Abstract
The associations of synaptic loss with amyloid-β (Aβ) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer’s disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aβ plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aβ42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aβ and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aβ deposition was associated with synaptic loss in the medial (r = −0.431, p < 0.001) and lateral (r = −0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aβ deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aβ42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = −0.412, p = 0.001/r = −0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aβ plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aβ plaques, and also can predict longitudinal synaptic loss.
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Data availability
The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Acknowledgements
The authors thank Jianfei Xiao for generous assistance with tracer production and Xiangqing Xie, Yue Qian, and Dan Zhou for assistance with patient recruitment.
Funding
This research was sponsored by the National Key R&D Program of China (2016YFC1306305 and 2018YFE0203600); the National Science Foundation of China (81801752, 81571345, 8217052097 and 82201583); the Shanghai Sailing Program (18YF1403200 and 19YF1405300); the startup fund of Huashan Hospital, Fudan University (2017QD081); the Shanghai Municipal Key Clinical Specialty (3030247006); the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01); and ZJLab Clinical Research Plan of SHDC (No. SHDC2020CR2056B).
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Qihao Guo, Yiyun Huang, Tengfei Guo, Jun Zhao, Yihui Guan, Binyin Li and Fang Xie contributed to the study’s conception and design. Material preparation and data collection and analysis were performed by Jie Wang, Xing Chen, Kun He, Zengping Lin, ZhiWen You and Yang Yang. Data analysis were performed by Jie Wang and Fang Xie. The first draft of the manuscript was written by Jie Wang and Qi Huang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Wang, J., Huang, Q., Chen, X. et al. Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer’s disease. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02501-z
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DOI: https://doi.org/10.1038/s41380-024-02501-z