Synaptic dysfunction is one of the earliest processes involved in Alzheimer’s disease (AD) and is closely associated with cognitive decline. However, currently available blood biomarkers primarily reflect other pathological processes, such as amyloid and tau pathology, neurodegeneration, or glial activation, while few biomarkers are available to detect early synaptic alterations through a blood sample.
β-synuclein is a protein predominantly located at presynaptic terminals that has emerged as a potential biomarker of synaptic dysfunction and damage in neurodegenerative diseases. However, its behaviour in blood during the earliest stages of AD remains poorly characterised.
This study, published in Alzheimer’s & Dementia, provides new evidence that blood β-synuclein levels increase early across the AD continuum in people with Down syndrome (DS), preceding changes in other established blood biomarkers of the disease.
What was done in this study?
This cross-sectional study analysed serum β-synuclein levels in a cohort of 131 participants, including adults with DS across different clinical stages of AD and cognitively unimpaired euploid controls. β-synuclein was quantified using immunoprecipitation coupled with mass spectrometry, and its relationship with clinical stage and age was investigated. Associations with other blood-based AD biomarkers, cognitive measures, and structural and metabolic neuroimaging markers were also examined.
Main findings
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β-synuclein levels progressively increased across the clinical AD continuum in adults with DS, with alterations already detectable during the asymptomatic stages of the disease
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Increases in β-synuclein were detectable approximately 21 years before the diagnosis of prodromal AD, suggesting that synaptic alterations can be identified in blood decades before the onset of clinical symptoms
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Changes in β-synuclein preceded alterations in other established blood biomarkers of AD, including p-tau217, neurofilament light (NfL), and GFAP, by more than 7 years
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Higher β-synuclein levels were associated with poorer cognitive performance, including measures of episodic memory, as well as with cortical atrophy and cerebral hypometabolism in brain regions vulnerable to AD
Why is this important?
These findings position β-synuclein as a promising early blood-based biomarker of synaptic dysfunction in AD associated with DS, capable of detecting changes decades before the onset of symptoms and earlier than other established blood biomarkers.
The possibility of monitoring synaptic alterations through a blood sample could complement current biomarkers of amyloid and tau pathology, neurodegeneration, and glial activation, providing a more comprehensive picture of the different biological processes occurring during the earliest stages of AD.
Furthermore, blood biomarkers sensitive to such early changes could be particularly relevant for monitoring disease progression and supporting the design and follow-up of future clinical trials in people with DS, including the evaluation of therapeutic interventions initiated before the onset of symptoms.