Biomarkers.

Background: Lewy body pathology consisting of aggregated alpha-Synuclein (a-Syn) is the hallmark pathology in Parkinson's disease, yet a-Syn aggregates are also commonly observed post-mortem as a co-pathology in Alzheimer's disease (AD) patients. Preclinical research has shown that a-Syn can amplify Ab-associated tau seeding and aggregation, hence a-Syn co-pathology may contribute to the Ab-induced progression of tau pathology in AD. To address this, we combined a novel CSF-based RT-QuIC seed-amplification assay to determine a-Syn positivity, with PET-neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a-Syn co-pathology accelerates Ab-driven tau accumulation.

Method: In 261 Ab-positive vs. 272 Ab-negative subjects ranging from cognitively normal to dementia we employed amyloid-PET, Flortaucipir tau-PET and a CSF-based a-Syn RT-QuIC assay for in vivo detection of abnormal a-Syn aggregation. A subset of 136 Ab-positive vs. 102 Ab-negative subjects had longitudinal tau-PET across ∼2.5years. Using linear regression, we tested whether a-Syn positivity was linked to stronger Ab-related tau aggregation (i.e. interaction a-Syn x amyloid-PET on tau-PET).

Result: Prevalence of a-Syn positivity rose across increasing clinical severity and was particularly pronounced in Ab+ (i.e. CN/MCI/Dementia=20/23/47%) vs. Ab- subjects (i.e. CN/MCI/Dementia=15/10/29%), suggesting that a-Syn co-pathology is more common in clinically advanced AD (chi-squared-test, p<0.001). When testing the interaction between a-Syn and global amyloid-PET, we found that a-Syn positivity was associated with stronger Ab-related tau deposition (Figure 1A, p<0.001), and faster Ab-related tau accumulation rates (Figure 1B, p=0.010) in typical tau vulnerable brain regions (i.e. temporal meta ROI), adjusting for age and sex. Regional analyses confirmed that higher regional amyloid-PET was associated with stronger temporal-lobe tau deposition (Figure 2A) and faster tau accumulation in downstream regions (Figure 2B) in a-Syn positive individuals. In addition, there was an independent effect of a-Syn positivity on faster temporal lobe tau accumulation rates controlling for age, sex and global amyloid, suggesting that a-Syn may also independently contribute to tau aggregation (Figure 3).

Conclusion: a-Syn co-pathology as detected by CSF seed-amplification assays is more common at clinically advanced AD and related to faster Ab-related tau aggregation. This suggests that a-Syn co-pathology may actively contribute to AD-related tau accumulation and therefore contribute to dementia development.