Individuals with Down syndrome (DS) have a genetically determined form of Alzheimer's disease (AD) due to the amyloid precursor protein (APP) 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%-100% after age 65-a marked contrast to 10%-15% in the general population. Recent breakthroughs in sporadic AD, including anti-amyloid 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-(including ethical considerations, recruitment barriers, and cognitive assessment adaptations), and emerging research efforts. Addressing these gaps is essential to ensure equitable access to disease-modifying therapies for individuals with DS. HIGHLIGHTS: Despite recent progress in Alzheimer's disease (AD) treatments for the general population-particularly monoclonal anti-amyloid therapies such as lecanemab and donanemab-individuals with Down syndrome (DS) were excluded from pivotal trials, leaving significant gaps in knowledge regarding safety and efficacy. A key concern in DS is the heightened risk of amyloid-related imaging abnormalities (ARIAs), a known side effect of anti-amyloid therapies, which may be aggravated by the increased prevalence and severity of cerebral amyloid angiopathy (CAA) in this population. 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-DS, ABATE, HERO, ALADDIN, and LESS-AD, are beginning to address these gaps. Beyond amyloid-targeting therapies, investigating alternative mechanisms such as tau pathology, neuroinflammation, and synaptic dysfunction is key to advancing treatments for DS-related AD. 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.