Down Syndrome Clinical Trials - Study of Alzheimer's Disease in Down Syndrome

This is an observational, multi-center, longitudinal cohort study to characterize adults with DS ages 25 years and above enrolled at specialized care centers. The aim is to assess changes in cognition, behavior, function and health over approximately 32 months. Blood will be collected for the development of plasma AD biomarkers useful in the DS population.

Adults with DS face a markedly increased risk of Alzheimer's Disease (AD). DS, the most common genetic cause of AD, is due to trisomy for all or part of a third copy of chromosome 21. It is typically associated with the presence of a number of abnormal clinical phenotypes, including craniofacial anatomy, and is universally characterized by mild to moderate intellectual disability. Almost all adults with DS develop AD-like neuropathology by the age of 40. While dementia may not be universal, the prevalence of AD in DS increases from 9% to 23% between the ages of 35 and 49 years, 55% in those between 50 and 59 years, and estimates place it as greater than 75% in those 60 years of age and above. The average age at which dementia is diagnosed is 55 years . Given shared clinical and neuropathological features, and in view of shared genetic risk, this disorder is now termed AD in DS (AD-DS).

Among the genes on chromosome 21 triplicated in DS the evidence is compelling that increased gene dose for amyloid precursor protein (APP), with increased levels of the APP protein and its products, is necessary for AD-DS. Other chromosome 21 genes may impact AD-DS as may genes on other chromosomes, including variants that also increase the probability of AD, but a uniquely important role is played by increased dose for APP. Given the APP gene dose-dependence of AD-DS, and the recognition that a rare form of FAD is due to APP gene duplication, it is not surprising that AD and AD-DS share common neuropathologies, including accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Indeed, the neuropathological hallmarks of AD-DS are very similar if not identical to AD. Thus, like AD, beta-amyloid (Aβ) - principally Aβ42 - is the isoform of Aβ that dominates in diffuse deposits and then in mature plaques; Aβ40 accumulates around cerebral vessels with significantly higher frequencies in DS than in AD, recapitulating the congophilic angiopathy of AD. However, distinct from AD, Aβ accumulation in DS occurs in young people with deposition in diffuse plaques in those in the teenage years, decades earlier than in both aged controls and individuals with AD. As in AD, amyloid deposition appears before NFT formation and is present significantly before the development of dementia. An important question is whether it is possible to prevent or mitigate the cognitive deficits and other symptoms associated with AD-DS. Ascertaining the preclinical and prodromal stages of the dementia could be particularly valuable. This approach has significantly advanced the field in studies on other cases of genetically caused AD, i.e. those with familial AD (FAD) due to mutations in APP or in its processing enzymes Presenilin 1 and 2. Given this rationale, we will characterize the preclinical and prodromal stages of AD-DS by conducting longitudinal observations that incorporate medical history and measures of cognition, behavior, and function in adults with DS aged 25 years and above. The goal is to chart the cognitive, behavioral and functional status of a population at high risk for AD-DS.

Specialty centers in the U.S. care for large populations of persons with DS and form the team of recruiting sites in this study. The DS-CTN is a clinical research and trials network of specialty centers in the U.S. expertly equipped to conduct work extending from design, to execution, to analysis and publication of research that benefits the DS population through discovery and delivery of effective treatments. The DS-CTN currently consists of 11 member sites in the U.S. specializing in DS, and is comprised of scientific investigators and clinicians, largely but not exclusively from academic research centers, whose focus is on clinical trials in the DS population. The DS-CTN will support this observational study through enrollment and longitudinal follow-up of participants. DS-CTN member sites will also support this study by contributing expert feedback into protocol and data entry field development, while also offering important feedback and input on the conduct and flow of the study. The DS-CTN will be responsible for the analysis and publication of the study data.

Males and females, aged 25 and older, with a diagnosis of DS, typically supported by karyotype analysis documenting full trisomy for chromosome 21 or complete unbalanced translocation of chromosome 21.

Enrollment will be balanced by the following age strata: 25 to 34 years old (target 25% of enrollment), 35 to 44 (target 50% of enrollment), 45 years and older (target 25% of enrollment).