Decades of molecular research have resulted in the identification of many molecular mechanisms underlying Alzheimer’s disease (AD), yet no efficacious treatments are available. The progressive, neurodegenerative processes that underlie the key symptom of impaired cognition are ultimately fatal, however a link between molecular dysfunction and cognitive decline remains elusive. To date, technologies for studying AD have had either molecular specificity or brain-wide spatial resolution, but have been unable to integrate multiple layers of observation without prohibitive expense. In this talk, I will describe our efforts to map neurodegenerative-like molecular pathology in whole mouse brain using novel large-tissue processing techniques. I will present preliminary data to show the power of these tools in Alzheimer’s research at the brain-wide and microcircuit scales, and suggest the conclusions we can draw from this type of information. From our data and others, it is clear that emerging technologies for brain-wide investigation will improve experimental resolve, leading to a more nuanced understanding of the disease and its multifaceted etiology.