The potential of erythrocyte α-synuclein to differentiate dementia with Lewy bodies from Parkinson’s and Alzheimer’s diseases

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease (AD). Early differentiation of these disorders is crucial for managing core symptoms; however, existing biomarkers remain insufficient. DLB shares motor and cognitive symptoms with Parkinson's disease (PD), and both are classified as synucleinopathies due to abnormal α-synuclein aggregation. Although α-synuclein is predominantly expressed in the central nervous system, it is also abundant in erythrocytes. Recent studies suggest a potential link between erythrocyte-derived α-synuclein and synucleinopathy pathology. Additionally, we previously reported that both erythrocytes and circulating medium and large extracellular vesicles (m/lEVs) in plasma from healthy subjects contain full-length and C-terminally truncated α-synuclein. In this study, we found that erythrocyte α-synuclein levels were significantly lower in DLB compared to AD, PD and healthy controls. Furthermore, α-synuclein levels in circulating m/lEVs were elevated in patients with neurodegenerative diseases. These findings provide new insights into the role of peripheral α-synuclein and suggest its potential utility as a diagnostic marker for DLB. While further validation is needed, erythrocyte-derived α-synuclein may complement nuclear medicine assessments in distinguishing DLB from other neurodegenerative disorders.