{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T12:43:09Z","timestamp":1770813789494,"version":"3.50.1"},"reference-count":59,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"APPAC, Centro Universitario de Ciencias de la Salud"},{"name":"SECIHTI-M\u00e9xico Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) exhibits marked genetic heterogeneity between early-onset (EOAD) and late-onset (LOAD) forms. EOAD is typically associated with highly penetrant variants, whereas LOAD follows a polygenic architecture dominated by non-coding variation. However, the tissue-specific regulatory consequences of these variants remain insufficiently characterized. This study aimed to compare the regulatory genomic architectures underlying EOAD and LOAD using a multi-tissue integrative approach. Methods: GWAS-associated variants for EOAD and LOAD were retrieved from the GWAS Catalog using a relaxed significance threshold (p &lt; 1 \u00d7 10\u22125). Variants were functionally annotated and integrated with GTEx v8 eQTL data across 13 neurologically relevant tissues and peripheral blood. Regulatory effects were evaluated using eQTL slope estimates. Basal gene expression patterns were assessed using GTEx RNA-seq data, and protein\u2013protein interaction and functional enrichment analyses were performed using the STRING database. Results: A total of 287 variants were analyzed (32 EOAD, 255 LOAD), with minimal overlap. EOAD exhibited a highly focal regulatory profile, identifying GSE1 as the sole eQTL-regulated gene, restricted to the dorsolateral prefrontal cortex (BA9). In contrast, LOAD displayed a broad multi-tissue regulatory architecture involving APH1B, APOE, CEP63, and HAVCR2, with heterogeneous tissue-specific effects. LOAD-regulated genes converged on pathways related to \u03b3-secretase activity, amyloid precursor protein processing, and Notch signaling, whereas GSE1-associated interactions were enriched for chromatin organization and epigenetic repression. Conclusions: EOAD and LOAD exhibit distinct regulatory genomic architectures, with EOAD characterized by focal, region-specific regulation and LOAD by widespread, tissue-dependent effects, highlighting stage-specific molecular mechanisms contributing to AD heterogeneity.<\/jats:p>","DOI":"10.3390\/genes17020186","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:48:08Z","timestamp":1770025688000},"page":"186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Regulatory Genomic Architectures Distinguish Early-Onset from Late-Onset Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-3089","authenticated-orcid":false,"given":"Iliannis Yisel","family":"Roa-Bruz\u00f3n","sequence":"first","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"},{"name":"Instituto de Investigaci\u00f3n en Ciencias Biom\u00e9dicas, Centro Universitario de Ciencias de la Salud, Departamento de Cl\u00ednicas M\u00e9dicas, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celeste Patricia","family":"Gazc\u00f3n-Rivas","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"},{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Neurociencias Translacionales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9788-1106","authenticated-orcid":false,"given":"Asbiel Felipe","family":"Garibaldi-R\u00edos","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"},{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9443-7905","authenticated-orcid":false,"given":"Luis F\u00e9lix","family":"Duany-Almira","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"},{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Neurociencias Translacionales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-1693","authenticated-orcid":false,"given":"Martha Patricia","family":"Gallegos-Arreola","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0836-4186","authenticated-orcid":false,"given":"Claudia Azucena","family":"Palafox-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Ciencias Biom\u00e9dicas, Centro Universitario de Ciencias de la Salud, Departamento de Cl\u00ednicas M\u00e9dicas, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-2514","authenticated-orcid":false,"given":"Daniel","family":"Ortu\u00f1o-Sahag\u00fan","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Neurociencias Translacionales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Eduardo","family":"Figuera","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel Alejandro","family":"Rico-M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"},{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-022X","authenticated-orcid":false,"given":"Yeminia","family":"Valle","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Neurociencias Translacionales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jal, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(2024). 2024 Alzheimer\u2019s disease facts and figures. Alzheimers Dement. J. Alzheimers Assoc., 20, 3708\u20133821.","DOI":"10.1002\/alz.13809"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer Disease: An Update on Pathobiology and Treatment Strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial","volume":"330","author":"Sims","year":"2023","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Valdez-Gaxiola, C.A., Rosales-Leycegui, F., Gaxiola-Rubio, A., Moreno-Ortiz, J.M., and Figuera, L.E. (2024). Early- and Late-Onset Alzheimer\u2019s Disease: Two Sides of the Same Coin?. Diseases, 12.","DOI":"10.3390\/diseases12060110"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1038\/s41380-022-01531-9","article-title":"Dissecting the clinical heterogeneity of early-onset Alzheimer\u2019s