Review Highlights Microglial Lipid Metabolism as Key Target for Perioperative Neurocognitive Risk

A newly published review outlines how age-related impairments in microglial lipid handling and organelle crosstalk prime the aging brain for perioperative neurocognitive disorders, highlighting TREM2 and FADS1 as high-priority therapeutic targets.

Researchers from Zhejiang University published a mechanism-focused narrative review examining how impaired microglial lipid handling serves as an interface between brain aging and perioperative cognitive vulnerability.

The authors structured the evidence along three principal axes: lipid sensing, uptake, and storage; lipid catabolism and polyunsaturated fatty acid (PUFA) remodeling; and lipid-redox injury leading to downstream synaptic and circuit dysfunction.

The strongest perioperative evidence was identified for age-associated microglial activation, TREM2-mediated immune modulation, FADS1-dependent lipid remodeling, and neuronal or astrocytic ferroptosis-related injury.

Broad neuroinflammatory models have historically failed to fully explain age-related susceptibility or failed cognitive recovery following surgery in older patients.

By delineating specific lipid-metabolic pathways, the review establishes a testable framework that separates clinically and preclinically validated perioperative mechanisms from general aging or ischemic processes.

Mechanisms involving microglial lipid catabolism by multifunctional enzyme type 2 (MFE-2), APOE4-associated triglyceride metabolism, and TREM2-dependent lipid-droplet regulation remain supported primarily by non-perioperative neurodegeneration models, indicating where further translational research is required.

This framework provides biotechnology companies focused on age-related cognitive decline with specific metabolic and receptor targets, such as TREM2 and FADS1, for drug development.

Highlighting ferroptosis-related injury emphasizes the potential market for lipid-redox protective therapeutics and antioxidants targeted to the central nervous system during the perioperative window.

Preclinical and clinical studies evaluating whether interventions targeting microglial TREM2 activation or FADS1-dependent lipid remodeling can prevent or mitigate post-surgical cognitive decline in older cohorts.