APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.

Advanced glycation end products (AGEs) accumulate with aging and have been implicated in neurodegeneration, yet their relationship with the APOE4 genotype and downstream inflammatory signaling remains poorly understood. Here, we show that APOE4 is associated with greater age-dependent AGE accumulation and APOE glycation in the aging brain compared with APOE3 in animal models. These changes are accompanied by mitochondrial dysfunction and increased release of mitochondrial DNA (mtDNA) into the cytosol, providing a potential trigger for innate immune activation. Consistent with enhanced innate immune signaling, APOE4 brains exhibit increased cGAS expression and phosphorylation of STING, TBK1, and IRF3, together with elevated type I interferon and pro-inflammatory responses. This activation is particularly prominent in microglia, as demonstrated by increased cGAS-DNA interactions and greater colocalization of cGAS signaling with Iba1-positive cells. APOE4 mice further display increased levels of cGAMP and IFN-β, as well as enhanced expression of pro-inflammatory cytokines and interferon-stimulated genes. Mechanistically, exposure of primary microglia to AGEs induces cytosolic mtDNA release and activates cGAS-STING signaling, whereas pharmacological inhibition of the receptor for advanced glycation end products (RAGE) attenuates these responses. Together, these findings identify an association between the APOE4-AGE axis, mitochondrial dysfunction, mtDNA release, and enhanced cGAS-STING-related inflammatory signaling in the aging brain, while the in vitro studies support a functional contribution of AGE-RAGE signaling to these responses in primary microglia.