INTRODUCTION: Synaptic dysfunction and degeneration are central events in 
Alzheimer's disease (AD) pathophysiology that are thought to occur early in 
disease progression. Synaptic pathology may be studied by examining protein 
biomarkers specific for different synaptic elements. We recently showed that the 
dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 
(Ng48-76), is markedly increased in cerebrospinal fluid (CSF) in AD and that 
Ng48-76 is the dominant peptide in human brain tissue. The aim of this study was 
to characterize Ng in plasma and CSF using mass spectrometry and to investigate 
the performance of plasma Ng as an AD biomarker.
METHODS: Paired plasma and CSF samples from patients with AD (n = 25) and 
healthy controls (n = 20) were analyzed in parallel using an immunoassay 
developed in-house on the Meso Scale Discovery platform and hybrid 
immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients 
with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. 
High-resolution mass spectrometry was used for identification of endogenous 
plasma Ng peptides.
RESULTS: Ng in human plasma is present as several endogenous peptides. Of the 16 
endogenous Ng peptides identified, seven were unique for plasma and not 
detectable in CSF. However, Ng48-76 was not present in plasma. CSF Ng was 
significantly increased in AD compared with controls (P < 0.0001), whereas the 
plasma Ng levels were similar between the groups in both studies. Plasma and CSF 
Ng levels showed no correlation. CSF Ng was stable during storage at -20°C for 
up to 2 days, and no de novo generation of peptides were detected.
CONCLUSIONS: For the first time, to our knowledge, we have identified several 
endogenous Ng peptides in human plasma. In agreement with previous studies, we 
show that CSF Ng is significantly increased in AD as compared with healthy 
controls. The origin of Ng in plasma and its possible use as a biomarker need to 
be further investigated. The results suggest that CSF Ng, in particular Ng48-76, 
might reflect the neurodegenerative processes within the brain, indicating a 
role for Ng as a potential novel clinical biomarker for synaptic function in AD.