The most common neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, all display distinct clinical presentations. The basis of these distinct clinical presentations is the enhanced vulnerability of specific neuronal cell types to death or dysfunction in each disease, despite widespread expression of disease-associated genes. The goal of our research group is to elucidate the basis of this enhanced vulnerability in neurodegenerative disease, and we view it as a window for discovering valuable insights into the cell biology of disease-relevant neuronal cell types, while also identifying new therapeutic targets. Our work uses innovative approaches to address these long-standing questions of enhanced vulnerability, including translating ribosome affinity purification (TRAP) and in vivo genome-wide screening in the CNS. Additionally, in recent years we have used single cell sequencing approaches for the study of the CNS, inducing our recent single cell studies of the human cerebrovasculature, Huntington’s disease, and ALD/FTLD.