Summary

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.

Title

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

Authors

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

Journal Information

Cell Reports Medicine (2025)

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