General anesthesia is an essential component of modern surgical and diagnostic care. Although it is overall safe in younger and healthy individuals, the situation is markedly different in patients with underlying neurological conditions like Alzheimer´s disease (AD), where perioperative neurological complications are common. However, the underlying mechanisms and tissue-level interaction between AD-related pathology, cerebral energy metabolism, and anesthetic exposure remain incompletely understood. We investigated acute entorhinal cortex slices from wild-type (WT) and AD-like APPPS1 transgenic mice under control conditions and sequentially exposed them to 1% and 3% isoflurane. Depth-resolved oxygen measurements were used to calculate the cerebral metabolic rate of oxygen (CMRO₂), while extracellular potassium dynamics were recorded using ion-sensitive microelectrodes. Glial markers were assessed by immunohistochemistry, and proteomic profiling was integrated with kinetic metabolic modeling. APPPS1 brain slices showed reduced stimulation-induced increases in CMRO₂ compared with WT tissue, indicating diminished metabolic reserve, whereas unstimulated oxygen consumption differed modestly between genotypes. Isoflurane suppressed CMRO₂ in a concentration-dependent manner in both genotypes. Extracellular potassium levels increased with isoflurane, whereas stimulation-induced potassium transients were reduced, with largely preserved clearance dynamics across genotypes. Immunohistochemistry confirmed microglial activation in APPPS1 tissue but revealed no acute isoflurane-induced glial response. Proteomics consequently indicated immune and inflammatory remodeling, whereas metabolic modeling suggested reduced glycolytic capacity under high energetic demand. Thus, APPPS1 entorhinal cortex tissue retains unstimulated metabolic function but exhibits impaired metabolic reserve during neuronal activation.