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Nature Aging, May 20 2025, | https://doi.org/10.1038/s43587-025-00872-8
Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer's disease
Gyujin Heo1,2,28, Ying Xu1,2,28, Erming Wang3,4, Muhammad Ali1,2, Hamilton Se-Hwee Oh5,6,7, Patricia Moran-Losada6,7,8, Federica Anastasi9,10,11, Armand González Escalante9,10,12, Raquel Puerta13,14, Soomin Song1,2, Jigyasha Timsina1,2, Menghan Liu1,2, Daniel Western1,2, Katherine Gong1,2, Yike Chen1,2, Pat Kohlfeld 1,2, Allison Flynn1,2, Alvin G. Thomas 1,2, Joseph Lowery1,2, John C. Morris15, David M. Holtzman15,16,17, Joel S. Perlmutter18, Suzanne E. Schindler15, Natalia Vilor-Tejedor9,10,11,19, Marc Suárez-Calvet9,10,20, Pablo García-González13,21, Marta Marquié13,21, Maria Victoria Fernández13,21, Mercè Boada13,21, Amanda Cano13,21, Agustín Ruiz13,21,22, Bin Zhang3,4,23,24,25, David A. Bennett26, Tammie Benzinger18, Tony Wyss-Coray7, Laura Ibanez1,2,15, Yun Ju Sung1,2,27 & Carlos Cruchaga1,2,15,16,17
1Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
2NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA.
3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA.
6The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
7Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
8Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
9Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
10Hospital del Mar Research Institute, Barcelona, Spain. 11Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
12Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
13Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
14PhD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
15Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
16Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA.
17Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA.
18Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
19Department of Genetics, Radboud UMC, Nijmegen, Netherlands.
20Servei de Neurologia, Hospital del Mar, Barcelona, Spain.
21Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, Spain.
22Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
23Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
24Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
25Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
26Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA.
27Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
28These authors contributed equally: Gyujin Heo, Ying Xu.
Corresponding author
Correspondence to Carlos Cruchaga.
1Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
2NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA.
3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA.
6The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
7Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
8Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
9Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
10Hospital del Mar Research Institute, Barcelona, Spain. 11Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
12Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
13Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
14PhD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
15Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
16Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA.
17Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA.
18Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
19Department of Genetics, Radboud UMC, Nijmegen, Netherlands.
20Servei de Neurologia, Hospital del Mar, Barcelona, Spain.
21Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, Spain.
22Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
23Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
24Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
25Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
26Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA.
27Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
28These authors contributed equally: Gyujin Heo, Ying Xu.
Corresponding author
Correspondence to Carlos Cruchaga.
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.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-22)
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