Office for People With Developmental Disabilities

Print: Print this page

Highlights of Down Syndrome Research at IBR



Down syndrome is the most common genetic form of developmental disabilities, with a prevalence of 1 in 733 live births in the United States, and 5,000 affected infants born each year. DS is caused most commonly by an extra copy of chromosome 21(trisomy 21), and this extra chromosome interferes with normal growth and development. Children with Down syndrome are at a significantly higher risk for certain conditions, while adults with Down syndrome are extremely resistant to other diseases. Therefore, it is important for parents, health care professionals, and teachers to have a clear and accurate understanding of each affected individual’s medical concerns and level of developmental functioning.

Adults with Down syndrome experience a number of health concerns typically associated with old age, including an increased risk for Alzheimer’s disease, and their life expectancy is well below that of most other people. However, the long-term outcome for people with Down syndrome is not as dire as once thought. Some adults with Down syndrome are now living into their late 60s and 70s with few, if any, major signs of Alzheimer’s disease—and dementia is far from a certainty, as originally thought as few as 35 years ago.

IBR’s Aging Research Program improves understanding of risks of dementia in individuals with Down syndrome

IBR’s Aging Research Program, in collaboration with Columbia University and Kennedy Krieger Institute at Johns Hopkins University, has studied the effects of dementia and “normal” aging on adaptive skills, neuropsychological and cognitive functioning, health, and neuropsychiatric status in adults with Down syndrome for over 25 years. Financial support for this program has come from OPWDD and the National Institutes of Health.

Earlier studies of this program showed the following:

  1. That risk for dementia among adults with Down syndrome was lower than expected in their 30s and early 40s, but increased substantially thereafter;
  2. That some health-related factors, including cholesterol level, ApoE genotype, and estrogen levels, influence whether a specific individual with Down syndrome will be at higher or lower risk for dementia; and 
  3. That risk of Alzheimer’s disease for adults with intellectual disability who do not have Down syndrome appears to be similar to the risk in the neurotypical population.

The current studies of the Aging Research Program have a number of goals:

  1. To determine the role of the basic biological mechanisms that underlie Alzheimer’s disease in adults with Down syndrome. 
  2. To determine if risk for Alzheimer’s disease within the elderly population with Down syndrome might be associated with aspects of the metabolic syndrome. 
  3. To ascertain the contribution of genetic variants that may influence cognitive functioning, risk for Alzheimer’s disease, and age at onset of Alzheimer’s disease in adults with Down syndrome. 
  4. To develop empirically validated methods for identifying the presence of mild cognitive impairment, which is impairment that is intermediate between declines associated with “normal” brain aging and the deficits that occur in conjunction with Alzheimer’s disease.

Achieving these goals will help explain why dementia does not develop or is postponed in some individuals with Down syndrome, despite the overall higher risk seen in this population. It also will establish how dementia can be identified in its earliest stages, possibly leading to earlier identification of individuals who would benefit from treatments as they become available.

For families and providers, findings from IBR’s Aging Research Program have helped improve understanding of the real risks for dementia in individuals with Down syndrome, thereby aiding in planning and in promoting more effective differential diagnosis, especially at earlier ages when risk for dementia due to Alzheimer’s disease remains low.

Telomeres are shorter in people with Down syndrome and dementia/mild cognitive impairment

An IBR research group has shown in preliminary studies that people with DS and dementia/mild cognitive impairment (MCI) have shorter telomeres than do their peers with DS who do not have dementia/MCI. Telomeres are located at the ends of chromosomes. The scientists hope to expand these studies to answer the question of whether telomere shortening may serve as a biomarker/predictor of MCI and dementia in people with DS. The results of these studies are expected to also apply to the general population.

Long-term running alleviates some behavioral and molecular abnormalities in a mouse model of Down syndrome

In a study of whether voluntary daily running, sustained over several months, improves cognition and motor function and modifies the levels in the brain of selected proteins in a mouse model of Down syndrome, IBR scientists found that the brain, especially the cerebellum, displays great plasticity and a robust response in numerous pathways and cellular responses to voluntary exercise. This finding suggests that epigenetic factors such as physical exercise can significantly modify the disease course of even a very complex genetic disorder such as Down syndrome and that a properly designed exercise program could be a valuable supplement to future pharmacologic therapies for people with Down syndrome.

