People with Down syndrome (DS) face a significantly elevated risk of developing Alzheimer's disease (AD) at an early age, yet they are frequently excluded from clinical trials aimed at developing new AD therapies. This exclusion leaves a critical gap in understanding the efficacy and safety of these treatments for this vulnerable population.
The Urgency of Including People with DS in AD Trials
Individuals with DS invariably develop Alzheimer's pathology by age 40, leading to a 95% risk of dementia by age 70. As life expectancy for people with DS increases, AD has become the leading cause of death in this population. Despite the approval of anti-amyloid antibody therapies for AD, clinical development programs have largely overlooked individuals with DS.
"The exclusion of people with DS from AD therapy trials leaves patients and families to make care decisions, like choosing a medication, without any evidence of efficacy and safety," note Andrea Pfeifer, CEO of AC Immune S.A., and Michael Rafii, MD, Ph.D. from the Keck School of Medicine, University of Southern California, in a recent article. They emphasize that this exclusion creates barriers to treatment and may lead to the use of less effective therapies.
Unique Considerations for DS-Associated AD (DSAD)
DSAD shares similarities with other forms of AD but exhibits key differences. The disease manifests earlier and progresses more rapidly in individuals with DS. The accumulation of amyloid beta plaques, a hallmark of AD, is driven by an extra copy of the amyloid precursor protein gene on chromosome 21.
Furthermore, the lifelong accumulation of amyloid raises concerns about the risk of amyloid-related imaging abnormalities (ARIA) associated with anti-amyloid antibodies. A recent study in JAMA Neurology indicated that lecanemab, an anti-amyloid antibody, extensively bound to blood vessels in brain tissue from individuals with DS. Current treatment guidelines recommend withholding anti-amyloid antibody treatment for individuals with DS until safety studies are conducted.
Adapting Clinical Trials for People with DS
Including people with DS in clinical trials requires careful consideration of their unique needs. Intellectual disability, common in individuals with DS, necessitates adapting clinical and cognitive endpoints used to assess efficacy. Standard cognitive tests may not be suitable due to floor effects, highlighting the need for specialized assessment scales.
"In DSAD trials, the assessment scales used to measure memory and cognition are different from those used in AD trials for the general population," Pfeifer and Rafii explain. They also note the challenges in finding appropriate trial sites with the expertise to recruit individuals with DS.
Other challenges include obtaining informed consent, creating accessible study materials, and accommodating potential difficulties with imaging assessments like PET scans and MRI. Additionally, younger, more active lifestyles of people with DS require consideration of the burden of trial participation.
AC Immune's ABATE Study: A Step Towards Inclusion
AC Immune S.A. is actively addressing the need for inclusive research through its ABATE study. This study is evaluating an anti-amyloid immunotherapy candidate in both individuals with DS and those with mild cognitive impairment (MCI). The trial design includes two prospectively defined cohorts, with the DS cohort opened only after interim safety results were obtained from the MCI cohort.
The ABATE study is currently recruiting patients across 14 sites in the U.S., U.K., and Spain, with completion expected in 2026. The study incorporates feedback from individuals with DS, caregivers, and patient advocacy groups to ensure cultural appropriateness and address concerns about safety and trust.
By addressing the unique challenges and incorporating the perspectives of the DS community, researchers can pave the way for more inclusive and effective clinical trials for Alzheimer's disease.
