Association of alpha-synuclein co-pathology with beta-amyloid and phosphorylated tau levels in Alzheimer’s disease

Misfolded α-synuclein (α-syn) aggregates can be present in the cerebrospinal fluid (CSF) of individuals with Alzheimer’s disease (AD), even in the absence of clinical signs of synucleinopathy. This co-pathology may influence AD progression at the molecular level. Detection of α-synuclein aggregates using seed amplification assay (SAA) enables stratification of AD patients beyond classical biomarkers included in the AT(N) framework. The AT(N) framework allows biological classification of AD based on its core pathological processes: β-amyloid aggregation (A), tau accumulation and hyperphosphorylation (T), and non-specific neurodegeneration (N). This study aimed to explore whether α-syn co-pathology, detected by SAA, is associated with altered concentrations and longitudinal trajectories of CSF β-amyloid 42 (Aβ42) and phosphorylated tau 181 (p-tau181) in the biomarker-defined AD group. Data from A+T+ participants (N = 609) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analysed, using Roche Elecsys electrochemiluminescence immunoassay (ECLIA) and SAA results. Substantial discrepancies between clinical diagnosis and AT profiles were observed. Twenty-nine percent of A+T+ participants were α-synpositive (S+), indicating a high prevalence of α-syn co-pathology in biologically defined AD. Cross-sectional comparisons revealed that S+ individuals had lower baseline Aβ42 concentrations compared to α-synnegative (S−) participants. Linear mixed-effects models (LMEMs) showed a significantly steeper decline in Aβ42 over time in the S+ group, supporting the hypothesis that misfolded α-syn aggregation accelerates amyloid aggregation. However, p-tau181 levels increased more slowly in S+ than in S− individuals, contrary to expectations. These associations remained significant after adjustment for age, sex, diagnosis, and APOE-ε4 genotype. These findings suggest that α-syn co-pathology may affect AD progression through its interaction with Aβ42 and support its integration into biomarker-based classification frameworks.