Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer's disease.

Journal: Nature aging
Published Date:

Abstract

Proteomic studies have been instrumental in identifying brain, cerebrospinal fluid and plasma proteins associated with Alzheimer's disease (AD). Here, we comprehensively examined 6,905 aptamers corresponding to 6,106 unique proteins in plasma in more than 3,300 well-characterized individuals to identify new proteins, pathways and predictive models for AD. We identified 416 proteins (294 new) associated with clinical AD status and validated the findings in two external datasets representing more than 7,000 samples. AD-related proteins reflected blood-brain barrier disruption and other processes implicated in AD, such as lipid dysregulation or immune responses. A machine learning model was used to identify a set of seven proteins that were highly predictive of both clinical AD (area under the curve (AUC) of >0.72) and biomarker-defined AD status (AUC of >0.88), which were replicated in multiple external cohorts and orthogonal platforms. These findings underscore the potential of using plasma proteins as biomarkers for the early detection and monitoring of AD and for guiding treatment decisions.

Authors

  • Gyujin Heo
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Ying Xu
    School of Biological and Food Engineering Changzhou University Changzhou Jiangsu China.
  • Erming Wang
    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Muhammad Ali
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Hamilton Se-Hwee Oh
    Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA.
  • Patricia Moran-Losada
    The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
  • Federica Anastasi
    Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
  • Armand González Escalante
    Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
  • Raquel Puerta
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Soomin Song
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Jigyasha Timsina
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Menghan Liu
    Department of Health Management, The First Affiliated Hospital of Shandong First Medical University and Qianfoshan Hospital, Jinan City, Shandong Province, China.
  • Daniel Western
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Katherine Gong
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Yike Chen
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Pat Kohlfeld
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Allison Flynn
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Alvin G Thomas
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Joseph Lowery
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • John C Morris
    Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
  • David M Holtzman
    Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • Joel S Perlmutter
    Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
  • Suzanne E Schindler
    Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • Natalia Vilor-Tejedor
    Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
  • Marc Suárez-Calvet
    Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
  • Pablo García-González
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Marta Marquié
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Maria Victoria Fernández
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Mercè Boada
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Amanda Cano
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Agustín Ruiz
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Bin Zhang
    Department of Psychiatry, Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • David A Bennett
    Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
  • Tammie Benzinger
    Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA.
  • Tony Wyss-Coray
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
  • Laura Ibanez
    Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Yun Ju Sung
    Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
  • Carlos Cruchaga
    Washington University in St. Louis, St. Louis, Missouri, USA.