Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G.. Nature reviews. Neurology, 2019-07-31
Topic: Amyloid, tau and blood-test diagnosis
Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.
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APA 7th
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C., & Bu, G. (2019). Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature reviews. Neurology. https://doi.org/10.1038/s41582-019-0228-7
Vancouver
Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature reviews. Neurology. 2019. doi:10.1038/s41582-019-0228-7. PMID: 31367008.
BibTeX
@article{yamazaki2019-31367008,
author = {Yamazaki, Y. and Zhao, N. and Caulfield, T. R. and Liu, C. C. and Bu, G.},
title = {{Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies}},
journal = {Nature reviews. Neurology},
year = {2019},
doi = {10.1038/s41582-019-0228-7},
pmid = {31367008},
url = {https://doi.org/10.1038/s41582-019-0228-7}
}
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Key findings
- Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele.
- Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers.
Why it matters
This 2019 review summarises research showing that, compared with the common ε3 version of the APOE gene, the ε4 version raises the risk of late-onset Alzheimer's and the ε2 version lowers it. The authors say evidence suggests ε4 works largely by causing earlier and heavier amyloid buildup, but also point to effects on tau, the brain's immune cells (microglia), fat transport, synapses, sugar metabolism and blood vessels. It discusses APOE as a possible target for precision-medicine treatment, but it reports no treatment results and gives no risk figures, so it cannot tell an individual their own risk.
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Study details
- Evidence strengthLow
How this study scored 53/100
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 | 2 / 5 | 2019 — 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 | 7 / 7 | Cited 1,418 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 157.6 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 4 / 6 | Cited 19.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 63 other studies in this library |
| Still being cited | 4 / 4 | Cited 671 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 | 0 / 3 | Mayo Clinic in Florida: institution h-index 681 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 31367008) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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