Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer's disease

Astrocytes play a critical role in brain homeostasis and normal functions but their changes along the spatiotemporal progression of Alzheimer's disease (AD) neuropathology remain largely unknown. Here we performed single-nucleus RNA-sequencing on brain regions along the stereotypical progression of AD pathology from donors ranging the entire normal aging-AD continuum comprising 628,943 astrocyte nuclei from 32 donors across 5 brain regions. We discovered temporal gene-expression-trajectories with gene sets differentially activated at various disease stages. Surprisingly, a gene set enriched in proteostasis and energy metabolism, was upregulated in late-stage but unexpectedly returned to baseline levels in end-stage, suggesting exhaustion of response in "burnt-out" astrocytes. The spatial gene-expression-trajectories revealed that astrocytic genes of tripartite synapses are dysregulated in parallel to the stereotypical progression of tangle pathology across regions. We identified astrocyte heterogeneity across brain regions with a continuum from homeostatic to reactive cells through "intermediate" transitional states. These findings suggest complex astrocytic dysfunction in AD neurodegeneration. ### Competing Interest Statement MEW, AW, KZ, FL, GL, TP, JT, AA, TK, RVT, KB, and EHK are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. BTH has a family member who works at Novartis and owns stock in Novartis, serves on the scientific advisory board of Dewpoint and owns stock, serves on a scientific advisory board or is a consultant for Abbvie, Arvinas, Biogen, Novartis, Cell Signaling Technologies, Sangamo, Sanofi, Takeda, US Department of Justice, and Vigil, and his laboratory is supported by sponsored research agreements with Abbvie, F Prime, and Spark as well as research grants from the NIH (PI), the Cure Alzheimer's Fund (PI), the Tau Consortium (PI), The JPB Foundation (PI), the Alzheimer's Association (mentor), and BrightFocus (mentor).