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These therapies have added to the traditional symptomatic treatments and to the drugs for treating Alzheimer disease in the general population repurposed for Down syndrome. Defining next\u2010generation therapeutics will involve biomarker\u2010based therapeutic decision\u2010making, and preventive and multimodal interventions. However, translation of specific findings into effective therapeutic strategies has been disappointingly slow and has failed in many cases at the clinical level, leading to reduced credibility of mouse studies. This is aggravated by a tendency to favour large\u2010magnitude effects and highly significant findings, leading to high expectations but also to a biased view of the complex pathophysiology of Down syndrome. Here, we review some of the most recent and promising strategies for ameliorating the cognitive state of individuals with Down syndrome. We studied the landscape of preclinical and clinical studies and conducted a thorough literature search on PubMed and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> for articles published between June 2012 and August 2022 on therapies for ameliorating cognitive function in individuals with Down syndrome. We critically assess current therapeutic approaches, why therapies fail in clinical trials in Down syndrome, and what could be the path forward. We discuss some intrinsic difficulties for translational research, and the need for a framework that improves the detection of drug efficacy to avoid discarding compounds too early from the companies\u2019 pipelines.<\/jats:p>","DOI":"10.1111\/dmcn.15517","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T17:34:56Z","timestamp":1674581696000},"page":"870-884","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["State\u2010of\u2010the\u2010art therapy for Down syndrome"],"prefix":"10.1111","volume":"65","author":[{"given":"Nicola","family":"Lorenzon","sequence":"first","affiliation":[{"name":"Centre for Genomic Regulation The Barcelona Institute of Science and Technology  Barcelona Spain"},{"name":"Universitat Pompeu Fabra  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanluis","family":"Musoles\u2010Lle\u00f3","sequence":"additional","affiliation":[{"name":"Centre for Genomic Regulation The Barcelona Institute of Science and Technology  Barcelona Spain"},{"name":"Universitat Pompeu Fabra  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Turrisi","sequence":"additional","affiliation":[{"name":"Centre for Genomic Regulation The Barcelona Institute of Science and Technology  Barcelona Spain"},{"name":"Universitat Pompeu Fabra  Barcelona Spain"},{"name":"Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program Hospital del Mar Medical Research Institute  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gomis\u2010Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program Hospital del Mar Medical Research Institute  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"De\u00a0La\u00a0Torre","sequence":"additional","affiliation":[{"name":"Universitat Pompeu Fabra  Barcelona Spain"},{"name":"Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program Hospital del Mar Medical Research Institute  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y la Nutrici\u00f3n Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-6865","authenticated-orcid":false,"given":"Mara","family":"Dierssen","sequence":"additional","affiliation":[{"name":"Centre for Genomic Regulation The Barcelona Institute of Science and Technology  Barcelona Spain"},{"name":"Universitat Pompeu Fabra  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3314"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70112-5"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00245-3"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00670"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.877711"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2018.10.006"},{"key":"e_1_2_11_8_1","first-page":"371","article-title":"Combination of Genetics and Nanotechnology for Down Syndrome Modification: A Potential Hypothesis and Review of the Literature","volume":"48","author":"Tafazoli 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