Tau extent is associated with lower cognition in Down syndrome-related Alzheimer's disease

¹⁸F-MK6240 is a second-generation tau positron emission tomography (PET) tracer with high dynamic range able to detect early tau pathology in Alzheimer's disease, however, its binding characteristics have not been evaluated in Down syndrome (DS), which is a population at high risk for early Alzheimer's disease onset. Past Down DS tau PET studies used ¹⁸F-Flortaucipir, which suffers from off-target binding in early-stage regions, limiting pathology confirmation. This study evaluates the binding of ¹⁸F-MK6240 in DS and examines the relationship between tau extent and cognition.

Tau Extent was measured in participants from the Trial Ready Cohort-Down Syndrome using ¹⁸F-MK6240 and from the Alzheimer Alzheimer's Biomarker Consortium-Down Syndrome using ¹⁸F-Flortaucipir. Data were compared, harmonized, and explored in relationship to cognitive endpoints with consideration of age, sex, apolipoprotein E (APOE) ε4 status, and level of intellectual disability.

¹⁸F-MK6240 showed binding in the mesial temporal lobe shortly following the onset of beta-amyloid plaques, similar to our observations with ¹⁸F-Flortaucipir. Increased tau extent correlated with lower episodic memory and overall cognitive performance scores. Age, intellectual disability level, and sex also influenced cognitive scores.

This first evaluation of ¹⁸F-MK6240 in DS demonstrates its suitability as a sensitive biomarker for Alzheimer's disease tau pathology. Furthermore, the inverse associations between Tau Extent as measured by both ¹⁸F-MK6240 and ¹⁸F-Flortaucipir and cognitive outcomes highlight the potential of these biomarkers to evaluate signs of early cognitive change, underscoring the urgent need to include this population in early clinical interventions.