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Historically, individuals with atypical presentations have not been included in large\u2010scale clinical trials, which typically focus on late\u2010onset, sporadic amnestic\u2010predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid\u2010targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early\u2010onset amnestic and non\u2010amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome\u2010specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.<\/jats:p>","DOI":"10.1002\/alz.71521","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:00:48Z","timestamp":1782212448000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action"],"prefix":"10.1002","volume":"22","author":[{"given":"Nick","family":"Corriveau\u2010Lecavalier","sequence":"first","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neus","family":"Falg\u00e0s","sequence":"additional","affiliation":[{"name":"Alzheimer's Unit and Other Cognitive Disorders, Neurology Service Hospital Cl\u00ednic de Barcelona Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona \u2010IDIBAPS  Barcelona Spain"},{"name":"Universitat de Barcelona  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Putcha","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Frontotemporal Disorders Unit Massachusetts General Hospital &amp; Department of Neurology  Boston Massachusetts USA"},{"name":"Center for Brain Mind Medicine Brigham and Women's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Graff\u2010Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keir X. 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