{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:32:52Z","timestamp":1791232372245,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R61AG066543"],"award-info":[{"award-number":["1R61AG066543"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R33AG066543"],"award-info":[{"award-number":["R33AG066543"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["ICI23\/00032"],"award-info":[{"award-number":["ICI23\/00032"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Individuals with Down syndrome (DS) have a genetically determined form of Alzheimer's disease (AD) due to the amyloid precursor protein (<jats:italic>APP<\/jats:italic>) gene dose effect. Nearly all individuals with DS develop AD pathology by age 40. Although dementia is rare before this age, its incidence rises sharply thereafter. Longitudinal studies estimate a lifetime dementia risk exceeding 90%, with prevalence reaching 88%\u2013100% after age 65\u2014a marked contrast to 10%\u201315% in the general population. Recent breakthroughs in sporadic AD, including anti\u2010amyloid therapies such as lecanemab and donanemab, have shown efficacy in slowing progression. However, individuals with DS were excluded from these trials, leaving critical gaps in safety and efficacy data. This perspective highlights the current state of AD clinical trials in DS, key challenges\u2014(including ethical considerations, recruitment barriers, and cognitive assessment adaptations), and emerging research efforts. Addressing these gaps is essential to ensure equitable access to disease\u2010modifying therapies for individuals with DS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Despite recent progress in Alzheimer's disease (AD) treatments for the general population\u2014particularly monoclonal anti\u2010amyloid therapies such as lecanemab and donanemab\u2014individuals with Down syndrome (DS) were excluded from pivotal trials, leaving significant gaps in knowledge regarding safety and efficacy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A key concern in DS is the heightened risk of amyloid\u2010related imaging abnormalities (ARIAs), a known side effect of anti\u2010amyloid therapies, which may be aggravated by the increased prevalence and severity of cerebral amyloid angiopathy (CAA) in this population.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>For the first time, growing awareness of the nearly universal AD risk in DS is driving a stronger focus on tailored clinical research. Ongoing and forthcoming studies, including TRC\u2010DS, ABATE, HERO, ALADDIN, and LESS\u2010AD, are beginning to address these gaps.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Beyond amyloid\u2010targeting therapies, investigating alternative mechanisms such as tau pathology, neuroinflammation, and synaptic dysfunction is key to advancing treatments for DS\u2010related AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Collaboration between advocacy groups, researchers, and pharmaceutical companies is essential for overcoming barriers in AD clinical trials for DS, including ethical concerns, recruitment challenges, and the need for adapted cognitive assessments. This perspective also proposes strategies to enhance inclusivity in future studies, ensuring broader access to emerging treatments.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70258","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T10:39:28Z","timestamp":1751193568000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Current advances and unmet needs in Alzheimer's disease trials for individuals with Down syndrome: Navigating new therapeutic frontiers"],"prefix":"10.1002","volume":"21","author":[{"given":"Isabel","family":"Barroeta","sequence":"first","affiliation":[{"name":"Sant Pau Memory Unit Department of Neurology Institut d'Investigacions Biom\u00e8diques Sant Pau Hospital de Sant Pau, UniversitatAut\u00f2noma de Barcelona  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Videla","sequence":"additional","affiliation":[{"name":"Sant Pau Memory Unit Department of Neurology Institut d'Investigacions Biom\u00e8diques Sant Pau Hospital de Sant Pau, UniversitatAut\u00f2noma de Barcelona  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED)  Madrid Spain"},{"name":"Barcelona Down Medical Center Fundaci\u00f3 Catalana S\u00edndrome de Down  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Carmona\u2010Iragui","sequence":"additional","affiliation":[{"name":"Sant Pau Memory Unit Department of Neurology Institut d'Investigacions Biom\u00e8diques Sant Pau Hospital de Sant Pau, UniversitatAut\u00f2noma de Barcelona  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades 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