Circular RNAs in Alzheimer’s Disease: Mechanisms, Biomarkers, and EPAC Signalling in Ferroptosis

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and complex pathogenesis, involving amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation, driven by microglial shifts toward pro-inflammatory M1-like states, causing neuronal dysfunction and death, particularly by ferroptosis. Current diagnostic and therapeutic strategies remain limited, highlighting the need for novel molecular regulators. Circular RNAs (circRNAs) are covalently closed non-coding RNAs (ncRNAs), representing promising regulatory molecules and peripheral biomarkers. Evidence suggests that circRNAs regulate AD-related pathways, through microRNA (miRNA) sponging, including modulation of NF-κB/BACE1-dependent (nuclear-factor-kappa-B/beta-site APP-cleaving enzyme 1) amyloidogenic APP (amyloid precursor protein) processing and through disruption of NMDA (N-methyl-D-aspartate) receptor-dependent synaptic signaling, exemplified by circRIMS2-driven UBE2K (ubiquitin-conjugating enzyme E2K)-mediated GluN2B (glutamate ionotropic receptor NMDA type subunit-2B) degradation. Additionally, circRNAs represent promising non-invasive diagnostic biomarkers. Plasma hsa_circRNA_050263 showed high diagnostic accuracy for early-stage AD. CircRNAs may offer a therapeutic strategy for modulating cell-death pathways, particularly ferroptosis. Selectively targeting EPAC2 (exchange protein directly activated by cAMP2) may preserve EPAC2-associated neuroprotection, while limiting EPAC1-associated ferroptosis, although challenges such as blood–brain barrier delivery remain to be addressed. This review summarizes circRNA biogenesis, diagnostic potential, and roles in AD pathogenesis, and limitations and AD models, besides investigating the selective circRNA–EPAC axis.