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Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer's disease.
Cruchaga, Carlos; Ali, Muhammad; Shen, Yuanyuan; Do, Anh; Wang, Lihua; Western, Daniel; Liu, Menghan; Beric, Aleksandra; Budde, John; Gentsch, Jen; Schindler, Suzanne; Morris, John; Holtzman, David; Fernández, Maria; Ruiz, Agustín; Alvarez, Ignacio; Aguilar, Miquel; Pastor, Pau; Rutledge, Jarod; Oh, Hamilton; Wilson, Edward; Le Guen, Yann; Khalid, Rana; Robins, Chloe; Pulford, David; Ibanez, Laura; Wyss-Coray, Tony; Ju Sung, Yun.
Afiliação
  • Cruchaga C; Washington University School of Medicine.
  • Ali M; Washington University School of Medicine.
  • Shen Y; Washington University School of Medicine.
  • Do A; Washington University School of Medicine.
  • Wang L; Washington University School of Medicine.
  • Western D; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • Liu M; Washington University in St. Louis.
  • Beric A; Washington University School of Medicine.
  • Gentsch J; Washington University School of Medicine.
  • Schindler S; Washington University.
  • Morris J; Knight Alzheimer Disease Research Center.
  • Holtzman D; Washington University in St. Louis.
  • Fernández M; Washington University School of Medicine.
  • Ruiz A; Ace Alzheimer Center Barcelona.
  • Alvarez I; Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain.
  • Aguilar M; University Hospital Mutua Terrassa.
  • Pastor P; University Hospital Germans Trias i Pujol.
  • Rutledge J; Stanford University.
  • Oh H; Stanford University.
  • Wilson E; Stanford University.
  • Le Guen Y; Stanford University.
  • Khalid R; Stanford.
  • Robins C; GlaxoSmithKline.
  • Pulford D; GlaxoSmithKline.
  • Ibanez L; Washington University in St. Louis.
  • Wyss-Coray T; Stanford University.
  • Ju Sung Y; Washington University Medical School.
Res Sq ; 2024 Feb 16.
Article em En | MEDLINE | ID: mdl-38410465
ABSTRACT
Changes in Amyloid-ß (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).

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article