Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G.. Nature reviews. Neurology, 2013-01-08
Topic: Amyloid, tau and blood-test diagnosis
Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.
Key findings
- APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk.
- Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing.
- In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms.
Why it matters
This 2013 review summarises what was then known about the APOE gene: compared with the common ε3 version, carriers of ε4 are at increased risk of Alzheimer's disease, and of amyloid build-up in brain blood vessels and age-related cognitive decline, while ε2 is linked to lower risk. It describes how the protein versions differ in handling amyloid-β, brain lipids, glucose metabolism, inflammation and mitochondrial function, and discusses how therapies targeting apolipoprotein E might be designed. It reports no new data, gives no risk figures, and tests no treatment, so it cannot tell any individual how likely they are to develop the disease.
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Study details
- Evidence strengthLow
How this study scored 56/100
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 (Nature reviews. Neurology) |
| Journal's citation record | 3 / 4 | Nature Reviews Neurology: journal h-index 269 (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 | 1 / 5 | 2013 — within 20 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 | 7 / 7 | Cited 3,472 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 231.5 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 4 / 6 | Cited 18.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 5 / 6 | Cited by 126 other studies in this library |
| Still being cited | 4 / 4 | Cited 938 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Guojun Bu: h-index 120 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23296339) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 56 / 100 | — |
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APA 7th
Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology. https://doi.org/10.1038/nrneurol.2012.263
Vancouver
Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology. 2013. doi:10.1038/nrneurol.2012.263. PMID: 23296339.
BibTeX
@article{liu2013-23296339,
author = {Liu, C. C. and Kanekiyo, T. and Xu, H. and Bu, G.},
title = {{Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy}},
journal = {Nature reviews. Neurology},
year = {2013},
doi = {10.1038/nrneurol.2012.263},
pmid = {23296339},
url = {https://doi.org/10.1038/nrneurol.2012.263}
}
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