Biomarkers

Area of Science:

• Neurology
• Biomarkers
• Genetics

Background:

• Individuals with Down syndrome (DS) have a significantly higher risk of developing Alzheimer's disease (AD), with pathology often emerging in their thirties.
• The precise sequence of plasma biomarker, cognitive, and neuroimaging changes preceding clinical AD in DS is not well understood.
• The event-based model (EBM) is a data-driven approach to estimate disease progression sequences from cross-sectional data, accounting for individual variability.

Purpose of the Study:

• To apply the EBM to a cohort of adults with DS to determine the sequence of biomarker, cognitive, and neuroimaging changes before AD diagnosis.
• To stage individuals with DS along this identified disease progression sequence.

Main Methods:

• Utilized the event-based model (EBM) on data from 60 adults with Down syndrome (DS) and no current AD diagnosis.
• Examined clinical assessments, plasma biomarkers (e.g., amyloid-beta 42/40 ratio, p-tau, NfL, GFAP), and will incorporate structural MRI data.
• Aims to establish a multi-modal sequence of preclinical AD changes.

Main Results:

• Preliminary findings indicate that early AD changes in DS mirror those in sporadic and familial AD.
• Observed sequence: altered plasma amyloid-beta 42/40 ratio, followed by memory decline, neurodegeneration markers (p-tau, NfL), executive dysfunction, visuomotor deficits, and later neuroinflammation (GFAP).
• Structural MRI data will be integrated to refine the multi-modal progression sequence.

Conclusions:

• This research refines the understanding of AD progression timing in DS, aiding in optimizing cognitive testing, neuroimaging, and blood sampling strategies.
• The EBM provides individual-level staging, which could facilitate earlier diagnosis and improve clinical trial design for AD in the DS population.
• Integrating multiple data modalities (plasma biomarkers, cognitive, neuroimaging) offers deeper insights into preclinical AD stages in individuals with DS.