Down Syndrome Biomarker Initiative (DSBI)
Condition: Down Syndrome; Alzheimer's Disease
MeSH terms: Alzheimer Disease; Down Syndrome; Syndrome
Study type: Observational

Summary: 
      Non-randomized natural history study involving 12 subjects with Down Syndrome, who are aged
      30-60 years old. This study will observe 3 different groups: four non-demented subjects
      between ages 30-40 years old, four non-demented subjects between ages 40-50 years old, and
      four demented subjects 50-60 years old.

      Currently available longitudinal data in DS suggest a high rate of transition to dementia
      from the late 40s through the early 50s of these individuals. This, together with the
      universal presence of plaques in DS by their mid 40s makes this age range ideal for studying
      the development of AD.
    

Detailed description: 
      The overall goal of this project is to determine the relationships among the clinical,
      cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum
      of Alzheimer's disease (AD), as the pathology evolves from normal aging through very mild
      symptoms, to mild cognitive impairment (MCI), to dementia in adults with Down syndrome. This
      is a pilot study modeled after the Alzheimer's Disease Neuroimaging Initiative (ADNI) to
      inform the neuroscience community of AD in DS, identify diagnostic and prognostic markers,
      identify outcome measures that can be used in clinical trials, and help develop the most
      effective clinical trial scenarios.

      AD is the most common dementia in humans and over the next decades will account for a major
      and increasing morbidity and mortality in the US and worldwide. AD is usually a sporadic
      disease and the commonly accepted hypothesis as to its etiology is the amyloid cascade
      hypothesis. There is tremendous activity in the pharmaceutical industry and academia directed
      towards development of disease modifying treatments, most commonly targeting amyloid, but
      also tau and other mechanisms. Most efforts are directed towards Mild to Moderate AD or
      prodromal AD with relatively little work on prevention of AD due to various challenges,
      including identification of healthy people who would be treated.

      Down syndrome is the most common chromosomal disorder in humans, caused by triplication of
      chromosome 21, accounting for ~1/740 live births in the USA even with routine prenatal
      screening. In addition to mental retardation and the other classical signs of DS, 100% of
      people with DS will develop the pathological hallmarks of AD (plaques and tangles) by their
      40s and ~80% of people with DS will eventually develop clinical dementia. The primary cause
      is the triplication of the APP gene on chromosome 21, resulting in 50% greater levels of both
      APP mRNA and protein. That the disease in DS is indeed AD is supported by pathological,
      molecular, in-vitro, biomarker and clinical evidence.

      People with DS have been followed at major centers in the US and EU for decades with large
      amounts of clinical and psychometric data gathered and analyzed. There is, however, very
      little data on CSF biomarkers due to the difficulty of performing lumbar punctures in DS
      subjects. Only recently has data begun to be gathered from imaging modalities, including
      Amyloid imaging.

      There is no gold standard for the diagnosis of AD in this population and, due to the MR, the
      standard instruments cannot be used. Most major centers have developed specific instruments
      that can follow cognitive and functional performance and allow the detection of dementia. The
      data gathered over the past decades allows the construction of a curve describing the
      transition to dementia in this population and shows the transition beginning in the mid 40s
      with a steep slope around the age of 50.

      DS is, in effect, a population highly enriched for people who will, with a very high
      probability develop AD, and it is expected that only with an ADNI-like study can the
      investigators better understand the trajectory of transition to dementia in this population.

      The ultimate goal of this project is to develop treatments for the prevention of AD in this
      population. Because if the investigators would know at what age the slope of transition to
      dementia is steepest, a study could be done in a specific age range and require much fewer
      subjects and time and expense than a study in the general population (where it is currently
      impossible to determine which healthy individuals will likely develop dementia over the next
      few years and even if there were, thousands would have to be screened to ID these few). A
      study in the general population might need to enroll tens of thousands of subjects to observe
      sufficient transitions to dementia. The investigators estimate that such a study in DS would
      require about 170 subjects per arm for a 36 month study. Success in such a study would
      provide the confidence to commit the resources for a larger study in the general population.

      As mentioned above, there is minimal CSF data and imaging is only beginning. Thus biomarkers
      for AD in DS are less developed than in the general population. Additional biomarkers could
      be helpful in studying AD in DS. A biomarker that could increase the ability to predict
      transition to dementia in an individual (as opposed to the investigators current ability on a
      population level) would increase the efficiency of any study. The ability to track the
      progression or improvement of dementia might also be useful. If a biomarker indicated
      transition to dementia earlier than any clinical instrument, a prevention study could
      conceivably be conducted at younger ages with greater chance of success. In addition to DS,
      such a biomarker would also be useful in the general population.

      This study is a pilot study for a larger scale biomarker study which, as described, would
      enable better understanding of biomarkers and the natural history of AD in DS.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Community sample
      
Biospecimen description: 
      blood, urine, cerebrospinal fluid
    
Keywords: Down syndrome; Alzheimer's disease; biomarkers; amyloid; tau