A systems approach uncovers drivers of the multifocal emergence of an astrocyte state contributing to cognitive decline in Alzheimer's disease

Diverse cellular states have been mapped in Alzheimer's disease (AD) pathology, but their links to cognitive decline and the tissue signals driving their emergence remain unclear. We assembled a unified single-nucleus atlas from 867 diverse brains. Meta-analysis identified new cell-state associations with AD and prioritized a non-canonical reactive SLC38A2highSMTNhighCACNA1Dhigh astrocyte (Ast10) as a key link between neuropathologies and cognitive decline. To identify regulators of Ast10 emergence, we modeled ligand-receptor relationships. Independent datasets and two spatial modalities validated these drivers and revealed Ast10's multifocal distribution throughout the neocortex. Mechanistic validation in mouse and human astrocytes confirmed PLXNB1, JAM2 and SEMA4D as regulators. In cerebrospinal fluid from a SEMA4D-blocking antibody trial, Ast10 markers are pharmacologically modifiable, and their reduction tracks with cognitive stabilization. Ast10 may contribute to cognitive decline through disrupted presynaptic neurotransmitter release and may be a convergence point for AD and other neurodegenerative pathologies, a promising target for enhancing resilience to dementia.