Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer's disease

Background Aggregated alpha-Synuclein (alpha Syn) is a hallmark pathology in Parkinson's disease but also one of the most common co-pathologies in Alzheimer's disease (AD). Preclinical studies suggest that alpha Syn can exacerbate tau aggregation, implying that alpha Syn co-pathology may specifically contribute to the A beta-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine alpha Syn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether alpha Syn co-pathology accelerates A beta-driven tau accumulation and cognitive decline. Methods In 284 A beta-positive and 308 A beta-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based alpha Syn seed-amplification assay (SAA) to detect in vivo alpha Syn aggregation. CSF p-tau181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 A beta-positive and 135 A beta-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether alpha Syn SAA positivity was linked to stronger A beta-related increases in baseline fluid and PET tau biomarkers, faster A beta-driven tau-PET increase, and more rapid cognitive decline. Results alpha Syn SAA positivity was more common in A beta + vs. A beta- subjects and increased with clinical severity (p < 0.001). Most importantly, alpha Syn positivity was also associated with greater amyloid-associated CSF p-tau181 increases (p = 0.005) and higher tau-PET levels in AD-typical brain regions (p = 0.006). Longitudinal analyses confirmed further that alpha Syn positivity was associated with faster amyloid-related tau accumulation (p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology. Conclusions Our findings suggest that alpha Syn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider alpha Syn in AD research and treatment strategies.