First participant with Down syndrome joins Alzheimer’s prevention trial

Researchers have dosed the first participant in a clinical trial of an investigational medicine designed to lower the amount of amyloid precursor protein (APP) for the potential treatment of Alzheimer’s disease (AD), which is initially being studied in adults with Down syndrome (DS) who have a genetic risk of developing AD.

The focus on prevention represents a significant shift towards attacking Alzheimer’s disease earlier in its progression, rather than at the treatment stage. Those with Down syndrome are born with an extra chromosome that carries a gene pivotal to causing Alzheimer’s. The gene produces a protein that causes a buildup of plaques in the brain.

By the time most people with Down syndrome hit age 40, they have already developed these plaques. It may take another decade or more to develop symptoms, but eventually up to nine in 10 people with Down syndrome are expected to develop Alzheimer’s disease.

Seeking to change these odds, last month, researchers gave the first dose of an investigative drug to a participant in the new clinical trial, called the HERO study. The drug is designed to stop Alzheimer’s-causing plaques from forming in the brain.

Led by Ionis Pharmaceuticals, with investigative oversight by ATRI Medical Director Michael Rafii, MD, Ph.D., the study is expected to run for two years with an initial 30 participants at sites across the U.S. and Europe.

“What makes this study remarkable is that it targets the underlying genetic cause of Alzheimer’s disease in people with Down syndrome,” said Rafii.

Accelerating the pace of research into Alzheimer’s disease in the Down syndrome population

Though research first linked Alzheimer’s disease to those with Down syndrome more than 30 years ago, few clinical trials have been done for this group—until now. With this new effort, Rafii noted the growing number of clinical trials specifically designed for people with Down syndrome, including one called the ABATE study, launched last year.

Rafii is the coordinating principal investigator for ABATE, which is evaluating a vaccine intended to slow down Alzheimer’s in those with Down syndrome by targeting amyloid plaques in the brain.

Later in 2025, Rafii and the ATRI team will initiate the ALADDIN trial, which will investigate the use of donanemab in people with Down syndrome. Donanemab is already FDA-approved for Alzheimer’s in the general population.

“Now someone with Down syndrome can go into one of these specialized research clinics and select from several trials,” Rafii said. “That’s never been the case in this field. Ever.”

These trials represent just a slice of the recent progress made in Down syndrome research, described in a new Lancet article co-authored by Rafii and USC Associate Professor of Clinical Neurology and Pediatrics Jonathan D. Santoro, MD.

The HERO study is working closely with the Alzheimer’s Clinical Trials Consortium—Down Syndrome (ACTC-DS), a large, international consortium led by Rafii. ACTC-DS conducts research and clinical trials with a focus on advancing Alzheimer’s disease therapies for those with Down syndrome.

It also works closely with the Alzheimer’s Biomarker Consortium—Down Syndrome (ABC-DS), an observational study that has provided critical scientific information about how and when Alzheimer’s develops in people with Down syndrome.

ACTC-DS collaborates with advocacy groups such as the National Down Syndrome Society and the Global Down Syndrome Foundation to raise awareness about the genetic connection between Down syndrome and Alzheimer’s disease and incorporate input from an advisory group of individuals with Down syndrome and their loved ones. This feedback helps to ensure that the voices and needs of those with Down syndrome are prioritized in research.

The first project of the ACTC—DS created a cohort of 120 people with Down syndrome who could be ready to participate in clinical trials. The project exceeded its goal, enrolling over 350 people. This was particularly important, because too often those with Down syndrome do not receive adequate access to health care and are ineligible for clinical trials. Having interested participants already identified speeds up the pace of research.

How is this new investigational drug designed to work?

The new investigative drug being evaluated in this study, ION269, is designed to interrupt the production of amyloid plaques. ION269 is part of a class of medicines called antisense oligonucleotides.

Participants in the HERO study will receive an injection of the investigational drug into the lower back. The medicine will then travel to the brain where it is intended to work. The goal of the study is to assess safety and tolerability and the effects of this treatment on APP and amyloid plaques in the brain.

Before enrolling any participant, researchers secure the consent of both the candidate being considered and their legally authorized representatives. The consent materials are designed specifically for those with intellectual disabilities and have been reviewed by the ACTC-DS advisory group.

Researchers are seeking participants to take part in the HERO study, which began at Washington University School of Medicine in St. Louis. The University of Kansas Medical Center is another active study site. Many more research sites are expected to come on board in the coming months.