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Published on: April 18, 2025
Stage-Dependent β-Synuclein Links MRI and Cognitive Decline in Alzheimer's Disease
Ulaş Ay1,2, Merve Alaylioglu3, Erdi Sahin4
1Neuroimaging Unit, Hulusi Behçet Life Sciences Research Laboratory, Istanbul University, Istanbul, Turkey.
Objective:
Synaptic degeneration drives cognitive decline in Alzheimer's disease (AD), but synaptic biomarkers are scarce. Brain-enriched β-synuclein emerged as a synaptic damage marker. We investigated its diagnostic, prognostic, and structural correlates across the AD continuum.
Methods:
In a tertiary-center cohort (n = 306), CSF β-synuclein was measured. Cognitively unimpaired (CU), AD-MCI, AD dementia (ADD), and non-AD (FTD, PD, DLB, others) groups were included. ANCOVA compared groups (age/sex adjusted); ROC assessed diagnostic performance. Multivariable regression examined 2-year MMSE decline associations. Voxel-wise interaction models evaluated β-synuclein-gray matter volume (GMV) relationships.
Results:
CSF β-synuclein differed across groups (p < 0.001), with highest levels observed in AD-MCI and lower levels in ADD. AD-MCI levels exceeded CU/ADD. AD-MCI versus CU AUC was 0.874. Baseline β-synuclein predicted greater MMSE decline in AD-MCI (β = 0.72, p < 0.001) and ADD (β = 0.47, p = 0.017). Voxel-wise analyses revealed stage-dependent β-synuclein-GMV reversals in precentral and temporoparietal regions.
Conclusion:
CSF β-synuclein shows a stage-dependent pattern across the AD continuum, predicts cognitive decline, and dynamic structural coupling. It supports β-synuclein as a relevant synaptic biomarker in AD.
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