CSF SNAP‐25 dynamics in healthy aging and across the spectrum of Alzheimer's disease

Abstract

AbstractBackgroundThe turnover of synaptic proteins with aging and in different phases of AD is poorly understood. We measured CSF SNAP‐25, a protein localized to the presynaptic processes, using a novel SIMOA assay across 2 cohorts comparing cognitively normal young vs cognitively normal older adults as well as those with early and late MCI, in addition to those with dementia due to AD.MethodSubjects from the CSF Clinic were classified as cognitively normal or MCI based on NIA‐AA criteria in cohort 1. Subjects from the Johns Hopkins ADRC were classified clinically as cognitively normal, early MCI, late MCI and dementia in cohort 2. CSF SNAP‐25 was measured using a SIMOA assay on the Quanterix HD‐X. CSF AD biomarkers (abeta42, abeta40, total tau, ptau181) were measured using Fujirebio Lumipulse assays.ResultLevels of CSF SNAP‐25 were similar in cognitively normal young controls (YN) vs older controls (ON) in the first cohort with elevated levels in MCI (median [IQR] YN 66.0 [53.0,74.6], ON 57.7 [44.9,76.8], MCI 105.5 [97.3,124.1]; YN vs. ON p=0.44; ON vs. MCI p<0.001). In a validation cohort, CSF SNAP25 was similar in cognitively normal controls vs early MCI (median [IQR] ON 70.7 [60.3,86.8] EMCI 75.3 [60.3,92.6]; p=0.55). However, levels were elevated in late MCI and were higher than even in those with AD dementia (median [IQR] LMCI 150.5 [115.4,193.6] AD 97.8 [89.0,122.3]; LMCI vs. ON p<0.001; LMCI vs. AD p=0.014). CSF SNAP25 correlated better with CSF ptau181 across both cohorts (r=0.85, p <0.001) as compared to CSF amyloid ratio, abeta42/abeta40 (r=‐0.38, p <0.001). A CSF SNAP25 cut‐off of 121.85 pg/ml provided a sensitivity of 75% (95% CI: 51‐90%) and a specificity of 96% (95% CI: 81‐99%) in differentiating early and late MCI.ConclusionThe turnover of presynaptic SNAP25 as measured in CSF is relatively stable across the lifespan in healthy individuals. CSF SNAP25 levels correlate better with tau pathology rather than amyloid suggesting that increased SNAP25 turnover in CSF is not present the early preclinical phase of AD. Levels of CSF SNAP25 are elevated in the late MCI phase as compared to those in early MCI or dementia.