ABSTRACT Primary progressive aphasia (PPA) is a clinico-anatomical syndrome characterized by relatively isolated decline in speech and language abilities. PPA occurs when pathological and molecular changes of frontotemporal lobar degeneration tau (FTLD-tau), FTLD-TDP, or Alzheimer's disease (AD) selectively damage brain network that sustain speech and language functions. Since the beginning of this R01 program in 2004, we evaluated more than 400 PPA participants, collecting clinical and cognitive evaluations, detailed speech and language characterization, structural and functional MRI, and in most cases biomarkers, genetic and pathological data. Results from this unprecedented dataset led to more than 160 peer-reviewed papers, including current international clinical criteria, providing new insights into the clinical care and basic science of PPA individuals. Despite significant progress, crucial questions remain to be resolved. Pharmacological trials for neurodegenerative diseases causing PPA have started, and PPA patients are often excluded due to lack of quantitative, objective clinical outcome tools. Furthermore, recent studies show that non-linguistic symptoms, such as visuospatial and executive difficulties can occur in PPA, causing clinical heterogeneity and diagnostic challenges. Finally, while it is now known that PPA occurs because specific networks are vulnerable to disease, the structural, functional and molecular mechanisms of such vulnerability remain elusive. In this new cycle, we will translate research findings into scalable clinical tools, we will continue to investigate the cognitive and neural basis of PPA symptoms to improve diagnosis and treatment and probe this unique population to inform neuroscience research. We have assembled a strong team of collaborators to conduct an innovative, multidisciplinary project that will leverage cutting-edge technologies, theoretical neuroscience approaches, and innovative scientific methods. Results will advance and simplify differential diagnosis, reliably monitor symptom progression, and improve cognitive and neurobiological models of PPA. In Aim 1, we will apply automated acoustic and linguistic techniques to facilitate diagnosis across PPA variants and track disease progression; in Aim 2, we will investigate the neurocognitive basis of mathematical cognition, socio-emotional semantics and executive control of language to improve understanding of PPA symptoms and differential diagnosis; and in Aim 3, we will study neuroanatomy of PPA networks with MRI technology in vivo, and with histopathological and transcriptomics analyses of post-mortem brain tissue. In this renewal, we will examine a new cohort of 150 PPA patients longitudinally with a hybrid in-person and remote evaluation model. By year 23 of this R01, our cohort will include more than 550 PPA patients. This study will improve clinical care, inform treatment, and advance knowledge of the neural bases of language.