The aim of this study was to evaluate a comprehensive panel of alternative synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) as surrogate markers of early AD-related cognitive decline in non-trisomic cognitively normal controls (n = 20) and a large cohort of adults with DS (n = 80) from across the preclinical and clinical AD continuum, exploring their relationship to cognitive performance. This evidence concerns the gene NLGN2 and Alzheimer disease.