By Meghan McCarthy
In 2008, while running a memory disorders clinic Michael Rafii, MD, PhD, noticed an increasing number of adults with Down syndrome (DS) among his patients. Recognizing their unique needs and the lack of specialized care, Dr. Rafii acted by opening a second clinic specifically dedicated to adults with DS. At the time, he was also working on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) project.
“For me, it was an obvious question: Could there be an ADNI for Down syndrome given that they seem to be getting a genetic form of Alzheimer’s disease?”
The answer, at the time, was no.
This understanding sparked Dr. Rafii’s efforts to address this gap in research and clinical understanding.
Foundations
One hundred percent of adults with DS develop the pathology—or markers within brain tissue—of Alzheimer’s disease (AD) by age 40. The average age of AD diagnosis in this population is 54. While the life expectancy for individuals with DS has increased dramatically, it has plateaued in recent years, primarily due to AD being the leading cause of death in this group.
Current research suggests that the elevated risk of AD in individuals with DS is largely genetic, stemming from an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. However, AD research and clinical practices specific to individuals with DS remain significantly underdeveloped.
To address this, Dr. Rafii launched the Down Syndrome Biomarker Initiative (DSBI), a pilot study designed to validate the use of traditional AD diagnostic tools—such as imaging, blood tests, and cognitive assessments—in individuals with DS. A primary goal of the study was to measure memory changes independently of their intellectual disability. It was the first multi-modal biomarker study of AD in people with DS.
“People with Down syndrome are very capable of participating in these studies,” Dr. Rafii said.
Building Consortium trials
Following the success of the pilot, Dr. Rafii initiated clinical trials testing anti-amyloid vaccines and oral anti-amyloid compounds in individuals with DS. These efforts led to the establishment of the Alzheimer’s Biomarker Consortium for Down Syndrome (ABC-DS), funded by the National Institutes of Health (NIH). Dr. Rafii serves as one of the study’s Co- Investigators.
ABC-DS longitudinally tracks individuals with DS to identify biomarkers within this population. By studying the variation in dementia onset, researchers can better structure clinical trials and treatments. Over the past decade, ABC-DS has published more than 100 papers on the genetic causes, symptoms, and diagnostic guidelines for AD in individuals with DS. ABC-DS serves as the ADNI for DS and has provided fundamental information about the natural course of AD in people with DS and anchored this knowledge with biomarker data.
ABC-DS’s work paved the way for the creation of the Alzheimer’s Clinical Trials Consortium for Down Syndrome (ACTC-DS), which operates at over 20 international sites. ACTC-DS aims to deliver cutting-edge diagnostics and therapeutics to the DS population through clinical trial participation. Its first objective was developing a “trial-ready cohort,” a cohort of medically stable participants interested in research.
“I learned from my own clinic experiences that individuals with Down syndrome may not always get access to care that the general population does,” Dr. Rafii said. “Often, individuals with Down syndrome have undiagnosed conditions that could lead to exclusion from clinical trials.” TRC-DS allows individuals to get involved in clinical research and have a fast-track to clinical trials that that may be eligible for and interested in participating in.
ACTC-DS serves as a platform to conduct clinical trials specifically designed for people with DS. The consortium is currently involved in several key clinical trials:
- Trial-Ready Cohort – Down Syndrome (TRC-DS): This study enrolls medically stable participants to facilitate their swift inclusion in future clinical trials. www.trc-ds.org
- ABATE Study: Sponsored by AC Immune SA, a Swiss pharmaceutical company, this study tests a vaccine for Alzheimer’s disease in individuals with DS. www.abate-study.com
- HERO Study: Sponsored by Ionis, testing an anti-sense oligonucleotide (ASO) targeting the APP gene.(www.hero-study.com)
- ALADDIN- Upcoming clinical trial of Eli Lilly’s donanemab in adults with DS.
Addressing Drug Development
Although the U.S. Food and Drug Administration (FDA) has approved anti-amyloid therapies such as lecanemab and donanemab, individuals with DS were excluded from the clinical trials for these treatments. This exclusion creates significant uncertainties regarding its safety and efficacy in this population.
“There are treatments that are FDA approved, and we are very interested in helping understand how, if at all, they should be used for people with Down syndrome,” Dr. Rafii said. “Should they be given at a different dose or a different frequency? That’s what we have been planning at ACTC-DS for several years.”
Later this year, ACTC-DS will launch its third clinical trial, ALADDIN, to test donanemab in individuals with DS.
“People with Down syndrome have taught us about the genetic bases of Alzheimer’s disease,” Dr. Rafii said. “They deserve to get access, if they’re interested, in new treatments. My hope is that at any clinical trial site, an individual and their family will have a menu of research options to select from that they may be interested in participating.”
Until further research provides guidance, Dr. Rafii advises against using amyloid-lowering therapies such as lecanemab or donanemanb in individuals with DS. This is consistent with the published appropriate use criteria that recommend the same.
Representation
Respecting autonomy and decision-making capacity are central to ACTC-DS. The team’s research participant advisory board, which includes participants and their family members, provides feedback on topics ranging from trial protocols to consent forms.
[Above: Video testimonials of ACTC-DS participants]
Suggestions from the board have included improving the diversity of language and imagery in patient materials, addressing barriers to participation, and offering more flexible scheduling.
“People with Down syndrome have full-time jobs that they are responsible for,” Dr. Rafii noted. Last year, ACTC-DS established a Research Participant Group, comprised of individuals with DS and their family members who meet with the researchers quarterly to review protocols, consent forms and study related documents. “They have given us reams of feedback, all very helpful in moving us towards conducting clinical trials that are ideal for this population.”
While some individuals with DS and their families choose not to participate in research, many are highly motivated due to personal experiences with dementia.
“When individuals who have seen someone with Down syndrome undergo dementia and decline, they are highly motivated and their families are highly motivated,” Dr. Rafii said. “They see how prevalent this is, and that there is an extremely high risk of developing this genetic form of Alzheimer’s disease.”
A Vision for the Future
While ACTC-DS has made tremendous strides over the past decade, Dr. Rafii envisions a future where individuals with DS have equitable access to Alzheimer’s therapies.
“They are the world’s largest genetically determined population of AD,” said Dr. Rafii. “Trials need to be tailored to their needs. They should not be excluded any further from the amazing advances being made in this field. They should be brought in and offered several options, not just a single option, to participate in clinical trials.”
Dr. Michael Rafii is a professor of Neurology at the Keck School of Medicine at USC. He is the associate director of the Alzheimer’s Clinical Trial Consortium (ACTC) and the medical director of the ACTC Medical Safety Unit, where he oversees safety across all of the Institute’s portfolio of clinical trials. Dr. Rafii is the principal investigator for the ACTC-DS, Co-Director of the Clinical core of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and co-principal investigator of the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET). To learn more about Dr. Rafii’s background, please click here.