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Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease
Stevenson-Hoare J, Heslegrave A, Leonenko G, Fathalla D, Bellou E, Luckcuck L, Marshall R, Sims R et al.. Brain : a journal of neurology, 2023-02-01
Topic: Genetics and APOE
To define Alzheimer's disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer's disease instead of the risk of dementia. The prediction accuracy of Alzheimer's disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (P < 4.3 × 10-5). Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P = 0.011-4.78 × 10-8), except NfL. No novel genome-wide significant single nucleotide polymorphisms were found in the case-control design; however, in a case-only analysis, we found two independent genome-wide significant associations between the Aβ42/Aβ40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aβ40, Aβ42, GFAP and NfL biomarkers explain additional variation over and above APOE. We identified novel plausible genome wide-significant genes associated with Aβ42/Aβ40 ratio in a sample which is 50 times smaller than current genome-wide association studies in Alzheimer's disease.
Key findings
- To define Alzheimer's disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer's disease instead of the risk of dementia.
- The prediction accuracy of Alzheimer's disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL.
- All biomarkers were significantly associated with age in cases and controls (P < 4.3 × 10-5).
- Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases.
- In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P = 0.011-4.78 × 10-8), except NfL.
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Study details
- Study designcase-control study
- Participants1,439
- Evidence strengthModerate
How this study scored 71/100
Published in a leading specialty journal, and it is a case-control study. Scored zero for effect reported 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 41 of the 58 points we could judge it on, which is 71 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 6 / 12 | A case-control study |
| 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 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,439 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| 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 35383826) |
| Free to read | 2 / 2 | Free to read |
| Points | 41 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 41 of the 58 points we could judge it on is 71 out of 100. |
| Total | 71 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Stevenson-Hoare, J., Heslegrave, A., Leonenko, G., Fathalla, D., Bellou, E., Luckcuck, L., et al. (2023). Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease. Brain : a journal of neurology. https://doi.org/10.1093/brain/awac128
Vancouver
Stevenson-Hoare J, Heslegrave A, Leonenko G, Fathalla D, Bellou E, Luckcuck L, et al. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease. Brain : a journal of neurology. 2023. doi:10.1093/brain/awac128. PMID: 35383826.
BibTeX
@article{stevensonhoare2023-35383826,
author = {Stevenson-Hoare, J. and Heslegrave, A. and Leonenko, G. and Fathalla, D. and Bellou, E. and Luckcuck, L. and Marshall, R. and Sims, R. and others},
title = {{Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease}},
journal = {Brain : a journal of neurology},
year = {2023},
doi = {10.1093/brain/awac128},
pmid = {35383826},
url = {https://doi.org/10.1093/brain/awac128}
}
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