Spatial transcriptomics in Alzheimer’s disease: Mapping cellular dysregulation in the brain microenvironment

Alzheimer’s disease (AD), a leading cause of dementia, imposes a profound global burden, characterized by amyloid-β plaques, tau tangles, and progressive cognitive decline. Spatial transcriptomics (ST) has emerged as a transformative tool, mapping the brain’s complex microenvironment with unprecedented precision to reveal molecular underpinnings of AD pathology. This review explores ST’s role in dissecting the interactions of neurons, microglia, astrocytes, oligodendrocytes, and the neurovascular unit, uncovering spatially restricted dysregulation in regions like the hippocampus and cortex. By resolving plaque-induced inflammatory genes, synaptic loss markers, and vascular dysfunction, ST illuminates AD’s cellular heterogeneity across early/late stages and genetic/sporadic subtypes, offering a molecular blueprint for precision medicine. Open-access datasets, including GEO and comprehensive brain atlases, have accelerated these discoveries, fostering collaborative research into AD’s microenvironmental dynamics.ST’s clinical promise lies in its ability to inform therapeutic and diagnostic innovations. Biomarkers like microglial TREM2 and endothelial LRP1, identified through ST, guide patient stratification for anti-amyloid therapies and emerging microglial or vascular-targeted interventions, while enabling early detection through subtle entorhinal cortex changes. Despite challenges—resolution limits, data complexity, high costs, and ethical concerns—future directions, including AI-driven analysis, multi-omics integration, and novel platforms like STORM-seq, promise to overcome these hurdles. By bridging basic research and clinical practice, ST holds the potential to redefine AD management, offering hope for earlier diagnostics and personalized therapies to mitigate this devastating disease’s impact.