Microglial lipid metabolism in perioperative neurocognitive risk: aging-related priming, organelle crosstalk, and lipid-redox injury.

Perioperative neurocognitive disorders (PND) are clinically important complications in older surgical patients, but broad neuroinflammatory models do not fully explain age-related susceptibility or failed recovery. Aging alters microglial surveillance, phagocytosis, mitochondrial function, lipid handling, and inflammatory thresholds before surgery. This mechanism-focused narrative review, informed by a structured literature search, examines impaired microglial lipid handling as an interface between brain aging and perioperative cognitive vulnerability. Evidence is organized along three axes: lipid sensing, uptake, and storage; lipid catabolism and polyunsaturated fatty acid (PUFA) remodeling; and lipid-redox injury with downstream synaptic and circuit dysfunction. Direct perioperative support is strongest for age-associated microglial activation, immune modulation through triggering receptor expressed on myeloid cells 2 (TREM2), fatty acid desaturase 1 (FADS1)-dependent lipid remodeling, and neuronal or astrocytic ferroptosis-related injury. In contrast, microglial lipid catabolism mediated by multifunctional enzyme type 2 (MFE-2), apolipoprotein E4 (APOE4)-associated triglyceride metabolism, and TREM2-dependent lipid-droplet regulation are supported mainly by aging, neurodegeneration, or ischemic injury studies. Separating clinical and preclinical perioperative findings from nonperioperative mechanisms defines a testable lipid-neuroimmune framework for causal experiments, biomarker development, and mechanism-guided intervention.