Project Summary Mixed neuropathologies are the most common cause of the clinical syndrome of dementia, including Alzheimer's disease (AD), Lewy body dementia (LBD) and frontotemporal dementia (FTD). Exploiting novel constitutive and conditional knockout lines as well as transgenic mouse lines, we now propose a series of genetic approaches designed to uncover key knowledge gaps linking alpha-synuclein (αSyn) and tau biology, pathologies and their relationships to synaptic and cognitive function. Leveraging emerging evidence from independent groups including our own, we will test the central hypothesis that αSyn expression, independent of αSyn pathology, may impact the biology tau and/or tau-dependent pathology. In the light of novel findings reported in the preliminary results, we will i) test the hypothesis that αSyn regulates human tau selectively, but not mouse tau, ii) test the prediction that constitutive ablation of the SNCA gene encoding αSyn alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy, iii) test the hypothesis that conditional ablation of SNCA in forebrain excitatory neurons alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy, thereby providing a preclinical proof-of-principle that targeting this αSyn/tau coupling might be therapeutically beneficial in the context of FTD and LBD.