Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease
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...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61054-z |
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| author | 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 Erik C. B. Johnson |
| author_facet | 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 Erik C. B. Johnson |
| author_sort | Laia Montoliu-Gaya |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a260fac5cb9f42f4a0107d1767bb28ef |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-a260fac5cb9f42f4a0107d1767bb28ef2025-08-20T04:02:57ZengNature PortfolioNature Communications2041-17232025-07-0116112010.1038/s41467-025-61054-zProteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s diseaseLaia Montoliu-Gaya0Shijia Bian1Eric B. Dammer2Daniel Alcolea3Mathias Sauer4Mitchell Martá-Ariza5Nicholas J. Ashton6Olivia Belbin7Johannes Fuchs8Caroline M. Watson9Lingyan Ping10Duc M. Duong11Johanna Nilsson12Isabel Barroeta13Juan Lantero-Rodriguez14Laura Videla15Bessy Benejam16Blaine R. Roberts17Kaj Blennow18Nicholas T. Seyfried19Allan I. Levey20María Carmona-Iragui21Johan Gobom22Alberto Lleó23Thomas Wisniewski24Henrik Zetterberg25Juan Fortea26Erik C. B. Johnson27Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgDepartment of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory UniversityDepartment of Biochemistry, Emory University School of MedicineSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgDepartment of Neurology, NYU Grossman School of MedicineDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaProteomics Core Facility at Sahlgrenska Academy, University of GothenburgGoizueta Alzheimer’s Disease Research Center, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaDepartment of Biochemistry, Emory University School of MedicineDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgDepartment of Biochemistry, Emory University School of MedicineGoizueta Alzheimer’s Disease Research Center, Emory University School of MedicineSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaDepartment of Neurology, NYU Grossman School of MedicineDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of GothenburgSant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de BarcelonaGoizueta Alzheimer’s Disease Research Center, Emory University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-61054-z |
| spellingShingle | 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 Erik C. B. Johnson Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease Nature Communications |
| title | Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease |
| title_full | Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease |
| title_fullStr | Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease |
| title_full_unstemmed | Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease |
| title_short | Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease |
| title_sort | proteomic analysis of down syndrome cerebrospinal fluid compared to late onset and autosomal dominant alzheimer´s disease |
| url | https://doi.org/10.1038/s41467-025-61054-z |
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