disease","volume":"27","author":"Sirkis","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e512","DOI":"10.1212\/NXG.0000000000000512","article-title":"Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference?","volume":"6","author":"Reitz","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1038\/s41380-021-01249-0","article-title":"The Amyloid-\u03b2 Pathway in Alzheimer\u2019s Disease","volume":"26","author":"Hampel","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1177\/0891988710383571","article-title":"Genetics of Alzheimer Disease","volume":"23","author":"Bekris","year":"2010","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1038\/s41588-022-01208-7","article-title":"Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer\u2019s disease","volume":"54","author":"Holstege","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/s41398-021-01677-0","article-title":"Genetically regulated expression in late-onset Alzheimer\u2019s disease implicates risk genes within known and novel loci","volume":"11","author":"Chen","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"GTEx Consortium (2020). The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/s41597-020-00642-8","article-title":"Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions","volume":"7","author":"Sieberts","year":"2020","journal-title":"Sci. Data"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/ng.2802","article-title":"Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer\u2019s disease","volume":"45","author":"Lambert","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"751","DOI":"10.3233\/JAD-2011-101932","article-title":"Replication of BIN1 association with Alzheimer\u2019s disease and evaluation of genetic interactions","volume":"24","author":"Carrasquillo","year":"2011","journal-title":"J. Alzheimers Dis. JAD"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/tpj.2009.69","article-title":"A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer\u2019s disease","volume":"10","author":"Roses","year":"2010","journal-title":"Pharmacogenom. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.biopsych.2014.05.006","article-title":"Alzheimer\u2019s disease risk genes and mechanisms of disease pathogenesis","volume":"77","author":"Karch","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Xu, J., Duan, J., Cai, Z., Arai, C., Di, C., Venters, C.C., Xu, J., Jones, M., So, B.R., and Dreyfuss, G. (2024). TOMM40-APOE chimera linking Alzheimer\u2019s highest risk genes: A new pathway for mitochondria regulation and APOE4 pathogenesis. bioRxiv.","DOI":"10.1101\/2024.10.09.617477"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/hmg\/ddg007","article-title":"Results of a high-resolution genome screen of 437 Alzheimer\u2019s disease families","volume":"12","author":"Blacker","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s00401-020-02249-0","article-title":"A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer\u2019s disease","volume":"141","author":"Portelius","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s13311-022-01185-z","article-title":"Heterogeneity in Alzheimer\u2019s Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials","volume":"19","author":"Duara","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kolahchi, Z., Henkel, N., Eladawi, M.A., Villarreal, E.C., Kandimalla, P., Lundh, A., McCullumsmith, R.E., and Cuevas, E. (2024). Sex and Gender Differences in Alzheimer\u2019s Disease: Genetic, Hormonal, and Inflammation Impacts. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158485"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/nature24265","article-title":"Landscape of X chromosome inactivation across human tissues","volume":"550","author":"Tukiainen","year":"2017","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41582-018-0032-9","article-title":"Sex differences in Alzheimer disease\u2014The gateway to precision medicine","volume":"14","author":"Ferretti","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1126\/science.1222794","article-title":"Systematic localization of common disease-associated variation in regulatory DNA","volume":"337","author":"Maurano","year":"2012","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.tig.2021.08.010","article-title":"Uncovering the impact of noncoding variants in neurodegenerative brain diseases","volume":"38","author":"Frydas","year":"2022","journal-title":"Trends Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Andrade-Guerrero, J., Santiago-Balmaseda, A., Jeronimo-Aguilar, P., Vargas-Rodr\u00edguez, I., Cadena-Su\u00e1rez, A.R., S\u00e1nchez-Garibay, C., Pozo-Molina, G., M\u00e9ndez-Catal\u00e1, C.F., Cardenas-Aguayo, M.-D., and Diaz-Cintra, S. (2023). Alzheimer\u2019s Disease: An Updated Overview of Its Genetics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043754"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/s41588-021-00921-z","article-title":"A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer\u2019s disease","volume":"53","author":"Wightman","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13195-020-00611-8","article-title":"An analysis of genetically regulated gene expression across multiple tissues implicates novel gene candidates in Alzheimer\u2019s disease","volume":"12","author":"Gerring","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s13195-021-00919-z","article-title":"Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-\u03b2 deposition in Alzheimer\u2019s disease","volume":"13","author":"Park","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nn.4182","article-title":"Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci","volume":"19","author":"Hannon","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1186\/s12967-025-06739-1","article-title":"Multi-omics analysis for identifying cell-type-specific and bulk-level druggable targets in Alzheimer\u2019s disease","volume":"23","author":"Liu","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1212\/CON.0000000000000700","article-title":"Late-onset Alzheimer Disease","volume":"25","author":"Rabinovici","year":"2019","journal-title":"Contin. Lifelong Learn. