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.

Inclusion Criteria:

- Male and female subjects 30 to 60 years of age inclusive with chromosome karyotype of
Down Syndrome due to Trisomy 21.

- Subjects must have a study partner (parent or other reliable caregiver) who has at
least 10 hours of contact and who agrees to accompany the subject to all clinic
visits and provide information about the subject's behavior and symptoms.

- Participant is able to speak/communicate.

- Subject is willing and has no contraindications to MRI scanning.

- Participant or parent/legal guardian provides consent.

- Participant must agree to allow for indefinite storage of his/her data and samples.

Exclusion Criteria:

- Patients who are anarthric or mute.

- Patients who do not meet the criteria for the diagnosis of DS.

- Patients unwilling or unable to participate in all tests and procedures.

- Unstable medical or behavioral issues.

- Unable or unwilling to perform MRI and/or PET imaging.