Differential influence of synaptic biomarkers on synaptotagmin-1 according to amyloid status: A neural network study in older adults

Synaptic vulnerability is a central feature of brain aging and may precede the clinical manifestations of cognitive decline. Synaptotagmin-1 (SYT1), involved in synaptic vesicle exocytosis, has emerged as a key biomarker of synaptic function. This observational study explored the associations between SYT1 and several synaptic biomarkers (neurogranin, SNAP-25, and GAP-43) in 317 cognitively normal adults, according to amyloid status. Spearman correlations, bivariate linear regressions, and artificial neural network models were used to examine these relationships in an exploratory manner. Distinct association patterns were identified according to amyloid status: in the absence of amyloid pathology, SYT1 showed particularly strong associations with GAP-43, whereas in amyloid-positive individuals, neurogranin exhibited the strongest association with SYT1. These findings suggest that relationships among synaptic biomarkers vary according to the amyloid biological context, without implying causal mechanisms. The use of computational approaches thus enables the description of complex synaptic signatures at the preclinical stages of the Alzheimer's disease continuum.