Apolipoprotein E Isoforms and AMD
Abstract
The cholesterol transporting protein apolipoprotein E (ApoE) occurs in three allelic variants in humans unlike in other species. The resulting protein isoforms E2, E3 and E4 exhibit differences in lipid binding, integrating into lipoprotein particles and affinity for lipoprotein receptors. ApoE isoforms confer genetic risk for several diseases of aging including atherosclerosis, Alzheimer's disease, and age-related macular degeneration (AMD). A single E4 allele increases the risk of developing Alzheimer's disease, whereas the E2 allele is protective. Intriguingly, the E4 allele is protective in AMD. Current thinking about different functions of ApoE isoforms comes largely from studies on Alzheimer's disease. These data cannot be directly extrapolated to AMD since the primary cells affected in these diseases (neurons vs. retinal pigment epithelium) are so different. Here, we propose that ApoE serves a fundamentally different purpose in regulating cholesterol homeostasis in the retinal pigment epithelium and this could explain why allelic risk factors are flipped for AMD compared to Alzheimer's disease.
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Drusen, the autofluorescent lipid particles prominent in the diseased eye, accumulate and likely oxidize extracellularly.
“since drusen, the autofluorescent lipid particles that are prominent in the diseased eye, accumulate and likely oxidize extracellularly74.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [74]
Section 1.3.3 (p. 5) describes drusen as lipid-rich lesions in Bruch’s membrane characteristic of AMD, and section 1.4 (p. 5) says oxidized cholesterol is a core component. The copy does not describe drusen as autofluorescent or say that they likely oxidize after accumulating extracellularly. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThis may explain why APOE2 is a risk factor for age-related macular degeneration.
“This may explain why APOE2 is a risk factor for age-related macular degeneration”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [74]
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Cites
Apolipoprotein E and cholesterol in aging and disease in the brain
de Chaves, E. P., Narayanaswami, V., Christoffersen, C., & Nielsen, L. B. (2008) · Future Lipidology · doi:10.2217/17460875.3.5.505 · Cited by 164 · see citing works
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Research works printed but not linked: 1
- Thakkinstian A, Bowe S, McEvoy M et al (2006) Association between apolipoprotein E polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis. Ame J Epidemiol 164:813-822
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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
Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
“74 Collectively, our data suggest the ApoE allelic series, in the lipidated form, may modify LOAD risk via two distinct but related mechanisms: (1) a protective mechanism mediated by decreased lipApoE-receptor interactions, as shown for ApoE2 and Christchurch; and (2) a deleterious mechanism…”
La Cunza, N., Tan, L. X., Thamban, T., Germer, C. J., Rathnasamy, G., Toops, K. A., & Lakkaraju, A. (2021) · JCI Insight · doi:10.1172/jci.insight.142254 · Cited by 65 · see citing works
Self-citation
- Authors
- Toops, K. A., Tan, L. X., & Lakkaraju, A.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Lakkaraju, Aparna
- Venue
- Advances in Experimental Medicine and Biology
- Publisher
- Springer International Publishing
- Published
- 2015-10-02
- Volume
- 854
- Pages
- 3-9
- ISSN
- 0065-2598 (ISSN-L)
- 2214-8019
- OpenAlex
- W2261297404
- Cited by
- 41
- References
- 2
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 2
- FWCI
- 10.62
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Advances in experimental medicine and biology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, apolipoprotein E isoforms, age-related macular degeneration, Alzheimer's disease, genetic risk, retinal pigment epithelium, cholesterol homeostasis, lipoprotein binding, lipoprotein receptors, atherosclerosis
- MeSH terms
- Alleles, Alzheimer Disease, Cholesterol, Humans, Lipoproteins, Macular Degeneration, Neurons, Protein Binding, Receptors, LDL, Risk Factors, Atherosclerosis, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Retinal Pigment Epithelium
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