Clinical Manifestations

Tau PET tracers present distinct binding characteristics that might influence their trajectories and relationship with other biomarkers along the AD continuum. In a head-to-head study, we investigated the relationship between the emergence of PET tracers MK6240 and Flortaucipir, and plasma p-tau217 abnormalities as a function of Aβ PET deposition. We further assessed the concordance between tau PET and plasma p-tau217 positivity and its relationship with cognitive scores.

We evaluated 352 individuals from the HEAD study (205 cognitively unimpaired and 147 cognitively impaired) with Aβ PET, MK6240 and Flortaucipir tau PET, and plasma p-tau217 (ALZpath) and GFAP (Quanterix) measures. Tau PET Braak regions, plasma p-tau217 trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Biomarkers were z-scored anchored on young individuals (n = 19, < 28 years old) as anchors. Tau PET (Braak 1 region) and plasma p-tau217 were considered positive/abnormal when surpassing 2.5 z-score.

Among the tested markers, MK6240 was the earliest to show abnormality as a function of Centiloid, occurring at 22 Centiloids, followed by plasma p-tau217 at 38 Centiloid and Flortaucipir at Centiloid 56 (Figure 1). Tau PET and plasma p-tau217 positivity showed an overall high concordance (∼80% for both tracers; Figure 2). In MK6240 discordant cases, most individuals were MK6240+/p-tau217- (13.8%), while 6.6% were MK6240-/p-tau217+ (Figure 2A). For Flortaucipir, 15% of discordant cases were Flortaucipir-/p-tau217+, while 4.8% were Flortaucipir+/p-tau217- (Figure 2B). The discordant groups present higher Centiloid than the ptau217-/Tau- group and overall decreased scores in cognitive tests, except for p-tau217+/MK6240- group (Figure 3).

MK6240 becomes abnormal at lower levels of Aβ burden compared to plasma p-tau217 and Flortaucipir. The relatively high prevalence of discordant tau PET positive or plasma p-tau217 positive and suggests that some individuals may show tau PET positivity first, while others may exhibit plasma p-tau217 positivity first. The distinct cognitive profiles of this groups suggest potential clinical relevance, warranting further investigation.