PROJECT SUMMARY Identifying new molecular mechanisms of Alzheimer's disease (AD) pathogenesis is urgent. Regulation of RNA processing and translation can play a vital role in AD. Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA surveillance mechanism to degrade error-containing “faulty” transcripts as well as many naturally occurring “normal” transcripts. Multiple lines of evidence support the essential role of NMD in neural development, neural homeostasis, and neural degeneration. More recent studies show that deficits in the overall activity of NMD causally mediate tau-induced neurotoxicity, and the reactivation of NMD in defective neurons is neuroprotective. This supplement application built upon our parent award will systematically investigate the dysregulation of NMD as a risk factor and possible disease mechanism contributing to AD development. Our parent R01 project has revealed the genome-wide landscape of genetic variants associated with NMD regulation (i.e., NMD- QTLs) in the natural population of Genotype-Tissue Expression (GTEx). NMD-QTLs are much more likely to colocalize with disease SNPs, especially those associated with brain diseases. Brain tissues have distinct NMD-QTL signatures, particularly the disease-related NMD-QTLs. Notably, among the 1779 nonredundant AD-associated SNPs reported in the Genome-Wide Association Studies (GWAS) catalog, 111 are NMD-QTLs, further suggesting an essential role of NMD in AD. Guided by promising preliminary data, we hypothesize that systematical analyses of NMD regulation in the brain using public patient data and omics resources will be critical to dissecting novel mechanisms of AD pathology. In this supplement, we will integrate NMD dysregulation as a mechanism to explain AD-associated genetic variants and prioritize causal genes for AD. Successful completion of this project will be the prelude to understanding the role of NMD in AD.