CSF synaptic protein concentrations are raised in those with atypical Alzheimer’s disease but not frontotemporal dementia
Open accessAbstract
Background: Increased CSF levels of a number of synaptic markers have been reported in Alzheimer’s disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1. Methods: CSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls. Patients were stratified by their tau to Aβ 42 ratio: those with a ratio of > 1 considered as having likely AD pathology, i.e. an atypical form of AD (‘AD biomarker’ group [n = 18]), and < 1 as likely FTD pathology (‘FTD biomarker’ group [n = 48]). A subgroup analysis compared those in the FTD group with likely tau (n = 7) and TDP-43 (n = 18) pathology. Concentrations of neurogranin were measured using two different ELISAs (Ng22 and Ng36), and concentrations of two SNAP-25 fragments (SNAP-25tot and SNAP-25aa40) and synaptotagmin-1 were measured via mass spectrometry. Results: The AD biomarker group had significantly higher concentrations of all synaptic proteins compared to controls except for synaptotagmin-1 where there was only a trend to increased levels—Ng22, AD mean 232.2 (standard deviation 138.9) pg/ml, controls 137.6 (95.9); Ng36, 225.5 (148.8) pg/ml, 130.0 (80.9); SNAP-25tot, 71.4 (27.9) pM, 53.5 (11.7); SNAP-25aa40, 14.0 (6.3), 7.9 (2.3) pM; and synaptotagmin-1, 287.7 (156.0) pM, 238.3 (71.4). All synaptic measures were significantly higher in the atypical AD group than the FTD biomarker group except for Ng36 where there was only a trend to increased levels—Ng22, 114.0 (117.5); Ng36, 171.1 (75.2); SNAP-25tot, 49.2 (16.7); SNAP-25aa40, 8.2 (3.4); and synaptotagmin-1, 197.1 (78.9). No markers were higher in the FTD biomarker group than controls. No significant differences were seen in the subgroup analysis, but there was a trend to increased levels in those with likely tau pathology. Conclusions: No CSF synaptic proteins have been shown to be abnormal in those with likely FTD pathologically. Higher CSF synaptic protein concentrations of neurogranin, SNAP-25, and synaptotagmin-1 appear to be related to AD pathology.
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Strong associations can be found between some synaptic proteins but not all, and synaptic biomarkers have been reported to lack correlation with CSF neurofilament light levels.
“The diversity of synaptic pathology across several neurodegenerative dementia is further reflected by the fact that strong associations can be found between some synaptic proteins but not all, as well as the reported lack of correlation of synaptic biomarkers with CSF neurofilament light (NfL) levels [1, 9–11].”
Neurogranin is a protein present in the dendritic spine that regulates calcium influxes and is found to be increased in Alzheimer's disease.
“Another biomarker, neurogranin (Ng), is a protein present in the dendritic spine that regulates calcium influxes and is found to be increased in AD [10].”
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- Authors
- Clarke, M. T. M., Brinkmalm, A., Foiani, M. S., Woollacott, I. O. C., Heller, C., Heslegrave, A., Keshavan, A., Fox, N. C., Schott, J. M., Warren, J. D., Blennow, K., Zetterberg, H., & Rohrer, J. D.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- University of Gothenburg (SE)
- UK Dementia Research Institute (GB)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Rohrer, Jonathan D.
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2019-12
- Volume
- 11
- Issue
- 1
- Pages
- 105-105
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC6918699
- OpenAlex
- W2996155157
- Cited by
- 58
- References
- 31
- Citations by year
- 2025: 11 · 2024: 6 · 2023: 6 · 2022: 19 · 2021: 7 · 2020: 8 · 2019: 1
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Medical Research Council (MR/M008525/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- atypical Alzheimer's disease, frontotemporal dementia, cerebrospinal fluid biomarkers, synaptic proteins, neurogranin, SNAP-25, synaptotagmin-1, tau pathology, TDP-43 pathology, neurodegeneration, Alzheimer's disease, frontotemporal lobar degeneration, neurofibrillary tangles
- MeSH terms
- Aged, Alzheimer Disease, Female, Humans, Male, Middle Aged, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, tau Proteins, Synaptosomal-Associated Protein 25, Synaptotagmin I, Neurogranin, Frontotemporal Dementia
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