APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease
Nicholas Brookhouser, Sreedevi Raman, Carlye Frisch, Gayathri Srinivasan, David A Brafman. Molecular psychiatry, 2021-04-09
Topic: Genetics and APOE
Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer's disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.
Key findings
- Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD.
- On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent.
- While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored.
- Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects.
- In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 61/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 34 of the 56 points we could judge it on, which is 61 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33837271) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 34 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 34 of the 56 points we could judge it on is 61 out of 100. |
| Total | 61 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Brookhouser, N., Raman, S., Frisch, C., Srinivasan, G., & Brafman, D. A. (2021). APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease. Molecular psychiatry. https://doi.org/10.1038/s41380-021-01076-3
Vancouver
Brookhouser N, Raman S, Frisch C, Srinivasan G, Brafman DA. APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease. Molecular psychiatry. 2021. doi:10.1038/s41380-021-01076-3. PMID: 33837271.
BibTeX
@article{brookhouser2021-33837271,
author = {Brookhouser, Nicholas and Raman, Sreedevi and Frisch, Carlye and Srinivasan, Gayathri and Brafman, David A},
title = {{APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease}},
journal = {Molecular psychiatry},
year = {2021},
doi = {10.1038/s41380-021-01076-3},
pmid = {33837271},
url = {https://doi.org/10.1038/s41380-021-01076-3}
}
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