Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer’s disease

Yu Guo, Shi-Dong Chen, Jia You, Shu-Yi Huang, Yi-Lin Chen, Yi Zhang, Lin-Bo Wang, Xiao-Yu He, Yue-Ting Deng, Ya-Ru Zhang, Yu-Yuan Huang, Qiang Dong, Jian-Feng Feng, Wei Cheng and Jin-Tai Yu ()
Additional contact information
Yu Guo: Fudan University
Shi-Dong Chen: Fudan University
Jia You: Fudan University
Shu-Yi Huang: Fudan University
Yi-Lin Chen: Fudan University
Yi Zhang: Fudan University
Lin-Bo Wang: Fudan University
Xiao-Yu He: Fudan University
Yue-Ting Deng: Fudan University
Ya-Ru Zhang: Fudan University
Yu-Yuan Huang: Fudan University
Qiang Dong: Fudan University
Jian-Feng Feng: Fudan University
Wei Cheng: Fudan University
Jin-Tai Yu: Fudan University

Nature Human Behaviour, 2024, vol. 8, issue 10, 2047-2066

Abstract: 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 associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

Date: 2024
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DOI: 10.1038/s41562-024-01924-6

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