Genetic and Molecular Mechanisms of Synaptic Plasticity in Perioperative Delirium: From Neuroinflammation to Circuit Dysfunction and Recovery

Perioperative delirium is an acute disturbance of attention and awareness that arises when surgical stress interacts with limited brain reserve. Synaptic dysfunction provides a plausible connection between genetic susceptibility, neuroimmune responses and fluctuating network activity, but the strength of evidence differs substantially across these levels. This narrative review examines human genetic and molecular studies alongside experimental investigations of synaptic plasticity, with emphasis on recent primary research. Large association studies now support an association between APOE ε4 and delirium susceptibility, whereas blood transcriptomics and brain tissue profiling implicate complement regulation, immune responses and glial cell states. Experimental studies identify mechanisms involving complement-dependent synaptic engulfment, astrocytic cholesterol and glucose support, glutamate handling, mitochondrial stress and epigenetic regulation of BDNF–ARC signaling. These findings suggest that reversible changes in synaptic efficacy and slower structural remodeling can coexist, without requiring synapse loss to explain every delirium episode. Human neurogranin, neurofilament and electrophysiological studies also reveal important negative or context-dependent findings. Translation therefore requires separation of preoperative vulnerability from acute disease activity, direct assessment of attention and arousal, and evidence that a molecular intervention improves clinically meaningful outcomes. The phase 2 trial of the APOE mimetic CN-105 illustrates the distinction between mechanistic plausibility and clinical efficacy, as its benefit for delirium prevention remains unproven. A cell-specific, temporally resolved approach is needed to determine which synaptic mechanisms are causal, reversible and therapeutically accessible in human perioperative delirium.