Nature Medicine, Published online: 11 June 2026; doi:10.1038/s41591-026-04409-3 We analyzed brains from octogenarians and cognitively resilient centenarians to understand why some individuals with substantial Alzheimer’s disease pathology develop dementia whereas others remain cognitively intact. Spatial transcriptomics revealed gene expression changes in discrete tissue domains surrounding amyloid plaques and tau pathology that distinguish early, clinically silent, disease from later stages ass