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Cited by 17Dementia and Cognitive Impairment ResearchGenetic Associations and EpidemiologyAlzheimer's disease research and treatments

Biomarker identification for Alzheimer’s disease through integration of comprehensive Mendelian randomization and proteomics data

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Zhan, Hui, Cammann, Davis, Cummings, Jeffrey L., Dong, Xianjun, Chen, Jingchun·2025·Journal of Translational Medicine
DOI 10.1186/s12967-025-06317-5PMC PMC11884171
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Abstract

Background: Alzheimer’s disease (AD) is the main cause of dementia with few effective therapies. We aimed to identify potential plasma biomarkers or drug targets for AD by investigating the causal association between plasma proteins and AD by integrating comprehensive Mendelian randomization (MR) and multi-omics data. Methods: Using two-sample MR, cis protein quantitative trait loci ( cis -pQTLs) for 1,916 plasma proteins were used as an exposure to infer their causal effect on AD liability in individuals of European ancestry, with two large-scale AD genome-wide association study (GWAS) datasets as the outcome for discovery and replication. Significant causal relationships were validated by sensitivity analyses, reverse MR analysis, and Bayesian colocalization analysis. Additionally, we investigated the causal associations at the transcriptional level with cis gene expression quantitative trait loci ( cis -eQTLs) data across brain tissues and blood in European ancestry populations, as well as causal plasma proteins in African ancestry populations. Results: In those of European ancestry, the genetically predicted levels of five plasma proteins (BLNK, CD2AP, GRN, PILRA, and PILRB) were causally associated with AD. Among these five proteins, GRN was protective against AD, while the rest were risk factors. Consistent causal effects were found in the brain for cis -eQTLs of GRN , BLNK , and CD2AP , while the same was true for PILRA in the blood. None of the plasma proteins were significantly associated with AD in persons of African ancestry. Conclusions: Comprehensive MR analyses with multi-omics data identified five plasma proteins that had causal effects on AD, highlighting potential biomarkers or drug targets for better diagnosis and treatment for AD.

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  • The PILRA protein has been linked to Alzheimer's Disease (AD) in multiple MR studies using Olink pQTL instruments, but different directions of effect for PILRA on AD have been reported across studies using different platform's pQTL instruments.

    “The PILRA protein discussed above has been linked to Alzheimer’s Disease (AD) in multiple MR studies using Olink pQTL instruments27–29; however, different directions of effect for PILRA on AD have been reported across studies using different platform’s pQTL instruments.”

    From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [27]

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    Experimental — accuracy not yet measured

  • Several putatively impacted proteins are potential biomarkers or drug targets (for example, suPAR and PILRA).

    “It remains challenging to establish the pervasiveness of assay-interference effects; however, we note that several putatively impacted proteins are potential biomarkers or drug targets (for example, suPAR32,33 and PILRA27).”

    From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [27]

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Authors
Zhan, H., Cammann, D., Cummings, J. L., Dong, X., & Chen, J.
Affiliations
  • University of Nevada, Las Vegas (US)
  • Yale University (US)
Corresponding author
Chen, Jingchun
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-03-06
Volume
23
Issue
1
Pages
278-278
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-025-06317-5
PMC
PMC11884171
OpenAlex
W4408212948
Cited by
17
References
103
Citations by year
2026: 9 · 2025: 8
FWCI
11.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • IDSA Foundation (70823173)
  • Mountain West Clinical and Translational Research Infrastructure Network Program (U54GM104944)
  • National Institute on Aging (R15AG083618-01A1, R35AG71476, R25AG083721-01)
  • National Institute of General Medical Sciences (P20GM109025)
  • National Institute of Neurological Disorders and Stroke (RO1NS139383)
  • Alzheimer's Drug Discovery Foundation (Alzheimer's Drug Discovery Foundation)
  • Ted and Maria Quirk Endowment (Ted and Maria Quirk Endowment)
  • Joy Chambers-Grundy Endowment (Joy Chambers-Grundy Endowment)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, plasma biomarkers, therapeutic target, Mendelian randomization, plasma proteins, gene regulatory networks, BLNK, CD2AP, expression quantitative trait loci, protein quantitative trait loci, causal inference, multi-omics integration, African ancestry, European ancestry, brain gene expression
MeSH terms
Alzheimer Disease, Blood Proteins, Humans, Biomarkers, Genetic Predisposition to Disease, Quantitative Trait Loci, Proteomics, White People, Genome-Wide Association Study, Mendelian Randomization Analysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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