Down Syndrome Biomarker Initiative (DSBI)

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.