Alzheimer Biomarkers Consortium — Down Syndrome (ABC-DS)

• Background
• Goals and Measures
• Recruitment
• Study Sites and Investigators
• Available Data
• Resources

Background

Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD). Virtually all people with DS have neuropathological changes consistent with AD by age 40 years, including deposits of amyloid-beta (Aβ) in diffuse and neuritic plaques, and most will develop clinical symptoms of dementia by their late 60s. The high risk for DS-AD has been attributed, at least in part, to triplication and overexpression of the gene for the amyloid precursor protein (APP) on chromosome 21, leading to elevated levels of Aβ peptides. However, there is wide variation in age at onset of dementia among those with DS, ranging from younger than 40 to older than 70 years of age. This age range suggests that additional genetic, biological, and environmental factors modify the rate and degree of Aβ deposition or clearance, and that these factors may be important modifiers of risk, accelerating or slowing disease progression.

Development of empirically supported methods for early diagnosis of dementia in DS, biological characterization of the preclinical and early phases of DS-AD, and identification of risk factors for AD progression are critical to the early diagnosis of dementia and for the development of effective interventions and treatments. For more information about AD in people with DS, visit NIA's Alzheimer's Disease in People With Down Syndrome webpage.

The ABC-DS is a multidisciplinary, multisite longitudinal study examining biomarkers of DS-AD in a large cohort of adults with DS, ages 25 and older. The study initiated in 2015 with funding from NIA and NICHD. Initially ABC-DS was led by two teams of research collaborators — Neurodegeneration in Aging Down Syndrome (NiAD, U01AG051406 - B. Handen, PI) and Alzheimer's Disease in Down Syndrome (ADDS, U01AG051412 - N. Schupf, PI). In September 2020, the continuation of ABC-DS was funded by the NIA, NICHD, and the INCLUDE Project (U19AG068054 - PIs B. Handen, B. Christian, E. Head, and M. Mapstone).

Goals and Measures

The overall goals of this study are to:

• Identify sensitive neuropsychological measures of cognitive decline, neuroimaging, blood-based proteins and metabolites and genetic biomarkers, along with neuropathological features associated with transition from normal aging to mild cognitive impairment to clinical dementia in adults with DS
• Identify critical factors that link cerebral Aβ deposition to neurodegeneration and, ultimately, dementia
• Understand the relationships between biomarkers and pathways implicated in AD pathogenesis

The ABC-DS will also conduct projects to:

• Investigate how DS-AD parallels and differs from sporadic AD within an amyloid, tau, neurodegeneration (ATN) framework, and identify modifiers of risk of conversion/progression
• Identify genetic modifiers that may increase or decrease risk of the development of DS-AD; and
• Translate outcomes to a precision medicine framework and expedite clinical trials

Common core measures, collected at multiple time points to support longitudinal analyses, include:

• Direct cognitive and functional measures (tests of memory, visual spatial abilities, language, executive function, processing speed, mental status, and gait)
• Caregiver questionnaires (queries on functional abilities, mental status, neuropsychiatric symptoms, and dementia screening)
• Medical and neurological assessments (personal and family health history, medication usage, and a brief physical and neurological examination)
• Neuroimaging biomarkers (MRI-based measures of cortical thickness and volume, white matter abnormalities and microstructure and functional connectivity, as well as amyloid-, tau-, and FDG-PET)
• Blood-based biomarkers (a proteomics panel, a metabolomics panel, and an assay of plasma Aβ peptides—Aβ40, Aβ42, Aβ40/Aβ42 ratio, tau, and neurofilament light change protein), and in willing participants, cerebrospinal fluid (CSF) biomarkers
• Genetic studies (genome-wide association analysis focusing on variants in genes associated with AD and age at onset of AD and memory decline, and with individual differences in blood-based, imaging, and CSF biomarkers that are found to be associated with clinical disease progression including Aβ42, P181-tau, and total tau)
• For people willing to participate in brain donation, neuropathology will be assessed to link to cognitive, neuroimaging and fluid biomarkers.

There will be three to four cycles of assessment, at approximately 16-month intervals, over the five-year study. However, some procedures will only be included in selected cycles.

Recruitment

The ABC-DS study sites will continue to follow the original ABC-DS participants and recruit new participants to total 550 individuals and 50 sibling controls. Importantly, ABC-DS continues to work within the community to increase the diversity of individuals in the cohort of adults with DS. For more information about participating and study contacts, visit the study listing on Alzheimers.gov.

Study Sites and Investigators

ABC-DS is a multi-PI study led by Drs. Ben Handen (University of Pittsburgh), Brad Christian (University of Wisconsin Madison), Elizabeth Head and Mark Mapstone (University of California, Irvine). The following ABC-DS sites are actively recruiting study participants.