A study by researchers at the University of Gothenburg utilized isotope-encoded spatial biology (iSILK) to investigate the relationship between amyloid plaque age and cognitive decline in Alzheimer’s disease (AD). The findings revealed that older, more structurally compact plaques are associated with greater synaptic loss and neurotoxicity compared to newly formed deposits, independent of a patient’s age or disease stage. This challenges the traditional view that plaque burden alone correlates with cognitive impairment, emphasizing the importance of plaque maturation in disease progression. The study employed AppNL-F knock-in mice, which develop amyloid pathology resembling human AD. Mice were fed a nitrogen-15 isotope-enriched diet to "timestamp" plaque formation, allowing researchers to track deposition patterns over time. Multi-modal imaging, including mass spectrometry and hyperspectral microscopy, demonstrated that plaques grow from the inside out, with older central cores exhibiting greater structural maturity and neurotoxicity. Synaptic loss was most pronounced near mature plaques, supported by immunohistochemical and spatial transcriptomic data showing downregulation of synaptic genes and upregulation of immune-related pathways in plaque-adjacent regions. Clinically, these findings suggest that amyloid plaque age and structural maturity—rather than total burden—may better predict cognitive decline. Current amyloid PET imaging lacks the resolution to assess plaque age, potentially explaining why some patients with high plaque loads remain cognitively intact while others with lower burdens decline rapidly. Future research should explore tau pathology, refine single-cell spatial transcriptomics, and validate these findings in human tissue. The study underscores the need for advanced imaging techniques that assess plaque characteristics beyond mere quantity, which could improve AD diagnostics and therapeutic monitoring.