Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid

Area of Science:

• Neurology
• Genetics
• Biomarkers

Background:

• Down syndrome (DS), caused by Trisomy 21, significantly increases the risk of early-onset Alzheimer's disease (AD).
• Current amyloid-targeting monoclonal antibody (mAb) therapies for AD have not been evaluated in the DS population.
• Understanding AD progression in DS is crucial for developing targeted treatments.

Purpose of the Study:

• To investigate the prevalence of amyloid positron emission tomography (PET) positivity (A+) in adults with Down syndrome across different age groups.
• To assess the relationship between amyloid burden, memory function, and clinical status in individuals with DS.
• To inform the design of future clinical trials for mAb therapies in DS.

Main Methods:

• Analysis of cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) study.
• Amyloid status determined by amyloid-beta PET imaging using Centiloid thresholds.
• Episodic memory assessed via the modified Cued Recall Test; clinical status determined by consensus.

Main Results:

• A total of 409 adults with DS (mean age 44.83 years) were analyzed.
• Amyloid PET positivity (A+) prevalence and mean amyloid load increased significantly with age.
• Age-correlated declines in memory function and increased cognitive impairment were observed.

Conclusions:

• A rapid increase in amyloid-beta PET positivity occurs in Down syndrome individuals after age 40.
• There is a significant delay between the onset of amyloid positivity and clinical symptom manifestation in DS.
• Clinical trial designs for monoclonal antibody therapies in DS must account for age-related changes in AD pathology and presentation.