Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease

Jie Wang; Qi Huang; Xing Chen; Zhiwen You; Kun He; Qihao Guo; Yiyun Huang; Yang Yang; Zengping Lin; Tengfei Guo; Jun Zhao; Yihui Guan; Binyin Li; Fang Xie

doi:10.1038/s41380-024-02501-z

Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease

Mol Psychiatry. 2024 Apr 8. doi: 10.1038/s41380-024-02501-z. Online ahead of print.

Authors

Jie Wang^#¹, Qi Huang^#¹, Xing Chen², Zhiwen You², Kun He¹, Qihao Guo³, Yiyun Huang⁴, Yang Yang⁵, Zengping Lin⁶, Tengfei Guo⁷, Jun Zhao², Yihui Guan⁸, Binyin Li⁹, Fang Xie¹⁰

Affiliations

¹ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, 200040, China.
² Department of Nuclear Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 310000, China.
³ Department of Gerontology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
⁴ PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut, CT, 06520-8048, USA.
⁵ Beijing United Imaging Research Institute of Intelligent Imaging, Beijing, 100089, China.
⁶ Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, 201807, China.
⁷ Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Shenzhen, 518000, China.
⁸ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, 200040, China. guanyihui@hotmail.com.
⁹ Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. libinyin@126.com.
¹⁰ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, 200040, China. Fangxie@fudan.edu.cn.

^# Contributed equally.

PMID: 38589563
DOI: 10.1038/s41380-024-02501-z

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.