Plasma SNAP25 is increased in pre-clinical Alzheimer's disease and has prognostic value for cognitive decline and disease progression: a multi-cohort study

Synaptic dysfunction arises early in Alzheimer’s disease (AD) and contributes to cognitive decline. Yet, plasma biomarkers to evaluate synaptic functioning remains underexplored. We developed a novel immunoassay to detect the synaptic marker SNAP25 in plasma, aiming to evaluate the association of plasma SNAP25 with AD progression. Participants who were cognitively unimpaired or had subjective cognitive decline (CU or SCD Aβ+/Aβ-), mild cognitive impairment (MCI Aβ+), and AD dementia were included from multiple cohorts (n=884). Plasma SNAP25 levels were higher in all Aβ+ groups (p<0.01), from the CU/SCD stages onward, and levels increased more steeply over time in SCD Aβ+ than in SCD Aβ- individuals (βtime*amyloid status 0.08±0.02, p<0.001). Among SCD, higher baseline and steeper increases in plasma SNAP25 were associated with cognitive decline (both βtime*SNAP25 –0.02±0.01, p<0.001) and an increased risk of progression to MCI or dementia (HR 1.94 [95%CI 1.42–2.65], p<0.001). Among Aβ-, baseline plasma SNAP25 predicted Aβ status conversion to Aβ+ over four years with AUC 0.71 [0.57–0.85]. In conclusion, plasma SNAP25 emerges as a promising blood-based synaptic biomarker for prognosis and progression in the preclinical AD stages.