Alzheimer Biomarkers Consortium — Down Syndrome (ABC-DS)
Exploring the Connection Between Down Syndrome and Alzheimer's Disease
The Alzheimer Biomarkers Consortium-Down Syndrome (ABC-DS) is a longitudinal study funded by the National Institute on Aging (NIA), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institutes of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project. The goal of ABC-DS is to follow a cohort of adults with Down syndrome over time to identify early biomarkers that may herald the onset of Alzheimer's disease. The investigators hope that these biomarkers can be useful to inform clinical trials and improve the quality of life in people with Down syndrome and for the general population.
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, cerbrospinal 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.
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.
|Site||Investigator & Study Coordinator|
University of Pittsburgh (Coordinating Center), Pittsburgh, PA
Columbia University Irving Medical Center, New York, NY
|The New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY|
Harvard Medical School, Massachusetts General Hospital, Boston, MA
|University of Wisconsin-Madison, Waisman Center, Madison, WI|
|University of Cambridge, Cambridge, UK|
|University of California, Irvine, Irvine, CA|
|University of Kentucky: Sanders-Brown Center on Aging and the Kentucky Neuroscience Institute, Lexington, KY|
|Washington University in St. Louis School of Medicine, St. Louis, MO|
ABC-DS is committed to providing rapid public access to all data, clinical, cognitive and biomarker (fluid and imaging) data, without embargo, and access to the biological samples by qualified scientific investigators. ABC-DS data are transferred to the Laboratory of Neuro Imaging (LONI), for harmonization, documentation and de-identification; biospecimen samples are transferred and managed by the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) and an ABC-DS biospecimen bank. As of May 2021, data from the first and second wave of longitudinal data are available for requests.
Qualified investigators can submit requests for access to data and samples, and all requests will be reviewed by ABC-DS investigators and NIH staff. Approved data requests will be managed by the ABC-DS Biostatistics and Data Management Core for access to the clinical, cognitive, and neuroimaging data listed below. Upon approval and availability of biospecimen samples, NCRAD will distribute DNA, plasma and serum, and the ABC-DS biospecimen bank will distribute CSF. LONI will store the associated data for access by approved investigators.
Data and biospecimens available for requests:
- Plasma in 0.25 mL (250 uL) aliquots
- Serum in 0.25 mL (250 uL) aliquots
- Buffy coat in 1 mL aliquots
- CSF in 15-20 mL aliquots
- Fixed or fresh frozen brain tissue
- Medical and psychiatric history
- Physical and neurological exam results
- Caregiver assessment tools on adaptive functioning (Vineland 3), AD symptoms (DLD and NTG-EDSD), and psychiatric symptoms (Reiss)
- Neuropsychological battery results (DSMSE, Block Design, Tinetti Gait, Modified Cats & Dogs Task, Category Fluency, Cued Recall, Purdue Pegboard, Rivermead Behavioral Memory Test)
- Consensus diagnosis
The neuroimaging data are selected to mirror the ADNI protocols.
- PET – amyloid (PiB or florbetapir), tau (flortaucipir), and FDG
- MRI – T1-weighted structural, T2 FSE, T2-FLAIR, T2*, ASL, DTI, and rs-fMRI.
- APOE genotype
- GWAS (~760K SNPs)
- Data on over 50 sibling controls of participants with DS
- Primarily biospecimens and neuroimaging data
- Complete and submit the data/sample request form (ABC-DS Data or Biospecimen Request Form)
- Review and sign the ABC-DS Data Use Agreement
Note: Details and information for the collected data and biospecimens can be found in the ABC-DS Data Dictionary (PDF, 580K).
Any questions about ABC-DS data and/or biospecimens should be directed to: Joni Vander Bilt (Email Joni Vander Bilt).
Publication and Ancillary Studies Committee Co-Chairs
Brad Christian (Email Brad Christian)
Mark Mapstone (Email Mark Mapstone)
Sid O'Bryant (Email Sid O'Bryant)
A list of publications associated with ABC-DS data is available through: