Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer’s disease

There is accumulating evidence that synaptic loss precedes neuronal loss and correlates best with impaired memory formation in Alzheimer's disease (AD). Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) is a newly discovered marker indicating synaptic damage. We here test CSF SNAP-25 and SNAP-25/amyloid-β42 (Aβ42) ratio as a diagnostic marker for predicting cognitive decline and brain structural change in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We stratified 139 participants from the ADNI database into cognitively normal (CN; n = 52), stable mild cognitive impairment (sMCI; n = 22), progressive MCI (pMCI; n = 47), and dementia due to AD (n = 18). Spearman correlation was performed to test the relationships between biomarkers. Overall diagnostic accuracy (area under the curve (AUC)) was obtained from receiver operating curve (ROC) analyses. Cox proportional hazard models tested the effect of CSF SNAP-25 and SNAP-25/Aβ42 measures on the conversion from MCI to AD. Relationships between the CSF SNAP-25 levels, SNAP-25/Aβ42 ratio, and diagnostic groups were tested with linear regressions. Linear mixed-effects models and linear regression models were used to evaluate CSF SNAP-25 and SNAP-25/Aβ42 as predictors of AD features, including cognition measured by the Mini-Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI). CSF SNAP-25 and SNAP-25/Aβ42 were increased in patients with pMCI and AD compared with CN, and in pMCI and AD compared with sMCI. Cognitively normal subjects who progressed to MCI or AD during follow-up had increased SNAP-25/Aβ42 ratio compared with nonprogressors. CSF SNAP-25, especially SNAP-25/Aβ42, offers diagnostic utility for pMCI and AD. CSF SNAP-25 and SNAP-25/Aβ42 significantly predicted conversion from MCI to AD. In addition, elevated SNAP-25/Aβ42 ratio was associated with the rate of hippocampal atrophy in pMCI and the rate of change of cognitive impairment in CN over the follow-up period. These data suggest that both CSF SNAP-25 and SNAP-25/Aβ42 ratio are already increased at the early clinical stage of AD, and indicate the promise of CSF SNAP-25 and SNAP-25/Aβ42 ratio as diagnostic and prognostic biomarkers for the earliest symptomatic stage of AD.