Alpha-Synuclein co-pathology in Alzheimer’s Disease drives tau accumulation

The molecular basis for accelerated cognitive decline seen in Alzheimer’s Disease (AD) cases presenting with cortical alpha-Synuclein (SNCA/⍺-Syn) co-pathology is not well understood. We show that such AD co-pathology brains are characterized by an increased polygenic risk score for Parkinson’s Disease (PD), which is related to an enrichment in the MAPT H1 haplotype as well as risk factors known to increase SNCA transcription. AD + ASYN brains express higher levels of ⍺-Syn and neuronal microtubule-associated protein tau (MAPT), and increasing SNCA expression is sufficient to drive transcription, translation and phosphorylation of tau. In addition, tau is significantly elevated in subjects with a positive cerebrospinal fluid ⍺-Syn seeding aggregation assay. Our results reveal a hitherto unknown link between the pathogenesis of AD and PD whereby tau and ⍺-Syn synergistically drive dementia-related pathology.