Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer disease.

OBJECTIVE:To assess the ability of a combination of synaptic CSF biomarkers to separate Alzheimer disease (AD) and non-AD disorders and to help in the differential diagnosis between neurocognitive diseases. METHODS:This was a retrospective cross-sectional monocentric study. All participants explored with CSF assessments for neurocognitive decline were invited to participate. After complete clinical and imaging evaluations, 243 patients were included. CSF synaptic (GAP-43, neurogranin, SNAP-25 total, SNAP-25aa40, synaptotagmin-1) and AD biomarkers were blindly quantified with ELISA or mass spectrometry. Statistical analysis compared CSF levels between the various groups of AD dementias (n = 81), mild cognitive impairment (MCI)-AD (n = 30), other MCI (n = 49), other dementias (OD) (n = 49), and neurologic controls (n = 35) and their discriminatory powers. RESULTS:All synaptic biomarkers were significantly increased in patients with MCI-AD and AD-dementia compared to the other groups. All synaptic biomarkers could efficiently discriminate AD dementias from OD (AUC ≥0.80). All but synaptotagmin were also able to discriminate patients with MCI-AD from controls (area under the curve [AUC] ≥0.85) and those with AD dementias from controls (AUC ≥0.80). Overall, CSF SNAP-25aa40 had the highest discriminative power (AUC 0.93 between patients with AD dementias and controls or OD, AUC 0.90 between those with MCI-AD and controls). Higher levels were associated with 2 alleles of APOE ε4. CONCLUSION:All synaptic biomarkers tested had a good discriminatory power to distinguish patients with AD abnormal CSF from those with non-AD disorders. SNAP25aa40 demonstrated the highest power to discriminate AD CSF-positive patients from patients without AD and neurologic controls in this cohort. CLASSIFICATION OF EVIDENCE:This retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from those without AD.