A comprehensive analysis of methods for assessing polygenic burden on Alzheimer's disease pathology and risk beyond APOE
Altmann A, Scelsi MA, Shoai M, de Silva E, Aksman LM, Cash DM, Hardy J, Schott JM.. Brain communications, 2019-12-16
Topic: Amyloid, tau and blood-test diagnosis
Genome-wide association studies have identified dozens of loci that alter the risk to develop Alzheimer's disease. However, with the exception of the APOE -ε4 allele, most variants bear only little individual effect and have, therefore, limited diagnostic and prognostic value. Polygenic risk scores aim to collate the disease risk distributed across the genome in a single score. Recent works have demonstrated that polygenic risk scores designed for Alzheimer's disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers. Methodological innovations in polygenic risk modelling include the polygenic hazard score, which derives effect estimates for individual single nucleotide polymorphisms from survival analysis, and methods that account for linkage disequilibrium between genomic loci. In this work, using data from the Alzheimer's disease neuroimaging initiative, we compared different approaches to quantify polygenic disease burden for Alzheimer's disease and their association (beyond the APOE locus) with a broad range of Alzheimer's disease-related traits: cross-sectional CSF biomarker levels, cross-sectional cortical amyloid burden, clinical diagnosis, clinical progression, longitudinal loss of grey matter and longitudinal decline in cognitive function. We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy. However, for many other tested traits such as clinical disease progression, CSF amyloid, cognitive decline and cortical amyloid load, the additional effects of polygenic burden beyond APOE were of minor nature. Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores. Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE -ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE -ε4 homozygous participants. Lastly, on many of the tested traits, the major driving factor remained the APOE locus, with the exception of quantitative CSF-tau and p-tau measures.
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APA 7th
Altmann, A., Scelsi, M. A., Shoai, M., de Silva, E., Aksman, L. M., Cash, D. M., et al. (2020). A comprehensive analysis of methods for assessing polygenic burden on Alzheimer's disease pathology and risk beyond APOE. Brain communications. https://doi.org/10.1093/braincomms/fcz047
Vancouver
Altmann A, Scelsi MA, Shoai M, de Silva E, Aksman LM, Cash DM, et al. A comprehensive analysis of methods for assessing polygenic burden on Alzheimer's disease pathology and risk beyond APOE. Brain communications. 2020. doi:10.1093/braincomms/fcz047. PMID: 32226939.
BibTeX
@article{altmann2020-32226939,
author = {Altmann, A. and Scelsi, M. A. and Shoai, M. and de Silva, E. and Aksman, L. M. and Cash, D. M. and Hardy, J. and Schott, J. M.},
title = {{A comprehensive analysis of methods for assessing polygenic burden on Alzheimer's disease pathology and risk beyond APOE}},
journal = {Brain communications},
year = {2020},
doi = {10.1093/braincomms/fcz047},
pmid = {32226939},
url = {https://doi.org/10.1093/braincomms/fcz047}
}
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
- Recent works have demonstrated that polygenic risk scores designed for Alzheimer's disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers.
- We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy.
- Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores.
- Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE -ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE -ε4 homozygous participants.
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Study details
- Study designcross-sectional
- Evidence strengthModerate
How this study scored 55/100
Published in a leading specialty journal, and it is a snapshot of people at one point in 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 and multi-centre collaboration, so those were left out: it earned 32 of the 58 points we could judge it on, which is 55 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain communications) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 4 / 12 | A snapshot of people at one point in 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 | 2 / 5 | 2020 — 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 | 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 32226939) |
| Free to read | 2 / 2 | Free to read |
| Points | 32 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 32 of the 58 points we could judge it on is 55 out of 100. |
| Total | 55 / 100 | — |
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