21 Jan 2021 As Alzheimer’s tangle pathology progresses, neurodegeneration sweeps through the brain in a stereotypical fashion. But why do some neurons perish early on, while their neighbors persist until the bitter end? A study published January 11 in Nature Neuroscience addressed this question by tracing the gene-expression profiles of neurons in the brains of people who died in the early or late stages of the disease. Among myriad subpopulations of cells, the researchers zeroed in on subsets of excitatory neurons that express the transcription factor RORB as the first to succumb. Initially in the entorhinal cortex, and then later in the outer neocortex, excitatory neurons bearing this particular marker were selectively vulnerable to tau accumulation, and to death. The study, led by Lea Grinberg and Martin Kampmann, both at the University of California, San Francisco, also pegged a type of reactive astrocyte that may shirk its duties of protecting and nourishing neurons. In all, the findings hint at common mechanisms underlying selective vulnerability to AD pathogenesis in different regions of the brain.