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Genetic architecture of plasma Alzheimer disease biomarkers
Bradley J, Gorijala P, Schindler SE, Sung YJ, Ances B, Alzheimer’s Disease Neuroimaging Initiative, the Human Connectome Project, Fernandez MV et al.. Human molecular genetics, 2023-07-01
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
Genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarker levels have identified novel genes implicated in disease risk, onset and progression. However, lumbar punctures have limited availability and may be perceived as invasive. Blood collection is readily available and well accepted, but it is not clear whether plasma biomarkers will be informative for genetic studies. Here we perform genetic analyses on concentrations of plasma amyloid-β peptides Aβ40 (n = 1,467) and Aβ42 (n = 1,484), Aβ42/40 (n = 1467) total tau (n = 504), tau phosphorylated (p-tau181; n = 1079) and neurofilament light (NfL; n = 2,058). GWAS and gene-based analysis was used to identify single variant and genes associated with plasma levels. Finally, polygenic risk score and summary statistics were used to investigate overlapping genetic architecture between plasma biomarkers, CSF biomarkers and AD risk. We found a total of six genome-wide significant signals. APOE was associated with plasma Aβ42, Aβ42/40, tau, p-tau181 and NfL. We proposed 10 candidate functional genes on the basis of 12 single nucleotide polymorphism-biomarker pairs and brain differential gene expression analysis. We found a significant genetic overlap between CSF and plasma biomarkers. We also demonstrate that it is possible to improve the specificity and sensitivity of these biomarkers, when genetic variants regulating protein levels are included in the model. This current study using plasma biomarker levels as quantitative traits can be critical to identification of novel genes that impact AD and more accurate interpretation of plasma biomarker levels.
What this study adds
Evidence grade: Low
The record lists 1,467 participants. This genetic analysis found six genome-wide significant signals for plasma Alzheimer's biomarkers, with APOE associated with several of them, and showed genetic overlap between CSF and plasma biomarkers. It is about understanding the genetics of biomarkers, not about a 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
Bradley, J., Gorijala, P., Schindler, S. E., Sung, Y. J., Ances, B., Alzheimer’s Disease Neuroimaging Initiative, et al. (2023). Genetic architecture of plasma Alzheimer disease biomarkers. Human molecular genetics. https://doi.org/10.1093/hmg/ddad087
Vancouver
Bradley J, Gorijala P, Schindler SE, Sung YJ, Ances B, Alzheimer’s Disease Neuroimaging Initiative, et al. Genetic architecture of plasma Alzheimer disease biomarkers. Human molecular genetics. 2023. doi:10.1093/hmg/ddad087. PMID: 37208024.
BibTeX
@article{bradley2023-37208024,
author = {Bradley, J. and Gorijala, P. and Schindler, S. E. and Sung, Y. J. and Ances, B. and {Alzheimer’s Disease Neuroimaging Initiative} and {the Human Connectome Project} and Fernandez, M. V. and others},
title = {{Genetic architecture of plasma Alzheimer disease biomarkers}},
journal = {Human molecular genetics},
year = {2023},
doi = {10.1093/hmg/ddad087},
pmid = {37208024},
url = {https://doi.org/10.1093/hmg/ddad087}
}
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.
Key findings
- GWAS and gene-based analysis was used to identify single variant and genes associated with plasma levels.
- We found a total of six genome-wide significant signals.
- APOE was associated with plasma Aβ42, Aβ42/40, tau, p-tau181 and NfL.
- We found a significant genetic overlap between CSF and plasma biomarkers.
Why it matters
This genetic analysis found six genome-wide significant signals for plasma Alzheimer's biomarkers, with APOE associated with several of them, and showed genetic overlap between CSF and plasma biomarkers. It is about understanding the genetics of biomarkers, not about a treatment or cure.
New to this subject? Start with our plain-English guide: Blood tests & biomarkers →
Study details
- Participants1,467
- Evidence strengthLow
How this study scored 49/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Human molecular genetics) |
| Journal's citation record | 3 / 4 | Human Molecular Genetics: journal h-index 356 (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 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,467 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 19 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.8 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 2 / 6 | Cited 2.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 18 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Carlos C Cruchaga: h-index 102 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multicenter collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37208024) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 49 / 100 | — |
What each of these 20 components measures, and what this score is not →
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