The goal of the research in the Albers lab is to elucidate the pathogenic actions and physiological functions of genes and mechanisms that cause neurodegenerative disease and develop novel diagnostic and therapeutic approaches. Our principal hypothesis is that these genes and mechanisms conspire with the biology of aging to confer vulnerability to neurons by disrupting the integrity of neurons and neural circuits. The questions addressed by these studies intersect with fundamental questions in neuroscience, including how are connections in the nervous system modified by experience, how is the genome in neurons altered by aging, and how is the communication across these connections contribute to the propagation of neuronal death within neural circuits. We address these issues in the peripheral olfactory neural circuit of the mouse and human, a circuit that is evolutionarily conserved. The mouse circuit is genetically tractable, and the human circuit is vulnerable to neurodegenerative disease. We combine novel mouse models that express pathogenic and normal isoforms of the human amyloid precursor protein solely in a subset of olfactory neurons with multiphoton in vivo imaging, fluorescence activated cell sorting, deep sequencing, and other basic techniques of investigation. Examination of these lines has revealed a novel mechanism of propagated neurodegeneration within a neural circuit that is amenable to FDA approved drugs. We have recapitulated this mechanism in vitro and have applied systems approaches to elucidate the mechanisms and screen for drugs. In addition, we have conducted a CRISPR-Cas9 genome-wide screen to identify new targets that provide surprising insights to Alzheimer's and ALS pathogenesis. These laboratory approaches are complemented by parallel informatics, in silico drug trial in electronic health records, and clinical research with the ultimate goal of personalized clinical trials in patients with clear evidence of pathogenic mechanisms.