Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer’s Disease
Abstract
The APOEɛ4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOEɛ3 conventionally is considered as 'risk neutral' although APOEɛ3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOEɛ3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOEɛ4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients). Total plasma apoE levels were lower in APOEɛ4-carriers and overall correlated significantly to CSF Aβ42, p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOEɛ3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOEɛ3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers…
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The self-association measured here is distinct from the cysteine-dependent disulfide-linked dimers of ApoE that have been described in plasma and CSF.
“It is important to note that the self-association measured here is distinct from the cysteinedependent disulfide-linked dimers of ApoE that have been described in plasma and CSF (32,43).”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [43]
Plasma ApoE homodimer levels are reduced in APOEε3-carrying AD patients relative to controls.
“These cysteine-dependent ApoE3 homodimers and ApoE3-apoA-II complexes have been linked to HDL-related behavior and redox buffering (44,45), and plasma ApoE homodimer levels are reduced in APOEε3-carrying AD patients relative to controls (43), suggesting that these disulfide-linked species may themselves be functionally relevant in ways not captured by the NanoBiT assay.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [43]
Cysteine-dependent disulfide-linked ApoE species are unique to ApoE3 and ApoE2, which carry cysteine residues at position 112 and/or 158, and cannot form in ApoE4.
“Those disulfide-linked species are unique to ApoE3 and ApoE2, which carry cysteine residues at position 112 and/or 158, and cannot form in ApoE4.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [43]
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Rhea, E. M., Banks, W. A., & Raber, J. (2022) · Biomedicines · doi:10.3390/biomedicines10071582 · Cited by 76 · see citing works
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- Authors
- Patra, K., Giannisis, A., Edlund, A. K., Sando, S. B., Lauridsen, C., Berge, G., Grøntvedt, G. R., Bråthen, G., White, L. R., & Nielsen, H. M.
- Affiliations
- Stockholm University (SE)
- Norwegian University of Science and Technology (NO)
- St Olav's University Hospital (NO)
- Corresponding author
- Nielsen, Henrietta M.
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2019-10-15
- Volume
- 71
- Issue
- 4
- Pages
- 1217-1231
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2972373384
- Cited by
- 22
- References
- 9
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 2 · 2020: 1
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E
- MeSH terms
- Aged, Alzheimer Disease, Female, Homocysteine, Homozygote, Humans, Male, Biomarkers, Apolipoprotein A-II, tau Proteins, Protein Structure, Quaternary, Apolipoprotein E3, Apolipoprotein E4, Cognitive Dysfunction
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