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Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer's disease.

Research square | 2024

Changes in Amyloid-β (A), hyperphosphorylated Tau (T) in brain and cerebrospinal fluid (CSF) precedes AD symptoms, making CSF proteome a potential avenue to understand the pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 proteins dysregulated in AD, that were further validated in a third totally independent cohort. Machine learning was implemented to create and validate highly accurate and replicable (AUC>0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD and those AD cases with faster progression. The associated proteins cluster in four different protein pseudo-trajectories groups spanning the AD continuum and were enrichment in specific pathways including neuronal death, apoptosis and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfuncton(mid-stages), brain plasticity and longevity (mid-stages) and late microglia-neuron crosstalk (late stages).

Pubmed ID: 38410465 RIS Download

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: P30 AG066444
  • Agency: NIA NIH HHS, United States
    Id: RF1 AG053303
  • Agency: NIA NIH HHS, United States
    Id: U01 AG024904
  • Agency: NIA NIH HHS, United States
    Id: P01 AG003991
  • Agency: NIA NIH HHS, United States
    Id: RF1 AG074007
  • Agency: NIA NIH HHS, United States
    Id: U01 AG058922
  • Agency: NIA NIH HHS, United States
    Id: R01 AG044546
  • Agency: NIA NIH HHS, United States
    Id: P01 AG026276
  • Agency: NIA NIH HHS, United States
    Id: RF1 AG058501

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This is a list of tools and resources that we have found mentioned in this publication.


ADNI - Alzheimer's Disease Neuroimaging Initiative (tool)

RRID:SCR_003007

Database of the results of the ADNI study. ADNI is an initiative to develop biomarker-based methods to detect and track the progression of Alzheimer's disease (AD) that provides access to qualified scientists to their database of imaging, clinical, genomic, and biomarker data.

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Foundation for the National Institutes of Health (tool)

RRID:SCR_004493

A public charity whose mission is to support the NIH in its mission to improve health, by forming and facilitating public-private partnerships for biomedical research and training. Its vision is Building Partnerships for Discovery and Innovation to Improve Health. The FNIH draws together the world''s foremost researchers and resources, pressing the frontier to advance critical discoveries. They are recognized as the number-one medical research charity in the countryleveraging support, and convening high level partnerships, for the greatest impact on the most urgent medical challenges we face today. Grants are awarded as part of a public-private partnership with the National Heart, Lung, and Blood Institute (NHLBI) on behalf of The Heart Truth in support of women''s heart health education and research. Funding for the Community Action Program is provided by the FNIH through donations from individuals and corporations including The Heart Truth partners Belk Department Stores, Diet Coke, and Swarovski. Successful biomedical research relies upon the knowledge, training and dedication of those who conduct it. Bringing multiple disciplines to bear on health challenges requires innovation and collaboration on the part of scientists. Foundation for NIH partnerships operate in a variety of ways and formats to recruit, train, empower and retain their next generation of researchers. From lectures and multi-week courses, to scholarships and awards through fellowships and residential training programs, their programs respond to the needs of scientists at every level and stage in their careers.

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Alzheimer's and Dementia Resource Center (tool)

RRID:SCR_004924

The Alzheimer's and Dementia Resource Center (ADRC) facilitates tissue donations for the Brain Bank Research Program in order to help find better treatments, more diagnostic tools and a cure for Alzheimer's disease and dementia. The Brain Bank Program is administered by Mount Sinai Medical Center in Miami Beach and under contract with the Florida Department of Elder Affairs. ADRC also provides caregivers with the educational resources, spiritual comfort and emotional support. The ADRC facilitates training for professional caregivers that meets requirements for the Florida Department of Elder Affairs.

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STRING (tool)

RRID:SCR_005223

Database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations and are derived from four sources: Genomic Context, High-throughput experiments, (Conserved) Coexpression, and previous knowledge. STRING quantitatively integrates interaction data from these sources for a large number of organisms, and transfers information between these organisms where applicable. The database currently covers 5''214''234 proteins from 1133 organisms. (2013)

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KEGG (tool)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

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ggplot2 (tool)

RRID:SCR_014601

Open source software package for statistical programming language R to create plots based on grammar of graphics. Used for data visualization to break up graphs into semantic components such as scales and layers.

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clusterProfiler (tool)

RRID:SCR_016884

Software R package for statistical analysis and visualization of functional profiles for genes and gene clusters.

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CellMarker (tool)

RRID:SCR_018503

Database provides cell markers for various cell types in tissues of human and mouse. Manually curated resource of cell markers in human and mouse. Provides user-friendly interface for browsing, searching and downloading markers of diverse cell types of different tissues. Summarized marker prevalence in each cell type is graphically presented.

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survminer (data analysis software)

RRID:SCR_021094

Software R package provides functions for facilitating survival analysis and visualization.

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survival (software resource)

RRID:SCR_021137

Software R package contains core survival analysis routines, including definition of Surv objects, Kaplan-Meier and Aalen-Johansen (multi-state) curves, Cox models, and parametric accelerated failure time models.

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MetaCore (software resource)

RRID:SCR_008125

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on March 17, 2022. An integrated software suite for functional analysis of experimental data. The scope of data types includes microarray and SAGE gene expression, SNPs and CGH arrays, proteomics, metabolomics, pathway analysis, Y2H and other custom interactions. MetaCore is based on a proprietary manually curated database of human protein-protein, protein-DNA and protein compound interactions, metabolic and signaling pathways and the effects of bioactive molecules in gene expression.

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EnhancedVolcano (data processing software)

RRID:SCR_018931

Software R package to produce publication ready volcano plots with enhanced colouring and labeling. Used to visualise results of differential expression analyses.

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