Project Summary: Alzheimer's disease(AD) is the most prevalent form of dementia, accounting for approximately 60-70% of all dementia cases worldwide. It has been increasingly recognized that NAD+ depletion and elevated activity of the cGAS-STING pathway are implicated not only in normal aging but also in various neurodegenerative conditions, including Alzheimer's disease. NAD+ metabolite plays a pivotal role in maintaining cellular homeostasis and is considered one of the crucial hallmarks of aging and neurodegeneration. NAD+ depletion can trigger mitochondrial dysfunction, inflammation, impaired lysosomal and proteasomal function, compromised adaptive cellular stress responses, and hinder DNA repair mechanisms. Boosting NAD+ levels in animal models of AD has been shown to ameliorate pathological features of AD. Interestingly our recent studies have demonstrated that cGAS-STING activation induces NAD+ depletion in cell culture and mice. Considering this the novel mechanistic link between cGAS-STING signaling and NAD+ depletion, we propose to gain insights into the novel crosstalk between cGAS-STING pathways and NAD+ metabolism in the context of AD pathogenesis.