Plasma growth-associated protein 43 correlates with synaptic loss in Alzheimer's disease

Guoyu Lan; Binyin Li; Mengjie Wang; Aatmika Barve; Morvane Colin; Luc Buée; Laihong Zhang; Mingxing Jiang; Jie Yang; Anqi Li; Zhengbo He; Xin Zhou; Yalin Zhu; Yue Cai; Pan Sun; Lin Liu; Jieyin Li; Linting Chen; Lili Fang; Yiying Wang; Mingxu Li; Xuhui Chen; Dai Shi; Chenghui Ye; Xiang Fan; Qingyong Wang; Liemin Zhou; Zhen Liu; Ying Han; Lu Wang; Guanxun Cheng; Yihui Guan; Ruiqing Ni; Kevin Richetin; Fang Xie; Tengfei Guo

doi:10.1016/j.xcrm.2025.102508

Plasma growth-associated protein 43 correlates with synaptic loss in Alzheimer's disease

Cell Rep Med. 2025 Dec 16;6(12):102508. doi: 10.1016/j.xcrm.2025.102508.

Authors

Guoyu Lan¹, Binyin Li², Mengjie Wang³, Aatmika Barve⁴, Morvane Colin⁵, Luc Buée⁵, Laihong Zhang⁶, Mingxing Jiang⁷, Jie Yang⁸, Anqi Li⁹, Zhengbo He¹⁰, Xin Zhou¹¹, Yalin Zhu⁹, Yue Cai¹, Pan Sun¹, Lin Liu¹, Jieyin Li¹, Linting Chen¹, Lili Fang¹, Yiying Wang¹, Mingxu Li¹², Xuhui Chen¹³, Dai Shi¹⁴, Chenghui Ye¹⁴, Xiang Fan¹⁵, Qingyong Wang¹⁶, Liemin Zhou¹⁴, Zhen Liu¹, Ying Han¹⁷, Lu Wang¹⁸, Guanxun Cheng¹⁵, Yihui Guan³, Ruiqing Ni¹⁹, Kevin Richetin²⁰, Fang Xie²¹, Tengfei Guo²²

Affiliations

¹ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China.
² Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai 200040, China.
⁴ Centre for Psychiatric Neurosciences (CNP), Lausanne University Hospital (CHUV) - University of Lausanne (UNIL), 1015 Lausanne, Switzerland.
⁵ University Lille, Inserm, CHU-Lille, LilNCog-Lille Neuroscience & Cognition, 59000 Lille, France.
⁶ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510641, China.
⁷ Shenzhen Medical Academy of Research and Translation, Shenzhen 518132, China; Westlake University, Hangzhou 310024, China.
⁸ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
⁹ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong 999077, China.
¹⁰ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
¹¹ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; School of Biomedical Engineering, Hainan University, Haikou 570228, China.
¹² Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
¹³ Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518132, China.
¹⁴ Neurology Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China.
¹⁵ Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen 518132, China.
¹⁶ Department of Neurology, Shenzhen Guangming District People's Hospital, Shenzhen 518132, China.
¹⁷ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; School of Biomedical Engineering, Hainan University, Haikou 570228, China.
¹⁸ Department of Nuclear Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
¹⁹ Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland; Institute for Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland.
²⁰ Centre for Psychiatric Neurosciences (CNP), Lausanne University Hospital (CHUV) - University of Lausanne (UNIL), 1015 Lausanne, Switzerland; Leenaards Memory Centre, Lausanne University Hospital (CHUV) - University of Lausanne (UNIL), 1011 Lausanne, Switzerland; Department of Clinical Neuroscience (DNC), Laboratory of Neurotherapies and Neuromodulation, Lausanne University Hospital (CHUV) and University of Lausanne, 1011 Lausanne, Switzerland. Electronic address: kevin.richetin@chuv.ch.
²¹ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: fangxie@fudan.edu.cn.
²² Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China; Shenzhen Medical Academy of Research and Translation, Shenzhen 518132, China; Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Peking University, Shenzhen 518132, China. Electronic address: tengfei.guo@szbl.ac.cn.

Abstract

Synaptic loss is a hallmark of Alzheimer's disease (AD) but lacks robust blood-based biomarkers. We investigate growth-associated protein 43 (GAP-43), previously identified as a synaptic candidate in the cerebrospinal fluid (CSF). Postmortem proteomic profiling of brain-derived extracellular vesicles (n = 21) highlights GAP-43 as a central hub within synaptic protein networks co-depleted in AD and closely linked with proteins enriched in immune-, metabolic-, and synaptic-related modules. In two well-characterized Chinese AD cohorts (n = 785), we measure plasma GAP-43, including subgroups with CSF biomarkers (n = 72), SV2A-PET (positron emission tomography) (n = 85), tau-PET (n = 280), and magnetic resonance imaging (MRI) (n = 595). Plasma GAP-43 correlates with CSF GAP-43, neurofilament light, and both baseline and longitudinal synaptic PET. Elevated plasma GAP-43 is associated with greater tau aggregation, faster brain atrophy, and accelerated cognitive decline, particularly among cognitively unimpaired individuals. These findings support plasma GAP-43 as a promising biomarker of early synaptic degeneration and a potential tool for identifying individuals at risk of AD progression.

Keywords: Alzheimer’s disease; GAP-43; blood biomarkers; extracellular vesicles; neuropathology; synaptic loss.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / blood
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Biomarkers / blood
Biomarkers / cerebrospinal fluid
Brain / diagnostic imaging
Brain / metabolism
Brain / pathology
Cognitive Dysfunction / blood
Female
GAP-43 Protein* / blood
GAP-43 Protein* / cerebrospinal fluid
GAP-43 Protein* / metabolism
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Positron-Emission Tomography
Synapses* / metabolism
Synapses* / pathology
tau Proteins / metabolism

Substances

Biomarkers
GAP-43 Protein
tau Proteins