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

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Alzheimer’s disease; Amyloid-β; Synaptic loss; Synaptosomal-associated protein 25.

Fig. 1

CSF SNAP-25 levels and SNAP-25/Aβ42 ratio in different diagnostic groups. CSF SNAP-25 levels (a) and SNAP-25/Aβ42 ratio (c) in different diagnostic groups. CSF SNAP-25 levels (b) and SNAP-25/Aβ42 ratio (d) in the healthy control subjects who progressed to MCI or AD (progressive healthy controls). Differences between groups were tested by multiple-variable linear regression, adjusted for age and sex. *p < 0.05, **p < 0.01, ***p < 0.0001. Aβ amyloid-β, AD Alzheimer’s disease, CN cognitively normal, pCN progressively cognitive normal, pMCI progressive mild cognitive impairment, sCN stably cognitive normal, sMCI stable mild cognitive impairment, SNAP-25 synaptosomal-associated protein 25

Fig. 2

CSF SNAP-25 by diagnosis and amyloid pathology. The subjects included in the study were classified as Aβ⁺ or Aβ^–. CSF SNAP-25 in different combinations of clinical diagnosis and Aβ pathology. Differences between groups were tested by multiple-variable linear regression, adjusted for age and sex. *p < 0.05, **p < 0.01, ***p < 0.0001. AD Alzheimer’s disease, CN cognitively normal, pMCI progressive mild cognitive impairment, sMCI stable mild cognitive impairment, SNAP-25 synaptosomal-associated protein 25

Fig. 3

CSF SNAP-25 levels in relation to Aβ42. Correlations between CSF SNAP-25 levels and Aβ42 in different diagnostic groups. Aβ amyloid-β, AD Alzheimer’s disease, CN cognitively normal, pMCI progressive mild cognitive impairment, sMCI stable mild cognitive impairment, SNAP-25 synaptosomal-associated protein 25

Fig. 4

CSF SNAP-25 levels and SNAP-25/Aβ42 ratio in relation to tau biomarkers. Correlations between CSF SNAP-25 levels (a) and SNAP-25/Aβ42 ratio (b) and t-tau in different diagnostic groups. Correlations between CSF SNAP-25 levels (c) and SNAP-25/Aβ42 ratio (d) and p-tau in different diagnostic groups. Aβ amyloid-β, AD Alzheimer’s disease, CN cognitively normal, P-tau phosphorylated tau, pMCI progressive mild cognitive impairment, sMCI stable mild cognitive impairment, SNAP-25 synaptosomal-associated protein 25, T-tau total tau

Fig. 5

ROC analyses. ROC analyses were performed to test the CSF biomarkers and ratios in relation to clinical diagnoses for pMCI (a) and AD (b). Aβ amyloid-β, P-tau phosphorylated tau, SNAP-25 synaptosomal-associated protein 25, T-tau total tau

Fig. 6

Baseline CSF measures of SNAP-25 and SNAP-25/Aβ42 as predictors of conversion from MCI to AD. Survival from AD as a function of CSF SNAP-25 (a) and SNAP-25/Aβ42 (b) measures (dichotomized at the median values) are shown. Analyses were adjusted for age and gender. Cutoff values were 5.4 pg/ml and 0.037 for SNAP-25 and SNAP-25/Aβ42, respectively. Aβ amyloid-β, AD Alzheimer’s disease, SNAP-25 synaptosomal-associated protein 25

Fig. 7

CSF SNAP-25 and SNAP-25/Aβ42 in relation to cognition and future cognitive change. MMSE and ADAS-cog at baseline (a, e) and over time (b, f) as a function of baseline CSF SNAP-25 in different diagnostic groups. MMSE and ADAS-cog at baseline (c, g) and over time (d, h) as a function of baseline SNAP-25/Aβ42 in different diagnostic groups. Biomarker levels and ratios are standardized to z scores. Aβ amyloid-β, AD Alzheimer’s disease, ADAS-cog Alzheimer’s Disease Assessment Scale cognitive subscale, CN cognitively normal, MMSE Mini-Mental State Examination, pMCI progressive mild cognitive impairment, sMCI stable mild cognitive impairment, SNAP-25 synaptosomal-associated protein 25

Fig. 8

CSF SNAP-25 and SNAP-25/Aβ42 in relation to brain structure and WMH. Hippocampal volume, ventricular volume, and WMH at baseline (a, e, i) and over time (b, f, j) as a function of baseline CSF SNAP-25 in different diagnostic groups. Hippocampal volume, ventricular volume, and WMH at baseline (c, g, k) and over time (d, h, l) as a function of baseline SNAP-25/Aβ42 in different diagnostic groups. Biomarker levels and ratios are standardized to z scores. Aβ amyloid-β, AD Alzheimer’s disease, CN cognitively normal, pMCI progressive mild cognitive impairment, sMCI stable mild cognitive impairment, SNAP-25 synaptosomal-associated protein 25, WMH white matter hyperintensity