Advancing Treatment for Alzheimer Disease in Individuals with Down Syndrome

April 16-17, 2013

Executive Summary

The workshop "Advancing Treatments for Alzheimer Disease in Individuals with Down Syndrome" was held April 16-17, 2013 in Washington, D.C. The goal of the meeting was to bring the Alzheimer's disease (AD) and Down syndrome (DS) research and advocacy communities together to discuss and advance the development of treatments for AD in individuals with DS. The workshop was sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); the National Institute of Neurological Disorders and Stroke (NINDS); the National Institute on Aging (NIA), all within the National Institutes of Health (NIH); as well as the Down Syndrome Research and Treatment Foundation (DSRTF) and Research Down Syndrome (RDS).

The aim of the workshop was to integrate current research activities, research resources, and future opportunities to inform development of therapies for DS and AD. Specific goals included the following:

  • Develop a research agenda for advancing treatments for AD in DS.
  • Coordinate NIH efforts that will inform updates to the NIH Research Plan on DS (related to aging and dementia in individuals with DS).
  • Help inform the Administration for Community Living's implementation of the National Alzheimer's Project Act's (NAPA) Plan specifically with regard to special populations likely to acquire AD (e.g., individuals with DS). (For plan details, see

Approximately 60 participants and speakers focused on five topic areas, including:

  • Disease Mechanisms
  • Model Systems for the Study of Connections between DS and AD
  • Cognitive Outcome Measures
  • Biomarkers
  • Developing Therapeutics.

Each session was preceded by a series of specific questions for each speaker, panel members, and other participants to address in summary discussion sessions. These sessions were augmented by presentations on "NIH Resources to Inform Treatment Goals." At the conclusion of the meeting, the co-chairs of each session were asked to summarize the discussion, focusing upon three underlying questions about the research topic area of their session:

  • What are the strengths and weaknesses of strategies currently being undertaken?
  • What can be done right now?
  • What are the long-term objectives and how can we get there?

The following represents a summary of their conclusions.

Strengths of Current Research Strategies

Trisomy 21 (Down Syndrome; DS) is a genetic risk for AD with a well-defined, but complex, set of modifier genes and environmental factors that has strong existing genetic models in both human and mouse and new emerging models such as induced pluripotent stem cell (iPSC) and other model organisms, such as rats.

Currently, the DS research community is broadly focused, but small, and has the opportunity to expand into new collaborations with the AD research community and into research avenues to study AD in DS.

The current research community already benefits from cross-sectional and longitudinal studies that include various imaging modalities and targets in clinical trials that benefit from leveraging resources available within Alzheimer's Disease Research Centers (ADC) sites, funded by NIA.

Weaknesses of Current Research Strategies

  • There have been few collaborative efforts to recruit the limited number of individuals with DS available at any given site into longitudinal studies that focus on aging. These studies would allow investigators to make comparisons among adults who are younger and have had a much different life experience from older adults with DS.
  • There are insufficient research resources from humans and other model systems because of the limited availability of many of the newer mouse and cell models, common substrates, and common reagents. There is a real need to combine virtual and physical biorepositories, including brain banking efforts.
  • There is a lack of consensus among investigators concerning baseline assessments of clinical measures, outcomes, or testing strategies in model systems and human beings.
  • The research community lacks measures that are feasible throughout the lifespan, are applicable to a wide population, can be done in a short time frame, are sensitive to a broad range of functional levels, and are sensitive to decline over a short period of time, as seen in DS. Although some test batteries have been developed to assess cognitive function in DS, few of these tools have been validated for adults with DS with cognitive decline. Hence, there is a critical need for longitudinal studies to gather natural history data and to determine the effects of interventions that are based on a minimal dataset with common data elements.

Things to be done right now

  • Investigators could inventory current and planned studies that involve cognitive outcome measures in the aging DS population to accelerate research initiatives and to share data among existing and new research groups engaged in longitudinal studies that include a number of subjects of different age ranges, demographic features, and levels of function.
  • Investigators could use cross-sectional data to understand the trajectory of DS cognition and behavior, particularly among 10 to 40 year olds of both genders and couple this with studies of early neuronal loss and dysfunction in AD via imaging studies.
  • Investigators could utilize rat and iPSC models for DS and AD to develop better systems to predict drug responses in humans. They could begin "humanizing" mice by creating transgenic mice with the human versions of critical genes involved in AD pathogenesis such as β-amyloid precursor protein (APP), tau, β-APP-Cleaving Enzyme complex (BACE), γ-secretase, and presenilin 1 and presenilin 2 (PS1 and PS2).
  • Investigators could develop a minimum dataset of co-morbid factors like sleep apnea, gait disturbance, obesity, mother's age at birth, etc. to study in all subjects with DS. This dataset could be used to develop mouse and human tasks that could measure cognitive and other functional abilities with age.

Longer-term objectives

The majority of meeting participants agreed that building on existing Alzheimer's Disease Centers (ADCs) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) infrastructure, a consortium of NIH, FDA, industry, foundations, and research and advocacy communities, could be created to take research findings into the clinics. Such a consortium could develop consensus on two or three key measures of basic domains such as memory, learning and delayed recall. This could help bring research groups together in longitudinal studies that focus on aging. Such a group would need to develop core functional and adaptive behavior measures through a pilot study to pick key measures and compare them across different groups throughout the lifespan. However, there would need to be consensus on a gold standard definition for what constitutes mild cognitive impairment and AD in DS that includes definitions that are feasible for the average clinician.

Such a consortium could engage the National Alzheimer's Project Act (NAPA) Federal Advisory Committee, leaders in the AD research community, families, and the disability community at large to assist with recruitment and education of special populations in the importance of research involvement and participation. This could include engagement of the research community to pursue prevention and treatment strategies by capitalizing on the unique opportunity presented by DS to understand AD. Primary care physicians with expertise in caring for individuals with DS could also be instrumental in such recruitment strategies.