Spatiotemporal Resolution for Neurodegenerative Diseases: Linking Proteinopathy, Cellular Vulnerability, and Disease Trajectories.

Abstract

Neurodegenerative diseases (NDs) are a heterogeneous group of disorders characterized by selective and progressive degeneration of specific neuronal populations, often accompanied by glial dysfunction. Despite extensive investigation, proposed pathogenic models remain insufficient to fully explain selective vulnerability and stereotyped spatiotemporal patterns of neurodegeneration across diseases. Spatial omics technologies preserve anatomical context and enable interrogation of cell-type composition, molecular heterogeneity, and intercellular interactions within neural systems. In this review, we synthesize current concepts and technological advances in spatial omics and discuss how these approaches are reshaping our understanding of NDs. Spatial omics provides an integrative framework for linking pathological protein aggregation with selective cellular vulnerability, microenvironment-dependent interactions, and disease progression across molecular, cellular, and anatomical scales. We highlight emerging insights into pathology-associated gene modules, neuron-glia interactions, and mechanisms underlying regional vulnerability. Finally, we discuss multimodal data integration and future directions for translating spatially resolved molecular maps into mechanistic understanding.