Here we provide a brief description of our program to improve diagnostic accuracy in cases with phenotypically similar presentations that are due to distinct histopathologic abnormalities. We propose a staged approach to diagnosis, beginning with a screening assessment of specific, quantitative neuropsychological measures, and followed by assessments of imaging and biofluid biomarkers. Our goal is to determine the specific histopathologic abnormalities contributing to an individual's neurodegenerative condition.