Silencer variants are key drivers of gene upregulation in Alzheimer's disease.

Alzheimer's disease (AD), particularly late-onset AD, stands as the most prevalent neurodegenerative disorder globally. Owing to its substantial heritability, genetic studies have emerged as indispensable for elucidating genes and biological pathways driving AD onset and progression. However, genetic and molecular mechanisms underlying AD remain poorly defined, largely due to the pronounced heterogeneity of AD and the intricate interactions among AD genetic factors. Notably, approximately 90% of AD-associated genetic variants reside in intronic and intergenic regions, yet their functional significance has remained largely uncharacterized. To address this challenge, we developed a deep learning framework combining bulk and single-cell epigenomic data to evaluate the regulatory potential (i.e., silencing and activating strength) of noncoding AD variants in the dorsolateral prefrontal cortex (DLPFCs) and its major cell types. This model identified 1,457 silencer and 3,084 enhancer AD-associated variants in the DLPFC and binned them into silencer variants only (SL), enhancer variants only (EN), or both variant types (ENSL) classes. Each class exerts distinct cellular and molecular influences on AD pathogenesis. EN loci predominantly regulate housekeeping metabolic processes, whereas SL loci (including the genes