ABSTRACT Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer’s disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from

the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG,

PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in

discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly

targeting different pathomechanisms. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CSF PROTEOME PROFILING REVEALS BIOMARKERS TO DISCRIMINATE DEMENTIA WITH LEWY BODIES FROM ALZHEIMER´S DISEASE Article Open access 13

September 2023 CSF PROTEOME PROFILING ACROSS THE ALZHEIMER’S DISEASE SPECTRUM REFLECTS THE MULTIFACTORIAL NATURE OF THE DISEASE AND IDENTIFIES SPECIFIC BIOMARKER PANELS Article 10 November

2022 CEREBROSPINAL FLUID PROTEOMICS IN PATIENTS WITH ALZHEIMER’S DISEASE REVEALS FIVE MOLECULAR SUBTYPES WITH DISTINCT GENETIC RISK PROFILES Article Open access 09 January 2024 DATA

AVAILABILITY Data used in the preparation of this Article were obtained on 12 September 2023 from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database

(https://ida.loni.usc.edu/pages/access/studyData.jsp?project=ADNI) and the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data)

(RRID: SCR_006431). For up-to-date information on the study, visit http://adni.loni.usc.edu/ and www.ppmi-info.org. ADNI data are publicly available to bona fide researchers upon application

at https://adni.loni.usc.edu/, and PPMI data are publicly available to bona fide researchers upon application at https://www.ppmi-info.org/. Enrichment analysis data can be obtained from

the STRING website (https://cn.string-db.org/). Agora Druggability data can be obtained from https://www.synapse.org/. All data supporting the findings described in this paper are available

within the paper, in the Supplementary Information and from the corresponding author upon request. Source data are provided with this paper. CODE AVAILABILITY All software used in this study

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https://github.com/jasonHKU0907/AD_CSF_ADNI (2024). Download references ACKNOWLEDGEMENTS We thank all participants who donated their brains to the ADNI Neuropathology Core Center and PPMI

database. We also thank all investigators who collected and processed specimens and performed neuropathological assessments in ADNI and PPMI. As such, the investigators within the ADNI or

PPMI contributed to the design and implementation of the database and/or provided data but did not participate in the analysis or in the writing of this paper. A complete listing of ADNI

investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. We also thank all contributors to the ADNI and PPMI databases. Data

collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH12-2-0012). ADNI is

funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s

Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai, Inc.; Elan Pharmaceuticals,

Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research

& Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research;

Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of

Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org).

The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of

Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. PPMI, a public–private partnership, is funded by the Michael J.

Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson’s, AskBio, Avid

Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave

Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz

Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail

Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity

Therapeutics. We also thank all the participants and researchers from Agora (10.57718/agora-adknowledgeportal), a platform initially developed by the NIA-funded Accelerating Medicines

Partnership in AD consortium that shares evidence in support of AD target discovery. J.T.-Y. was funded by grants from the Science and Technology Innovation 2030 Major Projects

(2022ZD0211600), the National Natural Science Foundation of China (92249305), the Shanghai Municipal Science and Technology Major Project (2023SHZDZX02) and the Shanghai Municipal Health

Commission Emerging Interdisciplinary Research Project (2022JC01). W.C. was funded by the National Natural Science Foundation of China (82071997) and the Shanghai Rising-Star Program

(21QA1408700). J.F.-F. was funded by the National Key R&D Program of China (2018YFC1312904, 2019YFA0709502), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01)

and the 111 Project (No. B18015). Y.G. was funded by the National Postdoctoral Program for Innovative Talents (BX20240073). J.Y. was funded by the Shanghai Pujiang Talent Program (23PJD006).

S.D.-C. was funded by the National Postdoctoral Program for Innovative Talents (BX20230087). Further, we thank the ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key

Laboratory of Neurobiology and Frontiers Center for Brain Science of the Ministry of Education, Fudan University for support. The funders had no role in study design, data collection and

analysis, decision to publish or preparation of the manuscript. AUTHOR INFORMATION Author notes * These authors contributed equally: Yu Guo, Shi-Dong Chen, Jia You, Shu-Yi Huang, Yi-Lin

Chen. AUTHORS AND AFFILIATIONS * Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers

Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China Yu Guo, Shi-Dong Chen, Jia You, Shu-Yi Huang, Yi-Lin Chen, Yi Zhang, Xiao-Yu He, Yue-Ting Deng, Ya-Ru

Zhang, Yu-Yuan Huang, Qiang Dong, Wei Cheng & Jin-Tai Yu * Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China Jia You, Lin-Bo Wang, 

Jian-Feng Feng & Wei Cheng * Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China Jian-Feng Feng & 

Wei Cheng Authors * Yu Guo View author publications You can also search for this author inPubMed Google Scholar * Shi-Dong Chen View author publications You can also search for this author

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can also search for this author inPubMed Google Scholar * Yu-Yuan Huang View author publications You can also search for this author inPubMed Google Scholar * Qiang Dong View author

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CONTRIBUTIONS J.-T.Y. conceptualized and designed the study, interpreted the data and revised the manuscript. Y.G., S.-D.C., J.Y., S.-Y.H. and Y.-L.C. collected, analysed and interpreted the

data, and drafted and revised the manuscript. All authors participated in the revision of the manuscript, had full access to all the study data and accept responsibility for submission of

the paper for publication. CORRESPONDING AUTHOR Correspondence to Jin-Tai Yu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW

INFORMATION _Nature Human Behaviour_ thanks Gajanan Sathe, Christopher Whelan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL

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