Peptide 6 inhibits synaptic failure and alleviates learning and memory impairments in a mouse model of Down syndrome

The cognitive deficits in Down syndrome are associated with reduced neuroregenerative capacity in forming new neurons from neurostem cells and replacing the lost neuronal connectivity, called synapses, in the brain. One strategy for developing a therapy that will improve neuronal proliferation and connectivity in the brain is the use of proteins called neurotrophins to restore the homeostasis of the brain biochemical milieu. IBR scientists showed that long-term treatment with the neurotrophin peptide 6 in a mouse model of Down syndrome increased levels of the synaptic proteins that are crucial for synaptic plasticity and enhanced the pool of neural stem cells in the hippocampus. These findings indicate that peptide 6 can inhibit the learning and memory impairments in Down syndrome mice and suggest the potential of peptide 6 as a therapeutic treatment for Down syndrome.

The difference between age-associated loss of neuronal reserve in control adults and elderly, and in subjects diagnosed with Down syndrome  

The increase in human life expectancy has resulted in the rapid growth of the elderly population who have minimal or no intellectual deterioration. A study by IBR scientists of 15 brain structures in the brains of non-demented adults and elderly, 25 to 102 years of age, revealed the absence of significant neuronal loss in seven regions and topographically selective reduction of the neuronal reserve by 28% to 54% in the entorhinal cortex, Ammons horn, amygdala, thalamus, caudate nucleus, dentate nucleus, and Purkinje cells. A similar rate of neuronal loss in adults and the elderly, without signs of accelerating neuronal loss in agers or super-agers, reveals age-associated brain remodeling with a significant reduction of the neuronal reserve, not only in elderly but also in adults. The absence of a significant association between neuronal loss and the severity of neurofibrillary degeneration and β-amyloidosis indicates the separation of mechanisms of age-associated brain remodeling from the mechanism involved in Alzheimer disease.

A parallel IBR study of individuals with Down syndrome is focusing on estimation of brain region–specific reduction of neuronal reserve caused by developmental anomalies; estimation of the rate of neuronal loss in the third decade of life caused by accelerated aging; and the rate of neuronal loss in subjects older than 40 years of age affected by early onset of Alzheimer disease. These statistical models define major mechanisms contributing to early functional deterioration of individuals with Down syndrome.  

Over-expression of the gene DYRK1A contributes to altered brain development and to neurodegeneration in people with Down syndrome; DYRK1A inhibitors are potential therapeutic agents

IBR studies are focusing on the causes of altered brain development in Down syndrome. They have found that over-expression of the gene DYRK1A contributes to the deregulation of basic mechanisms of brain development, severe defects of neurogenesis in the memory and motor systems, delayed and abnormal neuronal growth, synaptic pathology, and numerous brain region–specific structural and functional alterations contributing to the clinical characteristics of Down syndrome, including memory and learning deficits.

Scientists at IBR have also found that DYRK1A contributes to the neurodegeneration, including neurofibrillary changes and the early onset of Alzheimer’s disease, that occurs in people with Down syndrome by 40 years of age. However, they found that the pattern of biochemical and neuropathological changes in individuals with Down syndrome/Alzheimer’s disease is different from that in individuals with sporadic Alzheimer’s disease in the general population.

These studies, combined with the results of other IBR studies, indicate that inhibition of DYRK1A offers a rational approach for therapeutic intervention for Down syndrome that will (a) reduce the developmental functional deficits, including intellectual deficits, and (b) prevent/delay age-associated neurodegeneration, neuronal loss, and dementia. IBR scientists are currently formulating a new approach for the design of specific Dyrk1A inhibitors as therapeutic agents.

Reduced levels of the protein SNCA contribute to cognitive deficits in Down syndrome

IBR scientists have found that levels of the protein called alpha-synuclein (SNCA) in a mouse model of Down syndrome and in individuals with Down syndrome are significantly reduced in two regions of the brain associated with memory and learning, the cortex and hippocampus. SNCA is involved in synaptic transmission between neurons. The researchers believe that the reduced levels of SNCA contribute to the cognitive deficits observed in individuals with Down syndrome. To understand the mechanism by which SNCA levels are regulated, the scientists analyzed methylation of SNCA in the mouse model of Down syndrome and found significantly reduced methylation. They also found that a component of green tea, EGCG, increased the SNCA levels. These scientists are now working to identify the factor(s) that are regulated by EGCG, which will be essential for developing a therapeutic agent that can diminish the negative effects of cognitive deficits in individuals with Down syndrome.