Clinically Accurate Diagnosis of Alzheimer's Disease via Single-Molecule Bioelectronic Label-Free Profiling of Multiple Blood Extracellular Vesicle Biomarkers

Jintao Zheng; Xiaohong Jiang; Shiyao Bai; Minchao Lai; Jiacheng Yu; Mingxi Chen; Runzhi Zhou; Yue Jia; Haoyang Yan; Zheng Liang; Dian Wang; Chuyan Wu; Shan Liu; Chenzhong Li; Jinguang Yang; Yang Luo; Cheng Jiang; Keying Guo

doi:10.1002/adma.202505262

Clinically Accurate Diagnosis of Alzheimer's Disease via Single-Molecule Bioelectronic Label-Free Profiling of Multiple Blood Extracellular Vesicle Biomarkers

Adv Mater. 2025 Jun 27:e2505262. doi: 10.1002/adma.202505262. Online ahead of print.

Authors

Jintao Zheng^{1

2}, Xiaohong Jiang^{1

2}, Shiyao Bai³, Minchao Lai⁴, Jiacheng Yu^{1

2}, Mingxi Chen¹, Runzhi Zhou^{1

2}, Yue Jia¹, Haoyang Yan^{1

2}, Zheng Liang¹, Dian Wang⁵, Chuyan Wu⁶, Shan Liu⁷, Chenzhong Li³, Jinguang Yang⁸, Yang Luo⁹, Cheng Jiang³, Keying Guo^{1

2

10

11}

Affiliations

¹ Department of Biotechnology and Food Engineering, Guangdong Technion-Israel Institute of Technology (GTIIT), Shantou, 515063, China.
² Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology (IIT), Haifa, 3200003, Israel.
³ School of Medicine, The Chinese University of Hong Kong (CUHK), Shenzhen, 518172, China.
⁴ Department of Neurology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
⁵ Department of Forensic Medicine, Shantou University Medical College (SUMC), Shantou, 515041, China.
⁶ Shantou University Medical College (SUMC), Shantou, 515041, China.
⁷ Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
⁸ Key Laboratory of Tobacco Pest Monitoring, Controlling and Integrated Management, Tobacco Research Institute of Chinese Academy of Agricultural Sciences, Qingdao, 266101, China.
⁹ School of Medicine, Chongqing University, Chongqing, 400417, China.
¹⁰ Guangdong Provincial Key Laboratory of Materials and Technologies for Energy Conversion, Guangdong Technion-Israel Institute of Technology (GTIIT), Shantou, 515063, China.
¹¹ Monash Institute of Pharmaceutical Sciences (MIPS), Monash University, Parkville, Victoria, 3052, Australia.

PMID: 40576521
DOI: 10.1002/adma.202505262

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no cure, making early diagnosis critical for mitigating its impact. Blood extracellular vesicles (EVs) hold promises as biomarkers for AD diagnosis, but current detection technologies lack the sensitivity and multiplexing capabilities needed for efficient diagnosis. Here, a novel label-free bioelectronic platform is presented based on an organic electrochemical transistor (OECT) integrated with a microelectrode array (MEA) for ultrasensitive detection of AD biomarkers in blood EVs, including amyloid-β (Aβ_1-40 and Aβ_1-42), total tau (t-tau), and phosphorylated tau (p-tau¹⁸¹). This platform achieves a detection limit as low as the zeptomolar (zM) level, enabling the detection of single-molecule targets. It provides a comprehensive multiplexed diagnostic model capable of delivering results within 20 min. Notably, the systematic integration of multiple AD biomarkers in blood EVs is demonstrated to significantly enhance diagnostic accuracy. This study presents a novel EVs-based multiplexed diagnostic model for AD, correctly classifying all clinical samples (n = 40), far exceeding the accuracy of a single biomarker. With its high sensitivity and rapid turnaround, this platform enables reliable AD diagnosis and holds the potential for tracking disease progression, offering a transformative tool to combat the societal burden of AD.

Keywords: alzheimer's disease; blood extracellular vesicles; label‐free bioelectronic platform; multiplexed diagnostic model; organic electrochemical transistor.

Abstract

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