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ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias
Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, Holtzman DM, Bu G.. Neuron, 2022-03-16
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
What this study adds
Evidence grade: Low
This is a narrative review. This paper proposes an 'ApoE Cascade Hypothesis' in which the biochemical properties of apoE set off a cascade of cellular and systems events that lead to Alzheimer's disease and age-related cognitive decline. It predicts that apoE-targeted therapies may be more effective if aimed at the early biochemical phase, but this is a hypothesis, not a tested treatment or cure.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Martens, Y. A., Zhao, N., Liu, C. C., Kanekiyo, T., Yang, A. J., Goate, A. M., et al. (2022). ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron. https://doi.org/10.1016/j.neuron.2022.03.004
Vancouver
Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, et al. ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron. 2022. doi:10.1016/j.neuron.2022.03.004. PMID: 35298921.
BibTeX
@article{martens2022-35298921,
author = {Martens, Y. A. and Zhao, N. and Liu, C. C. and Kanekiyo, T. and Yang, A. J. and Goate, A. M. and Holtzman, D. M. and Bu, G.},
title = {{ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias}},
journal = {Neuron},
year = {2022},
doi = {10.1016/j.neuron.2022.03.004},
pmid = {35298921},
url = {https://doi.org/10.1016/j.neuron.2022.03.004}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD).
- The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158).
- Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways.
- Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD.
- As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
Why it matters
This paper proposes an 'ApoE Cascade Hypothesis' in which the biochemical properties of apoE set off a cascade of cellular and systems events that lead to Alzheimer's disease and age-related cognitive decline. It predicts that apoE-targeted therapies may be more effective if aimed at the early biochemical phase, but this is a hypothesis, not a tested treatment or cure.
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Study details
- Evidence strengthLow
How this study scored 58/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neuron) |
| Journal's citation record | 4 / 4 | Neuron: journal h-index 689 (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 | 3 / 5 | 2022 — within 6 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 317 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 52.8 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 5 / 6 | Cited 34.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 9 other studies in this library |
| Still being cited | 4 / 4 | Cited 206 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 | 3 / 3 | National Institutes of Health: institution h-index 2,723 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35298921) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 58 / 100 | — |
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