CREative

To understand how Alzheimer’s disease reshapes the brain’s regulatory landscape cell type by cell type, I used Claude Science to analyze Droplet Paired-Tag data from 10 donors across the hippocampus and cerebellum. This method measures RNA together with two histone marks in the same nucleus: H3K27ac, associated with active enhancers, and H3K27me3, associated with Polycomb repression. The analysis produced a two-mark cis-regulatory atlas and identified coordinated pathway-level remodeling in specific cell types. The main finding was a region-specific glial chromatin switch in the AD-vulnerable hippocampus. Reactive astrocytes gained H3K27ac at inflammatory programs, including NF-κB, IL-1, and IL-6 signaling, while homeostatic astrocytes lost enhancer activity. At the same time, homeostatic microglia lost H3K27me3, suggesting de-repression or priming before full activation. These results support a testable model in which AD glial reactivity is an ordered, chromatin-encoded state transition, potentially initiated by local pathology. By integrating chromatin change, CRE–gene links, RNA expression, and AD genetics, the analysis also prioritized candidate targets, led by SORL1 in hippocampal microglia, and motivated a three-aim proposal to test where the switch occurs, what drives it, and why it matters.