Impaired glymphatic function is associated with synaptic loss in cognitive impairment
Abstract
Purpose To investigate the correlation between glymphatic impairment and synaptic loss and to explore whether this relationship is affected by amyloid-β (Aβ) pathology or reactive astrocytes in individuals spanning the Alzheimer's disease-related pathological spectrum. Methods We investigated the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as a biomarker of the glymphatic system. A total of 182 participants underwent synaptic vesicle glycoprotein 2 A (SV2A) PET/MRI and amyloid-β (Aβ) PET/CT imaging, with SV2A serving as a biomarker of synaptic density. Additionally, plasma Aβ42/40 ratios were measured in 139 participants, and glial fibrillary acidic protein (GFAP) levels were assessed in 143 participants. Controlling for age, sex, years of education, and cognitive status, we investigated the relationships between glymphatic system impairment and synaptic density, along with other biomarkers. Mediation analyses were conducted using the SPSS PROCESS macro (version 3.3) to examine whether synaptic density mediates the relationship between the ALPS index and cognitive performance. Results A lower ALPS index, indicating greater glymphatic impairment, was significantly associated with reduced synaptic density. The ALPS index was also significantly positively associated with the residual SV2A PET standardized uptake value ratio (SUVr) in the hippocampus of participants with Aβ deposition or greater plasma GFAP concentrations. The correlation betwe…
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SV2A levels eventually decrease in correlation with tau accumulation and glymphatic impairment in late-stage Alzheimer's.
“While SV2A levels eventually decrease in correlation with tau accumulation and glymphatic impairment in late-stage Alzheimer’s, certain regions may show a compensatory increase in SV2A binding during early disease stages [93,94,95].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [94]
Certain regions may show a compensatory increase in SV2A binding during early disease stages.
“While SV2A levels eventually decrease in correlation with tau accumulation and glymphatic impairment in late-stage Alzheimer’s, certain regions may show a compensatory increase in SV2A binding during early disease stages [93,94,95].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [94]
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References 58 · Cited by 6
- Authors
- He, K., Wang, J., Wu, J., Chen, X., Chen, H., Li, J., Guo, Q., Huang, Y. H., Guan, Y., Zhao, J., Li, B., Xie, F., & Huang, Q.
- Affiliations
- Fudan University (CN)
- Tongji University (CN)
- Shanghai Jiao Tong University (CN)
- Yale University (US)
- Corresponding author
- Zhao, Jun
- Li, Binyin
- Xie, Fang
- Huang, Qi
- Venue
- European Journal of Nuclear Medicine and Molecular Imaging
- Published
- 2025-12-27
- Volume
- 53
- Issue
- 4
- Pages
- 2799-2810
- ISSN
- 1619-7070 (ISSN-L)
- 1619-7089
- OpenAlex
- W7117371813
- Cited by
- 6
- References
- 58
- Citations by year
- 2026: 6
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Nuclear Medicine and Molecular Imaging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- STI2030-Major Projects (2022ZD0213800)
- Shanghai Municipal Health Commission (2025ZHYL035)
- National Natural Science Foundation of China (82572263)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- synaptic loss, synaptic density, Alzheimer's disease, amyloid-beta, reactive astrocytes, glial fibrillary acidic protein, hippocampus, perivascular spaces, cognitive impairment, diffusion tensor imaging, mediation analysis
- MeSH terms
- Positron Emission Tomography Computed Tomography, Glymphatic System, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Synapses, Biomarkers, Amyloid beta-Peptides, Diffusion Tensor Imaging, Cognitive Dysfunction
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