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To address this, we developed a deep learning framework that integrates bulk histone modification data with single-cell open chromatin profiles to evaluate the regulatory potential of noncoding variants. This model identified 1457 silencer and 3084 enhancer AD-associated variants in dorsolateral prefrontal cortex, classifying gene loci as silencer-only (SL), enhancer-only (EN), or dual-function (ENSL). EN loci predominantly regulate housekeeping metabolic processes, SL loci (including\n                    <jats:italic toggle=\"yes\">MS4A6A<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">HLA-D<\/jats:italic>\n                    ) are linked to immune responses (with ~70% substantially up-regulated in AD microglia), while ENSL loci are implicated in neurofibrillary tangle assembly. Our model achieves robust power in assessing the impact of regulatory variants, with ~70% directional concordance with experimental results. It identified rs636317 as a putative causal silencer variant, distinguishing it from a neutral variant located 11 base pairs away. This study advances understanding of the AD-associated regulatory landscape and provides a framework for ascertaining noncoding variants in AD pathogenesis.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adz3323","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:58:47Z","timestamp":1770836327000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Silencer variants are key drivers of gene up-regulation in Alzheimer\u2019s disease"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2992-3135","authenticated-orcid":true,"given":"Di","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9730-7732","authenticated-orcid":true,"given":"Ivan","family":"Ovcharenko","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ncl.2016.06.009"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01911-3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-179939"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.37765\/ajmc.2022.89236"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.056"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.188"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2024.100555"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm6131"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb5398"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0599-5"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104511"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.040"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107908"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00776-w"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07606-7"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adi5199"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1195-2"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abi8654"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08070-z"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2023.100404"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01533-5"},{"key":"e_1_3_2_25_2","first-page":"gr.280387.28012","article-title":"MPRAbase a Massively Parallel Reporter Assay database","author":"Zhao J.","year":"2025","unstructured":"J. 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