Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr 23;14(1):58.
doi: 10.1186/s13195-022-01002-x.

Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer's disease

Pia Kivisäkk  1 , Becky C Carlyle  2 , Thadryan Sweeney  2 , James P Quinn  2 , Christopher E Ramirez  2 , Bianca A Trombetta  2 , Muriel Mendes  3 , Mary Brock  3 , Carrie Rubel  4 , Julie Czerkowicz  4 , Danielle Graham  4 , Steven E Arnold  2
Affiliations

Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer's disease

Pia Kivisäkk et al. Alzheimers Res Ther. .

Abstract

Background: There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer's disease (AD). Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development.

Methods: We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. CSF samples from two well-characterized cohorts (n=178 and n=156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC).

Results: All subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders.

Conclusion: The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration.

Keywords: Alzheimer’s disease; Biomarkers; Cerebrospinal fluid; Neurodegenerative diseases; Neurogranin; PSD-95; SNAP-25; Synaptic markers.

PubMed Disclaimer

Conflict of interest statement

S. Arnold has received honoraria and/or travel expenses for lectures from Abbvie, Eisai, and Biogen and has served on scientific advisory boards of Corte, has received consulting fees from Athira, Cassava, Cognito Therapeutics, EIP Pharma and Orthogonal Neuroscience, and has received research grant support from NIH, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Abbvie, Amylyx, EIP Pharma, Merck, Janssen/Johnson & Johnson, Novartis, and vTv. M. Mendes and M. Brock are paid employees of Quanterix Corporation. C. Rubel, J. Czerkowicz, and D. Graham are paid employees of Biogen. The other authors report no declaration of interest.

Figures

Fig. 1
Fig. 1
Correlations between CSF levels of PSD-95, SNAP-25, and neurogranin stratified by diagnostic group
Fig. 2
Fig. 2
CSF levels of PSD-95 (A), SNAP-25 (C), and Neurogranin (E) in healthy controls (HC) and subjects with Alzheimer’s disease (AD), non-AD neurodegenerative diseases (NeuroDegen), and neurological controls (NeuroCtrl) from cohort I. CSF levels of PSD-95 (B), SNAP-25 (D), and neurogranin (F) by diagnosis. Solid green lines represent the median of the groups and dotted green lines represent the mean. Statistical analysis to determine differences between the individual NeuroDegen and NeuroCtrl diseases (B, D, and F) was not performed due to the large number of comparisons and small sample sizes, and graphs are included to provide information on outlier status
Fig. 3
Fig. 3
ROC-AUC curves for classification of AD vs HC (A), AD vs non-AD neurodegenerative diseases (B), and AD vs neurological controls (C) using PSD-95, SNAP-25, or neurogranin. The amyloid ß42/40 ratio and pTau181 are included as a reference. Graphs show AUC values with 95% confidence intervals
Fig. 4
Fig. 4
CSF levels of PSD-95 (A) and SNAP-25 (B) in healthy controls (HC) and subjects with AD, non-AD neurodegenerative diseases (NeuroDegen), and other neurological conditions (NeuroCtrl) from cohort II. PSD-95 (C) and SNAP-25 (D) levels in HC and AD subjects stratified by cognitive status. Asymptomatic refers to cognitively unimpaired subjects with positive CSF AD biomarkers. Solid green lines represent the median of the groups and dotted green lines represent mean
See this image and copyright information in PMC

References

    1. Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW, Jr, et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology. 2001;56(1):127–129. doi: 10.1212/WNL.56.1.127. - DOI - PubMed
    1. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298(5594):789–791. doi: 10.1126/science.1074069. - DOI - PubMed
    1. Blennow K, Bogdanovic N, Alafuzoff I, Ekman R, Davidsson P. Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J Neural Transm (Vienna) 1996;103(5):603–618. doi: 10.1007/BF01273157. - DOI - PubMed
    1. Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky ST, et al. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alzheimers Res Ther. 2020;12(1):21. doi: 10.1186/s13195-020-00588-4. - DOI - PMC - PubMed
    1. Camporesi E, Nilsson J, Brinkmalm A, Becker B, Ashton NJ, Blennow K, et al. Fluid biomarkers for synaptic dysfunction and loss. Biomark Insights. 2020;15:1177271920950319. doi: 10.1177/1177271920950319. - DOI - PMC - PubMed

Publication types

MeSH terms