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Summary
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MK6240 tau PET is the earliest biomarker to detect abnormalities in Alzheimer's disease, appearing before plasma p-tau217 and Flortaucipir. Concordance is high, but discordant cases suggest varied biomarker emergence, with potential clinical relevance.

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Area of Science:

  • Neuroimaging and biomarker research in Alzheimer's disease (AD).
  • Investigating the relationship between amyloid-beta (Aβ) deposition, tau pathology, and plasma biomarkers in the AD continuum.

Background:

  • Distinct binding characteristics of tau positron emission tomography (PET) tracers may influence their relationship with other AD biomarkers.
  • Understanding the emergence and concordance of tau PET tracers (MK6240, Flortaucipir) and plasma p-tau217 in relation to Aβ PET deposition is crucial for tracking AD progression.

Purpose of the Study:

  • To investigate the relationship between the emergence of MK6240 and Flortaucipir tau PET tracers and plasma p-tau217 abnormalities.
  • To assess the concordance between tau PET positivity and plasma p-tau217 positivity.
  • To evaluate the relationship between these biomarkers and cognitive scores in individuals across the AD continuum.

Main Methods:

  • Evaluated 352 individuals (205 cognitively unimpaired, 147 cognitively impaired) using Aβ PET, MK6240 and Flortaucipir tau PET, and plasma p-tau217 and GFAP.
  • Modeled tau PET Braak regions and plasma p-tau217 trajectories as functions of Aβ burden (Centiloid scale) using the Lowess method.
  • Defined positivity for tau PET (Braak 1 region) and plasma p-tau217 as exceeding 2.5 z-scores, anchored on young individuals.

Main Results:

  • MK6240 showed abnormality earliest (22 Centiloids), followed by plasma p-tau217 (38 Centiloids) and Flortaucipir (56 Centiloids).
  • High overall concordance (∼80%) was observed between tau PET and plasma p-tau217 positivity.
  • Discordant cases (e.g., MK6240+/p-tau217- or MK6240-/p-tau217+) exhibited distinct patterns of Aβ burden and cognitive performance, suggesting varied biomarker emergence.

Conclusions:

  • MK6240 becomes abnormal at lower Aβ burden levels compared to plasma p-tau217 and Flortaucipir.
  • The prevalence of discordant tau PET and plasma p-tau217 positivity indicates that some individuals may show tau PET positivity first, while others may show plasma p-tau217 positivity first.
  • Distinct cognitive profiles in discordant groups suggest potential clinical relevance, necessitating further investigation into their significance in AD progression.