Changes in serum β-synuclein precede blood biomarkers of Alzheimer pathology in Down syndrome

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.

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).

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).

These findings consolidate β-synuclein as an early blood-based biomarker of synaptic dysfunction and provide insight into early AD-related mechanisms.