Redefining Language and Neurodegeneration Through PPA：Clinical Phenotypes, Network Vulnerability, and Global Research Directions

Abstract

Primary progressive aphasia (PPA) offers a unique lens into understanding the neural organization of speech and language and the disease mechanisms of neurodegeneration. This article reflects on how the study of PPA―through its three canonical clinical variants：semantic, logopenic, and non-fluent/agrammatic―has transformed our understanding of speech and language networks, clinical-pathological correlations, and disease trajectories and vulnerabilities. Drawing from two decades of multidisciplinary clinical research across Europe, Asia, and the United States, we explored how large-scale PPA studies have revealed the complex brain networks involved in speech and language processing and shown that distinct molecular pathologies exhibit selective affinity towards these networks in variant-specific manners. We also expounded how language typology and neurodevelopmental trajectories critically shape disease manifestations, highlighting the need for linguistically tailored and multidimensional clinical care strategies that incorporate precision diagnosis tools, biomarker-driven diagnostics, speech rehabilitation, and emerging molecular based disease-modifying therapies. This perspective article advocates for ongoing international and cross-linguistic collaborations to refine diagnostic criteria and improve care for individuals with PPA worldwide, regardless of language and neurodevelopmental backgrounds.