Researchers outline trials targeting Alzheimer's in people with Down syndrome

Researchers told the council that adults with Down syndrome represent a high-risk group that can yield clear mechanistic insight and trial opportunities. Dr. Rafi, representing the Alzheimer's Therapeutic Research Institute and the ACTC coordinating center, reviewed why trisomy 21 drives overproduction of amyloid precursor protein (APP) and said that amyloid plaques are detectable in childhood on autopsy but are measurable by PET beginning around age 35. He said the Down syndrome population offers a relatively "pure" form of Alzheimer's pathology and is appropriate for trials built to address that biology.

Rafi described three active studies: ABATE (an active immunotherapy enrolling a small Down syndrome cohort), the ALADDIN study (a phase 4 donanemab trial enrolling people with Down syndrome who have elevated brain amyloid), and APPLAUSE (an intrathecal RNA inhibitor targeting APP). He also described the trial-ready cohort TRAC-DS (initial target 120 participants, now >550), the role of the DS Connect registry for referrals, and the involvement of community advisors in protocol and consent development. "We have 23 sites in the United States and 4 in Europe now connected to run these studies," he said, and urged continued recruitment and community engagement.

Panelists stressed returning results to participants and involving community members in study design and consent processes. Rafi said that results from small early trials are expected within the next two years and that ALADDIN will test safety and tolerability of donanemab for this population where previous pivotal trials excluded people with Down syndrome. The council flagged the need for careful safety monitoring and for clinical trial infrastructure that accommodates the population's practical needs (transportation, site accessibility, and clear return-of-results procedures).