Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease
Abstract Synaptic loss strongly correlates with cognitive impairment in Alzheimer’s disease (AD), yet the mechanism linking its origin and pattern remain unclear. Given that connected brain regions share molecular and synaptic features, and pathological tau, a key driver of synaptic degeneration, pr...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61497-4 |
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| author | Ying Luan Weiyi Wang Qi Huang Yan Wang Jana Nussbaumer Jie Wang Anna Steward Sebastian N. Roemer-Cassiano Yihui Guan Michael Ewers Michael Schöll Ruiqing Ni Binyin Li Nicolai Franzmeier Fang Xie |
| author_facet | Ying Luan Weiyi Wang Qi Huang Yan Wang Jana Nussbaumer Jie Wang Anna Steward Sebastian N. Roemer-Cassiano Yihui Guan Michael Ewers Michael Schöll Ruiqing Ni Binyin Li Nicolai Franzmeier Fang Xie |
| author_sort | Ying Luan |
| collection | DOAJ |
| description | Abstract Synaptic loss strongly correlates with cognitive impairment in Alzheimer’s disease (AD), yet the mechanism linking its origin and pattern remain unclear. Given that connected brain regions share molecular and synaptic features, and pathological tau, a key driver of synaptic degeneration, propagates through brain networks, we hypothesize that network architecture may influence synaptic loss in AD. By combining synaptic vesicle glycoprotein 2 A (SV2A) PET in 91 AD patients and 54 controls with normative connectome data, we show strongly connected regions exhibit similar levels of synaptic loss, and synaptic loss in one region is associated with connectivity-weighted synaptic loss in connected regions. Regions strongly connected to the epicenter show greater and faster synaptic loss. Plasma p-tau181 levels correlate with network-constrained synaptic loss, and post-mortem data confirm reduced SV2A expression in tau-rich areas. These findings support that synaptic vulnerability in AD is partially constrained by network topology and is modulated by phosphorylated tau. |
| format | Article |
| id | doaj-art-e79b04de0b9548a1b465cdecb382a82c |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e79b04de0b9548a1b465cdecb382a82c2025-08-20T03:05:14ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-61497-4Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s diseaseYing Luan0Weiyi Wang1Qi Huang2Yan Wang3Jana Nussbaumer4Jie Wang5Anna Steward6Sebastian N. Roemer-Cassiano7Yihui Guan8Michael Ewers9Michael Schöll10Ruiqing Ni11Binyin Li12Nicolai Franzmeier13Fang Xie14Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityDepartment of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityDepartment of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityDepartment of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityInstitute for Biomedical Engineering, ETH & University of Zurich, Institute for Regenerative Medicine University of ZurichDepartment of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityInstitute for Stroke and Dementia Research (ISD), University HospitalInstitute for Stroke and Dementia Research (ISD), University HospitalDepartment of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityInstitute for Stroke and Dementia Research (ISD), University HospitalWallenberg Centre for Molecular and Translational Medicine, University of GothenburgInstitute for Biomedical Engineering, ETH & University of Zurich, Institute for Regenerative Medicine University of ZurichDepartment of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineInstitute for Stroke and Dementia Research (ISD), University HospitalDepartment of Nuclear Medicine & PET Center, Huashan Hospital, Fudan UniversityAbstract Synaptic loss strongly correlates with cognitive impairment in Alzheimer’s disease (AD), yet the mechanism linking its origin and pattern remain unclear. Given that connected brain regions share molecular and synaptic features, and pathological tau, a key driver of synaptic degeneration, propagates through brain networks, we hypothesize that network architecture may influence synaptic loss in AD. By combining synaptic vesicle glycoprotein 2 A (SV2A) PET in 91 AD patients and 54 controls with normative connectome data, we show strongly connected regions exhibit similar levels of synaptic loss, and synaptic loss in one region is associated with connectivity-weighted synaptic loss in connected regions. Regions strongly connected to the epicenter show greater and faster synaptic loss. Plasma p-tau181 levels correlate with network-constrained synaptic loss, and post-mortem data confirm reduced SV2A expression in tau-rich areas. These findings support that synaptic vulnerability in AD is partially constrained by network topology and is modulated by phosphorylated tau.https://doi.org/10.1038/s41467-025-61497-4 |
| spellingShingle | Ying Luan Weiyi Wang Qi Huang Yan Wang Jana Nussbaumer Jie Wang Anna Steward Sebastian N. Roemer-Cassiano Yihui Guan Michael Ewers Michael Schöll Ruiqing Ni Binyin Li Nicolai Franzmeier Fang Xie Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease Nature Communications |
| title | Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease |
| title_full | Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease |
| title_fullStr | Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease |
| title_full_unstemmed | Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease |
| title_short | Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease |
| title_sort | synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in alzheimer s disease |
| url | https://doi.org/10.1038/s41467-025-61497-4 |
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