Approach motivation sharpens shared neural processing: dissociable beta and alpha synchrony.

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder affecting approximately 44 million people worldwide [–]. Disease progression varies among individuals, and clinical symptoms may develop over decades. AD is the leading cause of dementia, which is characterized by progressive impairment of memory and cognitive function []. As dementia advances, patients gradually lose independence in daily activities and require continuous care. Consequently, AD imposes a heavy burden on individuals and society [–]. While several mechanisms, including impaired mitophagy and cellular senescence, have been implicated in age-related neurodegeneration [–], genomic instability caused by excessive DNA damage or defective DNA repair is increasingly recognized as an important contributor to neurodegenerative disorders [, ]. In AD, oxidative stress, mitochondrial dysfunction, and neuronal injury may promote the accumulation of nuclear or mitochondrial DNA fragments outside their normal compartments []. These DNA species can be recognized by DNA sensors, a subset of pattern-recognition receptors that detect microbial or self-DNA and activate innate immune signaling []. In the context of neurodegeneration, inappropriate sensing of self-DNA may amplify inflammatory responses rather than provide host protection. This review focuses on the role of DNA sensors in AD progression and therapeutic modulation. We first briefly summarize the innate immune context of AD, particularly the bidirectional role of microglia in amyloid-β (Aβ) clearance and inflammatory injury. We then discuss major DNA-sensing pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), Z-DNA-binding protein 1 (ZBP1), interferon gamma-inducible protein 16 (IFI16), and DEAD-box helicase 41 (DDX41), and evaluate their links with type I interferon (IFN-I)-related pathology, tau-related inflammation, microglial activation, and synaptic dysfunction. Because microglial activation and neuroinflammation provide the cellular context in which many DNA-sensing pathways operate, the following section briefly summarizes innate immune responses in AD before focusing on individual DNA sensors.