Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition. Nevertheless, this is the most common dementia after Alzheimer disease (AD) in people younger than 65. The most common pathology associated with dementia in FTD is frontotemporal lobar degeneration (FTLD) due to transactive DNA binding protein of ~43 kD (TDP-43), known as FTLD-TDP. FTLD-TDP pathology is also found in ALS and many other conditions associated with aging including Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). Since our discovery of FTLD-TDP in human disease, major gaps in understanding the pathophysiology and spread of human FTLD-TDP pathology and poor antemortem identification of patients with dementia due to TDP-43 pathology have been immense impediments to developing disease-modifying treatments that aim to target this pathology. In this Program Project Grant (PPG), we propose a novel and unique multidisciplinary research program focused on elucidating pathophysiologic mechanisms of human TDP-43 pathology, identifying FTLD-TDP in vivo in dementia and aging, and understanding the clinical consequences of FTLD-TDP pathology. With greater insight into mechanisms of disease associated with TDP- 43 pathology, translational work will fill major gaps in in vivo diagnosis and prognosis. Administrative Core A is designed to provide administrative support including regulatory and financial management for the scientific work proposed by the five Projects and four Cores of this PPG, coordinate the interaction of these multidisciplinary Projects and Cores through an Internal Executive Committee (IEC) consisting of the Project Leaders (PLs) and Core Leaders (CLs), ensure that annual goals are maintained with guidance from an External Advisory Committee (EAC) of experts together with NIA staff, disseminate and coordinate our work with other scientists at and beyond University of Pennsylvania (Penn), engage young scientists in research investigating TDP-43, and disseminate knowledge to patients and families who have FTLD-TDP-related disorders. We achieve these goals through seven Specific Aims.