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Cited by 185Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer’s disease

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Öhrfelt, Annika, Brinkmalm, Ann, Dumurgier, Julien, Brinkmalm, Gunnar, Hansson, Oskar, Zetterberg, Henrik, Bouaziz-Amar, Elodie, Hugon, Jacques, Paquet, Claire, Blennow, Kaj·2016·Alzheimer's Research & Therapy
DOI 10.1186/s13195-016-0208-8PMC PMC5048479
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Abstract

BACKGROUND: Synaptic degeneration is a central pathogenic event in Alzheimer's disease that occurs early during the course of disease and correlates with cognitive symptoms. The pre-synaptic vesicle protein synaptotagmin-1 appears to be essential for the maintenance of an intact synaptic transmission and cognitive function. Synaptotagmin-1 in cerebrospinal fluid is a candidate Alzheimer biomarker for synaptic dysfunction that also may correlate with cognitive decline. METHODS: In this study, a novel mass spectrometry-based assay for measurement of cerebrospinal fluid synaptotagmin-1 was developed, and was evaluated in two independent sample sets of patients and controls. Sample set I included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 17, age 52-86 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 5, age 62-88 years), and controls (N = 17, age 41-82 years). Sample set II included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 24, age 52-84 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 18, age 58-83 years), and controls (N = 36, age 43-80 years). RESULTS: The reproducibility of the novel method showed coefficients of variation of the measured synaptotagmin-1 peptide 215-223 (VPYSELGGK) and peptide 238-245 (HDIIGEFK) of 14 % or below. In both investigated sample sets, the CSF levels of synaptotagmin-1 were significantly increased in patients with dementia due to Alzheimer's disease (P ≤ 0.0001) and in patients with mild cognitive impairment due to Alzheimer's disease (P < 0.001). In addition, in sample set I the synaptotagmin-1 level was significantly higher in patients with mild cognitive impairment due to Alzheimer's disease compared with patients with dementia due to Alzheimer's disease (P ≤ 0.05). CONCLUSIONS: Cerebrospinal fluid synaptotagmin-1 is a promising biomarker to monitor synaptic dysfunction and degeneration in Alzheimer's disease that may be useful for clinical diagnosis, to monitor effect on synaptic integrity by novel drug candidates, and to explore pathophysiology directly in patients with Alzheimer's disease.

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Fig. 1 Targeted HR-PRM-MS analyses of synaptotagmin in human CSF. Individual values for the HR-PRM-MS measured peak area ratios ((endogenous peptide/labeled peptide standard) × 1000) of immunoprecipitated synaptotagmin in CSF samples within sample set I (a, b) and sample set II (c, d). The four panels depict the measured levels of two tryptic peptides of synaptotagmin, 215–223 (VPYSELGGK) (a, c) and 238–245 (HDIIGEFK) (b, d). AD dementia due to Alzheimer’s disease, MCI-AD mild cognitive impairment due to Alzheimer’s disease
Fig. 1 Targeted HR-PRM-MS analyses of synaptotagmin in human CSF. Individual values for the HR-PRM-MS measured peak area ratios ((endogenous peptide/labeled peptide standard) × 1000) of immunoprecipitated synaptotagmin in CSF samples within sample set I (a, b) and sample set II (c, d). The four panels depict the measured levels of two tryptic peptides of synaptotagmin, 215–223 (VPYSELGGK) (a, c) and 238–245 (HDIIGEFK) (b, d). AD dementia due to Alzheimer’s disease, MCI-AD mild cognitive impairment due to Alzheimer’s diseaseCC BY · PubMed Central
Fig. 2 ROC curve analysis of synaptotagmin in human CSF. ROC curve analysis for synaptotagmin 215–223 (green and pink) and synaptotagmin 238–245 (turquoise and black) in CSF for differentiation of MCI due to Alzheimer’s disease (MCI-AD) from controls in sample set I and sample set II, respectively (a). ROC curve analysis for synaptotagmin 215–223 (green and pink) and synaptotagmin 238–245 (turquoise and black) in CSF for differentiation of dementia due to Alzheimer’s disease (AD) from controls in sample set I and sample set II, respectively (b). The area under the curve (95 % confidence interval) is shown in the included table (c). AD dementia due to Alzheimer’s disease, MCI-AD mild cognitive impairment due to Alzheimer’s disease (Color figure online)
Fig. 2 ROC curve analysis of synaptotagmin in human CSF. ROC curve analysis for synaptotagmin 215–223 (green and pink) and synaptotagmin 238–245 (turquoise and black) in CSF for differentiation of MCI due to Alzheimer’s disease (MCI-AD) from controls in sample set I and sample set II, respectively (a). ROC curve analysis for synaptotagmin 215–223 (green and pink) and synaptotagmin 238–245 (turquoise and black) in CSF for differentiation of dementia due to Alzheimer’s disease (AD) from controls in sample set I and sample set II, respectively (b). The area under the curve (95 % confidence interval) is shown in the included table (c). AD dementia due to Alzheimer’s disease, MCI-AD mild cognitive impairment due to Alzheimer’s disease (Color figure online)CC BY · PubMed Central

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Authors
Öhrfelt, A., Brinkmalm, A., Dumurgier, J., Brinkmalm, G., Hansson, O., Zetterberg, H., Bouaziz-Amar, E., Hugon, J., Paquet, C., & Blennow, K.
Affiliations
  • Sahlgrenska University Hospital (SE)
  • Inserm (FR)
  • Lund University (SE)
Corresponding author
Öhrfelt, Annika
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2016-10-03
Volume
8
Issue
1
Pages
41-41
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-016-0208-8
PMC
PMC5048479
OpenAlex
W2529693680
Cited by
184
References
40
Citations by year
2026: 6 · 2025: 17 · 2024: 35 · 2023: 18 · 2022: 31 · 2021: 22 · 2020: 26 · 2019: 14 · 2018: 13 · 2017: 2
FWCI
7.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Swedish Brain Power
  • Swedish research council
  • Swedish Alzheimer foundation
  • European research council
  • ALF
  • The Knut and Wallenberg foundation
  • Demensfonden
  • Eivind och Elsa K:son Sylvans stiftelse
  • the Wolfson foundation
  • Märtha och Gustaf Ågrens stiftelse
  • Gun och Bertil Stohnes Stiftelse
  • Stiftelsen gamla tjänarinnor
  • Magnus Bergvalls Stiftelse
  • Svenska Läkaresällskapet
  • Åhlén-stiftelsen
  • BMBF BIOMARK-APD
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
synaptotagmin-1, Alzheimer's disease, cerebrospinal fluid biomarkers, synaptic dysfunction, synaptic degeneration, mild cognitive impairment, dementia, cognitive decline, drug monitoring, neurodegeneration biomarkers, tau protein, neuroinflammation, neurofibrillary tangles, neurodegeneration
MeSH terms
Adult, Aged, Aged, 80 and over, Alzheimer Disease, Cognition Disorders, Dementia, Female, Humans, Male, Middle Aged, Peptide Fragments, Peptides, Psychiatric Status Rating Scales, ROC Curve, Mass Spectrometry, Amyloid beta-Peptides, tau Proteins, Immunoprecipitation, Synaptotagmin I

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