Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and...

Alzheimer disease (AD) pathology affects the transentorhinal/entorhinal region early but whether entorhinal cortex (EC) astrocytes are causal drivers or therapeutic targets remains unresolved. This narrative review evaluates EC astrocytes through an explicit evidence hierarchy. We distinguish: (1) human EC-specific neuropathology, imaging, and transcriptomic findings, (2) human AD astrocyte data lacking EC-cell resolution, (3) mechanistic evidence from animal and cellular models, and (4) translational hypotheses. Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC. We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts. These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling. Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms. EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.