Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition even though it is the most common cause of dementia after Alzheimer’s disease (AD) in people <65 years old. The most common frontotemporal lobar degeneration (FTLD) pathology associated with FTD is TDP-43 proteinopathy known as FTLD-TDP with the other major class consisting of cases of FTLD-Tau. Moreover, several autosomal dominant gene mutations and disease-associated genetic variants have been associated with FTD. Aside from genetic mutations that are associated with specific subtypes of FTLD, there are no known biomarkers for the vast majority of FTD patients with sporadic disease that can reliably distinguish patients with FTLD-TDP histopathology from those with FTLD-Tau pathology, nor from patients who present with clinical FTD but are atypical variants of pathological AD. The Neuropathology & Genetics Core will work with other cores and projects to improve our understanding of the TDP-related degeneration of multilevel neural networks examined in this Program Project Grant (PPG). This core will perform a comprehensive post- mortem brain autopsy examination to provide a definitive autopsy diagnosis for cases followed in the clinical core B and the neuroimaging core C. We will also perform a comprehensive genetic analysis of cases and controls to identify disease causing and associated genetic changes. Additional activities will including banking of tissues and nucleic acids, providing tissues, data and expertise to other investigators, and conducting RNA expression studies to further the aims of the research projects in the PPG.