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

Gyujin Heo^#^{1

2}, Ying Xu^#^{1

2}, Erming Wang^{3

4}, Muhammad Ali^{1

2}, Hamilton Se-Hwee Oh^{5

6

7}, Patricia Moran-Losada^{6

7

8}, Federica Anastasi^{9

10

11}, Armand González Escalante^{9

10

12}, Raquel Puerta^{13

14}, Soomin Song^{1

2}, Jigyasha Timsina^{1

2}, Menghan Liu^{1

2}, Daniel Western^{1

2}, Katherine Gong^{1

2}, Yike Chen^{1

2}, Pat Kohlfeld^{1

2}, Allison Flynn^{1

2}, Alvin G Thomas^{1

2}, Joseph Lowery^{1

2}, John C Morris¹⁵, David M Holtzman^{15

16

17}, Joel S Perlmutter¹⁸, Suzanne E Schindler¹⁵, Natalia Vilor-Tejedor^{9

10

11

19}, Marc Suárez-Calvet^{9

10

20}, Pablo García-González^{13

21}, Marta Marquié^{13

21}, Maria Victoria Fernández^{13

21}, Mercè Boada^{13

21}, Amanda Cano^{13

21}, Agustín Ruiz^{13

21

22}, Bin Zhang^{3

4

23

24

25}, David A Bennett²⁶, Tammie Benzinger¹⁸, Tony Wyss-Coray⁷, Laura Ibanez^{1

2

15}, Yun Ju Sung^{1

2

27}, Carlos Cruchaga^{28

29

30

31

32}

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
² NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁶ The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
⁷ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
⁸ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
¹⁰ Hospital del Mar Research Institute, Barcelona, Spain.
¹¹ Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
¹² Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
¹³ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
¹⁴ PhD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
¹⁵ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁶ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA.
¹⁷ Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA.
¹⁸ Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Genetics, Radboud UMC, Nijmegen, Netherlands.
²⁰ Servei de Neurologia, Hospital del Mar, Barcelona, Spain.
²¹ Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, Spain.
²² Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
²³ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁵ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁷ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
²⁸ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²⁹ NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.
³⁰ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
³¹ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.
³² Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.

^# Contributed equally.

PMID: 40394224
DOI: 10.1038/s43587-025-00872-8

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

Gyujin Heo et al. Nat Aging. 2025 Jun.

. 2025 Jun;5(6):1114-1131.

doi: 10.1038/s43587-025-00872-8. Epub 2025 May 20.

Authors

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
² NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁶ The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA.
⁷ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
⁸ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
¹⁰ Hospital del Mar Research Institute, Barcelona, Spain.
¹¹ Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
¹² Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
¹³ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
¹⁴ PhD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
¹⁵ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁶ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA.
¹⁷ Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA.
¹⁸ Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Genetics, Radboud UMC, Nijmegen, Netherlands.
²⁰ Servei de Neurologia, Hospital del Mar, Barcelona, Spain.
²¹ Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, Spain.
²² Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
²³ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁵ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁷ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
²⁸ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²⁹ NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.
³⁰ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
³¹ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.
³² Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.

^# Contributed equally.

PMID: 40394224
DOI: 10.1038/s43587-025-00872-8

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.

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Conflict of interest statement

Competing interests: C.C. has received research support from GSK and Eisai. C.C. is a member of the scientific advisory board of Circular Genomics and owns stocks. C.C. is a member of the scientific advisory board of ADmit. There is an invention disclosure for the prediction models, including protein IDs, alternative proteins and weights, cutoff and algorithms. C.C. has served on the scientific advisory boards of GSK and Novo Nordisk. D.M.H. is a cofounder with equity in C2N Diagnostics. D.M.H. is on the scientific advisory boards of Genentech, Denali, C2N Diagnostics and Cajal Neurosciences. D.M.H. consults for Asteroid, Acta Pharmaceuticals, Alnylam, Pfizer and Switch. T.W.-C. and H.S.-H.O. are cofounders and scientific advisors of Teal Omics and have received equity stakes. T.W.-C. is a cofounder and scientific advisor of Alkahest and Qinotto and has received equity stakes in these companies. S.E.S. has served on scientific advisory boards on biomarker testing and clinical care pathways for Eisai and Novo Nordisk and has received speaking fees for presentations on biomarker testing from Eisai, Eli Lilly and Novo Nordisk. M.S.-C. has received consultancy/speaker fees (paid to the institution) from Almirall, Eli Lilly, Novo Nordisk and Roche Diagnostics in the past 36 months. M.S.-C. has received consultancy fees or served on the advisory boards (paid to the institution) of Eli Lilly, Grifols, Novo Nordisk and Roche Diagnostics. M.S.-C. was granted a project and is a site investigator of a clinical trial (funding granted to the institution) by Roche Diagnostics. M.S.-C. did not receive any personal compensation from these organizations or any other for-profit organization. The other authors declare no competing interests.

Update of

Large-scale Plasma Proteomic Profiling Unveils Novel Diagnostic Biomarkers and Pathways for Alzheimer's Disease.
Cruchaga C, Heo G, Thomas A, Wang E, Oh H, Ali M, Timsina J, Song S, Liu M, Gong K, Western D, Chen Y, Kohlfeld P, Flynn A, Lowery J, Morris J, Holtzman D, Perlmutter J, Schindler S, Zhang B, Bennett D, Benzinger T, Wyss-Coray T, Ibanez L, Sung YJ, Xu Y, Losada PM, Anastasi F, Gonzalez-Escalante A, Puerta R, Vilor-Tejedor N, Suárez-Calvet M, Garcia-Gonzalez P, Fernández M, Boada M, Cano A, Ruiz A. Cruchaga C, et al. Res Sq [Preprint]. 2025 Mar 18:rs.3.rs-5167552. doi: 10.21203/rs.3.rs-5167552/v1. Res Sq. 2025. Update in: Nat Aging. 2025 Jun;5(6):1114-1131. doi: 10.1038/s43587-025-00872-8. PMID: 40166037 Free PMC article. Updated. Preprint.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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Grants and funding

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Medical