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhang, N.K., Zhang, S.K., Zhang, L.I., Tao, H.W., and Zhang, G.W. (2024). The neural basis of neuropsychiatric symptoms in Alzheimer\u2019s disease. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1487875"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Brabec, J.L., Lara, M.K., Tyler, A.L., and Mahoney, J.M. (2023). A multi-network approach to Alzheimer\u2019s Disease gene prioritization complements cis-regulatory prioritization with molecular quantitative trait loci. bioRxiv.","DOI":"10.1101\/2023.05.03.539189"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1038\/s41591-019-0611-3","article-title":"Resistance to autosomal dominant Alzheimer\u2019s in an APOE3-Christchurch homozygote: A case report","volume":"25","author":"Lopera","year":"2019","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1073\/pnas.98.4.1454","article-title":"CoREST is an integral component of the CoREST- human histone deacetylase complex","volume":"98","author":"You","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.cell.2005.03.013","article-title":"REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis","volume":"121","author":"Ballas","year":"2005","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature10849","article-title":"An epigenetic blockade of cognitive functions in the neurodegenerating brain","volume":"483","author":"Rei","year":"2012","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.molcel.2005.08.027","article-title":"Regulation of LSD1 histone demethylase activity by its associated factors","volume":"19","author":"Shi","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9873","DOI":"10.1073\/pnas.96.17.9873","article-title":"CoREST: A functional corepressor required for regulation of neural-specific gene expression","volume":"96","author":"Burger","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1038\/nn.3786","article-title":"Alzheimer\u2019s disease: Early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci","volume":"17","author":"Srivastava","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"Be","year":"2017","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13073-016-0355-3","article-title":"Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer\u2019s disease","volume":"8","author":"Wang","year":"2016","journal-title":"Genome Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","article-title":"Single-cell transcriptomic analysis of Alzheimer\u2019s disease","volume":"570","author":"Mathys","year":"2019","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41398-022-01913-1","article-title":"Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer\u2019s disease-associated genetic variants","volume":"12","author":"He","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41588-024-01685-y","article-title":"Cell subtype-specific effects of genetic variation in the Alzheimer\u2019s disease brain","volume":"56","author":"Fujita","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrm1406","article-title":"Gamma-secretase: Proteasome of the membrane?","volume":"5","author":"Kopan","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/19083","article-title":"A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain","volume":"398","author":"Annaert","year":"1999","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1146\/annurev-pharmtox-010814-124309","article-title":"Learning by failing: Ideas and concepts to tackle \u03b3-secretases in Alzheimer\u2019s disease and beyond","volume":"55","year":"2015","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1212\/WNL.46.1.130","article-title":"The spectrum of behavioral changes in Alzheimer\u2019s disease","volume":"46","author":"Mega","year":"1996","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.mam.2015.05.005","article-title":"Neuropsychiatric symptoms in Alzheimer\u2019s disease: What might be associated brain circuits?","volume":"43\u201344","author":"Rosenberg","year":"2015","journal-title":"Mol. Asp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.jalz.2011.05.2410","article-title":"Neuropsychiatric symptoms in Alzheimer\u2019s disease","volume":"7","author":"Lyketsos","year":"2011","journal-title":"Alzheimers Dement. J. Alzheimers Assoc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.jalz.2015.05.017","article-title":"Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment","volume":"12","author":"Ismail","year":"2016","journal-title":"Alzheimers Dement. J. Alzheimers Assoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.neuron.2009.03.024","article-title":"Neurodegenerative diseases target large-scale human brain networks","volume":"62","author":"Seeley","year":"2009","journal-title":"Neuron"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1440.011","article-title":"The Brain\u2019s Default Network","volume":"1124","author":"Buckner","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nrd4051","article-title":"Validating therapeutic targets through human genetics","volume":"12","author":"Plenge","year":"2013","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/186\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T11:34:23Z","timestamp":1770723263000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,31]]},"references-count":59,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["genes17020186"],"URL":"https:\/\/doi.org\/10.3390\/genes17020186","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,31]]}}}