Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease

Laia Montoliu-Gaya, Shijia Bian, Eric B. Dammer, Daniel Alcolea, Mathias Sauer, Mitchell Martá-Ariza, Nicholas J. Ashton, Olivia Belbin, Johannes Fuchs, Caroline M. Watson, Lingyan Ping, Duc M. Duong, Johanna Nilsson, Isabel Barroeta, Juan Lantero-Rodriguez, Laura Videla, Bessy Benejam, Blaine R. Roberts, Kaj Blennow, Nicholas T. Seyfried, Allan I. Levey, María Carmona-Iragui, Johan Gobom, Alberto Lleó, Thomas Wisniewski, Henrik Zetterberg, Juan Fortea () and Erik C. B. Johnson ()
Additional contact information
Laia Montoliu-Gaya: The Sahlgrenska Academy at the University of Gothenburg
Shijia Bian: Emory University
Eric B. Dammer: Emory University School of Medicine
Daniel Alcolea: Universitat Autònoma de Barcelona
Mathias Sauer: The Sahlgrenska Academy at the University of Gothenburg
Mitchell Martá-Ariza: NYU Grossman School of Medicine
Nicholas J. Ashton: The Sahlgrenska Academy at the University of Gothenburg
Olivia Belbin: Universitat Autònoma de Barcelona
Johannes Fuchs: University of Gothenburg
Caroline M. Watson: Emory University School of Medicine
Lingyan Ping: Emory University School of Medicine
Duc M. Duong: Emory University School of Medicine
Johanna Nilsson: The Sahlgrenska Academy at the University of Gothenburg
Isabel Barroeta: Universitat Autònoma de Barcelona
Juan Lantero-Rodriguez: The Sahlgrenska Academy at the University of Gothenburg
Laura Videla: Universitat Autònoma de Barcelona
Bessy Benejam: Universitat Autònoma de Barcelona
Blaine R. Roberts: Emory University School of Medicine
Kaj Blennow: The Sahlgrenska Academy at the University of Gothenburg
Nicholas T. Seyfried: Emory University School of Medicine
Allan I. Levey: Emory University School of Medicine
María Carmona-Iragui: Universitat Autònoma de Barcelona
Johan Gobom: The Sahlgrenska Academy at the University of Gothenburg
Alberto Lleó: Universitat Autònoma de Barcelona
Thomas Wisniewski: NYU Grossman School of Medicine
Henrik Zetterberg: The Sahlgrenska Academy at the University of Gothenburg
Juan Fortea: Universitat Autònoma de Barcelona
Erik C. B. Johnson: Emory University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Almost all individuals with Down Syndrome (DS) develop Alzheimer’s disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD pathophysiology from asymptomatic to dementia stages and compared the proteomic biomarker changes in DS to those observed in LOAD and ADAD. Although many proteomic alterations were shared across DS, LOAD, and ADAD, DS demonstrated more severe changes in immune-related proteins, extracellular matrix pathways, and plasma proteins likely related to blood-brain barrier dysfunction compared to LOAD. These changes were present in young adults with DS prior to the onset of Aβ or tau pathology, suggesting they are associated with trisomy 21 and may serve as risk factors for DSAD. DSAD showed an earlier increase in markers of axonal and white matter pathology and earlier changes in markers potentially associated with cerebral amyloid angiopathy compared to ADAD. The unique features of DSAD may have important implications for treatment strategies in this population.

Date: 2025
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DOI: 10.1038/s41467-025-61054-z

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