Project Summary Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) are characterized by the deposition of pathological proteins, such as pathological tau in AD and coritcobasal degeneration (CBD), among others, and pathological a-synuclein (a-syn) in Lewy body dementia (LBD). Transmission of pathological proteins along the neuronal network is believed to be a key mechanism for disease progression. However, the underlying molecular mechanisms that modulate this transmission process remain largely unknown. For one, it is well documented that the conformational diversity of a-syn and tau contribute to disease heterogeneity, but it is unclear how conformer type influences the progression of pathology. Further, the mediation of the disease process by gene expression is incompletely understood, particularly in the context of network transmission. Understanding these molecular mechanisms will provide critical insights into the selective vulnerability of different brain regions to pathological protein transmission and identify new targets for drug development. Here, we propose to identify candidate genes that are responsible for this selective regional vulnerability to distinct pathological ɑ-Syn and tau conformations using mathematical modeling, thereby providing a heretofore inaccessible, mechanistic understanding of the heterogeneity of AD/ADRD. We will combine our computational approach with new in vivo mouse synucleinopathy and tauopathy datasets as well as a high-throughput in vitro screening platform for the functional validation of genes. The focus on mouse proteinopathy is motivated by the long track record of success in using these models as proxies for human disease and the high degree of experimental control they afford. Our approach is novel both in terms of mathematical modeling and the experimental systems explored. In the first phase (R21) of our proposal, we will quantify the a-syn pathology induced by injecting 2 different conformers: PFF and GCI. We will then apply a novel mathematical model, NexIS2, which explains the accumulation and transmission of pathology over time in terms of both gene-independent and gene-mediated processes, allowing us to identify in silico candidate genes that could be key mediators of disease progression. These genes will be functionally validated with high-throughput in vitro screening of induced pathology in primary neuron culture. The best genes will then be fed back into NexIS2 to create a comprehensive model of network transmission for each conformer. In the second phase (R33), we will apply this established pipeline to identify the key gene mediators of transmission for a third a-syn conformer (LB a-syn) and 2 distinct tau conformers (AD- tau and CBD-tau). We will also examine the effect of amyloid on tauopathy progression in a joint mouse model using NexIS2. Our approach could become a computational test bed for future hypothesis generation and testing, and should have broader app...