Cell reports. Medicine · 2025
Plasma growth-associated protein 43 correlates with synaptic loss in Alzheimer's disease.
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Lan Guoyu, Li Binyin, Wang Mengjie, Barve Aatmika, Colin Morvane, Buée Luc, Zhang Laihong, Jiang Mingxing, Yang Jie, Li Anqi, He Zhengbo, Zhou Xin, Zhu Yalin, Cai Yue, Sun Pan, Liu Lin, Li Jieyin, Chen Linting, Fang Lili, Wang Yiying, Li Mingxu, Chen Xuhui, Shi Dai, Ye Chenghui, Fan Xiang, Wang Qingyong, Zhou Liemin, Liu Zhen, Han Ying, Wang Lu, Cheng Guanxun, Guan Yihui, Ni Ruiqing, Richetin Kevin, Xie Fang, Guo Tengfei
Аннотация
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.