Genetic architecture of plasma Alzheimer disease biomarkers
Open accessAbstract
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.
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Shared genetic regulators across multiple tissues indicate some genetic overlap across tissues, although that overlap seems to be driven by either pleiotropic regions (APOE) or cis-signals.
“indicating that shared genetic regulators across multiple tissues, 8 and suggesting some genetic overlap across tissues, although that overlap seems to be driven by either pleiotropic regions (APOE) or cis‐signals.”
From A genetic and proteomic comparison of key AD biomarkers across tissues (2024) · cites this paper as [8]
The ‘Overlap genetic architecture of plasma biomarkers with other AD phenotypes’ section reports genetic overlap between plasma and CSF biomarkers, strongest at APOE. The Discussion says overlap outside APOE is relatively low. These passages support the APOE part, but do not identify cis-signals as a driver of the overlap or establish the claim across multiple tissues beyond plasma and CSF; page numbers are not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA previous study found genetic overlap between plasma and CSF in pQTLs of key AD genes.
“At the genetic level, a previous study from Bradley and coauthors 8 found genetic overlap between plasma and CSF in protein quantitative trait loci (pQTLs) of key AD genes.”
From A genetic and proteomic comparison of key AD biomarkers across tissues (2024) · cites this paper as [8]
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A genetic and proteomic comparison of key AD biomarkers across tissues
Marsh, T. W., Western, D., Timsina, J., Gorijala, P., Yang, C., Pastor, P., Liu, M., Morris, J. C., Bateman, R. J., Schindler, S. E., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14139 · Cited by 6 · see citing works
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- Authors
- Bradley, J., Gorijala, P., Schindler, S. E., Sung, Y. J., Ances, B., the Alzheimer’s Disease Neuroimaging Initiative, T. H. C. P., Ertekin-Taner, N., Younkin, S., Golde, T., Price, N., Bennett, D., Gaiteri, C., De Jager, P., Zhang, B., Schadt, E., Ehrlich, M., Haroutunian, V., Gandy, S., Iijima, K., Noggle, S., Mangravite, L., Fernandez, M. V., & Cruchaga, C.
- Affiliations
- Washington University in St. Louis (US)
- Department of Psychiatry, Washington University School of Medicine , St. Louis, MO 63110 , USA
- Corresponding author
- Cruchaga, Carlos
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-05-19
- Volume
- 32
- Issue
- 15
- Pages
- 2532-2543
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC10360384
- OpenAlex
- W4377086941
- Cited by
- 20
- References
- 4
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 5 · 2023: 1
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01AG044546, RO1AG070941, P01AG003991, RF1AG053303, RF1AG058501, U01AG058922, R44 AG059489, P30AG066444, P01AG03991, P01AG026276)
- Bright Focus (CA2016636)
- Gerald and Henrietta Rauenhorst Foundation
- Alzheimer's Drug Discovery Foundation (GC-201711-2013978)
- Chan Zuckerberg Initiative
- Alzheimer's Association Zenith Fellows Award (ZEN-22-848604)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, plasma biomarkers, cerebrospinal fluid biomarkers, amyloid-beta, tau protein, phosphorylated tau, neurofilament light chain, apolipoprotein E, genetic architecture, polygenic risk score, genetic overlap, single nucleotide polymorphisms
- MeSH terms
- Alzheimer Disease, Humans, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, tau Proteins, Genome-Wide Association Study
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