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Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2
Jacob A Marsh, Guangming Huang, Kevin Bowling, Alan E Renton, Ellen Ziegemeier, Torri Ball, Cyril Pottier, Carlos Cruchaga et al.. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2025-01-27
Topic: Genetics and APOE
Autosomal dominant Alzheimer's disease (ADAD) is driven by rare variants in APP, PSEN1, and PSEN2. Although more than 200 pathogenic variants in these genes are known to cause ADAD, other variants are benign, may act as risk factors, or may even reduce Alzheimer's disease risk (e.g. protective). Classifying novel variants in APP, PSEN1, or PSEN2 as pathogenic, risk, benign, or protective is a critical step in evaluating disease risk profiles which further impacts eligibility for clinical trials focused on the ADAD population. Here, we classify 53 novel variants in APP, PSEN1, and PSEN2 based on bioinformatic data and cell-based assays. We identified 6 benign variants, 2 risk variants, and 32 likely pathogenic variants. Thirteen variants were associated with reduced Aβ levels in cell-based assays, consistent with a potential protective effect. Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.
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APA 7th
Marsh, J. A., Huang, G., Bowling, K., Renton, A. E., Ziegemeier, E., Ball, T., et al. (2025). Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. https://doi.org/10.1016/j.neurot.2025.e00527
Vancouver
Marsh JA, Huang G, Bowling K, Renton AE, Ziegemeier E, Ball T, et al. Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2025. doi:10.1016/j.neurot.2025.e00527. PMID: 39875235.
BibTeX
@article{marsh2025-39875235,
author = {Marsh, Jacob A and Huang, Guangming and Bowling, Kevin and Renton, Alan E and Ziegemeier, Ellen and Ball, Torri and Pottier, Cyril and Cruchaga, Carlos and others},
title = {{Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2}},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
year = {2025},
doi = {10.1016/j.neurot.2025.e00527},
pmid = {39875235},
url = {https://doi.org/10.1016/j.neurot.2025.e00527}
}
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Key findings
- Thirteen variants were associated with reduced Aβ levels in cell-based assays, consistent with a potential protective effect.
- Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.
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Study details
- Evidence strengthLow
How this study scored 43/100
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. 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 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 4 / 5 | 2025 — within 3 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 39875235) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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