This study examined how APOE4 genotype interacts with age-related advanced glycation end product (AGE) accumulation to drive mitochondrial dysfunction, mtDNA cytosolic release, and cGAS-STING-mediated neuroinflammation in aging animal models and primary microglia in vitro.
APOE4 brains showed greater AGE accumulation, increased cytosolic mtDNA release, elevated cGAS expression, phosphorylation of STING/TBK1/IRF3, higher cGAMP and IFN-β levels, and upregulated pro-inflammatory cytokines vs. APOE3 controls; in primary microglia, AGE exposure activated cGAS-STING signaling, which was attenuated by pharmacological RAGE inhibition.
Findings are primarily from animal models and in vitro primary microglia, limiting direct translation to human disease; causal direction of APOE4-AGE interactions is not fully established; no human brain tissue validation is reported.
RAGE inhibition shows potential as a strategy to reduce AGE-driven neuroinflammation in APOE4 carriers, but this remains preclinical. Clinicians should be aware of the APOE4-AGE-cGAS-STING pathway as an emerging mechanism in Alzheimer's-related neuroinflammation.
