-4 · Cited by 39 · see citing works
Apolipoprotein profiling as a personalized approach to the diagnosis and treatment of dyslipidaemia
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Tarawneh, R. (2023) · Biomolecules · doi:10.3390/biom13050830 · Cited by 29 · see citing works
Vascular Lesions, <i>APOE</i> ε4, and Tau Pathology in Alzheimer Disease
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High-density Lipoprotein Inspired Lipid Nanoparticles for Systemic RNA delivery to the Brain
Xu, Z., Shalin, K., Do, V., Yan, A., & Gao, J. (2026) · doi:10.64898/2026.05.29.728695
- Authors
- Mahley, R. W.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Mahley, Robert W.
- ORCID
- Mahley, Robert W.
- Venue
- Journal of Molecular Medicine
- Published
- 2016-06-09
- Volume
- 94
- Issue
- 7
- Pages
- 739-746
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC4921111
- OpenAlex
- W2416854880
- Cited by
- 837
- References
- 75
- Citations by year
- 2026: 47 · 2025: 67 · 2024: 58 · 2023: 50 · 2022: 77 · 2021: 72 · 2020: 48 · 2019: 340 · 2018: 37 · 2017: 36 · 2016: 3 · 2015: 2
- FWCI
- 16.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (GB) (101786)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, APOE ε4, APOE2, APOE3, Alzheimer's disease, neurodegenerative diseases, cardiovascular disease, LDL receptor binding, cholesterol metabolism, domain interactions, tau phosphorylation, mitochondrial dysfunction, cytoskeletal alterations, atherosclerosis
- MeSH terms
- Cardiovascular Diseases, Cholesterol, Gene Expression Regulation, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Models, Molecular, Phosphorylation, Receptors, LDL, Signal Transduction, tau Proteins, Neurodegenerative Diseases, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Protein Interaction Domains and Motifs
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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