Alba Cervantes González, Alejandra O Morcillo-Nieto, Sara Serrano, Bessy Benejam, Laura Videla, Isabel Barroeta, Susana Fernández, Laura Del Hoyo Soriano, Aida S Hernandez, Lucía Maure-Blesa, Lídia Vaqué-Alcázar, Javier Arranz, Íñigo Rodríguez-Baz, Mateus R Aranha, Danna Perlaza, Laia Lidón, Daniel Alcolea, Alexandre Bejanin, María Carmona-Iragui, Juan Fortea, Alberto Lleó, Markus Otto, Patrick Oeckl, Olivia Belbin
β-synuclein levels were elevated in individuals with DS (p < 0.001), preceding symptom onset by two decades and changes in other blood biomarkers (tau phosphorylated at threonine 217, neurofilament light, glial fibrillary acidic protein) by several years. Higher β-synuclein was associated with cortical atrophy (p < 0.001) and hypometabolism (p < 0.001) in AD-vulnerable regions and reduced episodic memory (p < 0.009).
INTRODUCTION: There is a need for early, objective markers of Alzheimer's disease (AD)-related synapse dysfunction in adults with Down syndrome (DS). The presynaptic protein β-synuclein is elevated in the blood of adults with DS. This study evaluates the positioning of these changes relative to changes in pathophysiological blood biomarkers along the AD continuum.
METHODS: We quantified serum β-synuclein using immunoprecipitation-mass spectrometry in a cross-sectional cohort (n = 131) spanning the AD continuum in adults with DS (n = 88) and cognitively unimpaired euploid controls (n = 43).
RESULTS: β-synuclein levels were elevated in individuals with DS (p < 0.001), preceding symptom onset by two decades and changes in other blood biomarkers (tau phosphorylated at threonine 217, neurofilament light, glial fibrillary acidic protein) by several years. Higher β-synuclein was associated with cortical atrophy (p < 0.001) and hypometabolism (p < 0.001) in AD-vulnerable regions and reduced episodic memory (p < 0.009).
DISCUSSION: These findings consolidate β-synuclein as an early blood-based biomarker of synaptic dysfunction and provide insight into early AD-related mechanisms.