Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease
Butterfield DA, Mattson MP.. Neurobiology of disease, 2020-02-06
Topic: Amyloid, tau and blood-test diagnosis
Inheritance of apolipoprotein E4 (APOE4) is a major risk factor for development of Alzheimer's disease (AD). This lipoprotein, in contrast to apoE2, has arginine residues at positions 112 and 158 in place of cysteines in the latter isoform. In apoE3, the Cys at residue 158 is replaced by an arginine residue. This differential amino acid composition of the three genotypes of APOE have profound influence on the structure, binding properties, and multiple functions of this lipoprotein. Moreover, AD brain is under a high degree of oxidative stress, including that associated with amyloid β-peptide (Aβ) oligomers. Lipid peroxidation produces the highly reactive and neurotoxic molecule, 4-hydroxynonenal (HNE) that forms covalent bonds with cysteine residues (Cys) [as well as with Lys and His residues]. Covalently modified Cys significantly alter structure and function of modified proteins. HNE bound to Cys residue(s) on apoE2 and apoE3 lessens the chance of HNE damage other proteins. apoE4, lacking Cys residues, is unable to scavenge HNE, permitting this latter neurotoxic molecule to lead to oxidative modification of neuronal proteins and eventual cell death. We posit that this lack of HNE scavenging activity in apoE4 significantly contributes to the association of APOE4 inheritance and increased risk of developing AD. Apoe knock-out mice provide insights into the role of this lipoprotein in oxidative stress. Targeted replacement mice in which the mouse gene of Apoe is separately replaced by the human APOE2, APOE3, or APOE4 genes, while keeping the mouse promoter assures the correct location and amount of the human protein isoform. Human APOE targeted replacement mice have been used to investigate the notion that oxidative damage to and death of neurons in AD and its earlier stages is related to APOE genotype. This current paper reviews the intersection of human APOE genotype, oxidative stress, and diminished function of this lipoprotein as a major contributing risk factor for development of AD. Discussion of potential therapeutic strategies to mitigate against the elevated risk of developing AD with inheritance of the APOE4 allele also is presented.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Butterfield, D. A., & Mattson, M. P. (2020). Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease. Neurobiology of disease. https://doi.org/10.1016/j.nbd.2020.104795
Vancouver
Butterfield DA, Mattson MP. Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease. Neurobiology of disease. 2020. doi:10.1016/j.nbd.2020.104795. PMID: 32036033.
BibTeX
@article{butterfield2020-32036033,
author = {Butterfield, D. A. and Mattson, M. P.},
title = {{Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease}},
journal = {Neurobiology of disease},
year = {2020},
doi = {10.1016/j.nbd.2020.104795},
pmid = {32036033},
url = {https://doi.org/10.1016/j.nbd.2020.104795}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
Key findings
- Moreover, AD brain is under a high degree of oxidative stress, including that associated with amyloid β-peptide (Aβ) oligomers.
- Covalently modified Cys significantly alter structure and function of modified proteins.
- We posit that this lack of HNE scavenging activity in apoE4 significantly contributes to the association of APOE4 inheritance and increased risk of developing AD.
Why it matters
This paper proposes that apoE4, lacking cysteine residues, cannot scavenge the neurotoxic molecule HNE, allowing oxidative damage to neuronal proteins and contributing to Alzheimer's disease risk. This is a hypothesis about mechanism and does not demonstrate any treatment or prevention.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 49/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of disease) |
| Journal's citation record | 2 / 4 | Neurobiology of Disease: journal h-index 225 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2020 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 188 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 23.5 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 4 / 6 | Cited 13.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 3 / 4 | Cited 78 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Mark P. Mattson: h-index 222 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Johns Hopkins University: institution h-index 2,306 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 32036033) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 49 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 22.
Later studies that cite this one
4 studies in the alzhub library list this one in their references.
Related studies in Genetics
Also tagged “precursor”
1,339 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.