Background: Characterizing the frequency of plasma phosphorylated tau 217 (p-tau217) positivity across age and the Alzheimer's disease (AD) continuum is relevant to screening for AD pathology and to understanding the disease's natural history. Here, we examined the frequency of p-tau217 positivity across age in cognitively unimpaired (CU) and cognitively impaired (CI) individuals and its association with A/T groups based on amyloid-β (Aβ) and tau positron emission tomography (PET).
Methods: We evaluated 4,372 individuals across the AD continuum from six cohorts (CU: n = 3,053; CI: n = 1,319) with available p-tau217 and Aβ PET data (Table 1). Tau PET SUVR in Braak I-II regions was available for 2,133 participants (1,571 CU; 562 CI). A+ was defined as Aβ PET Centiloids > 20. P-tau217+ and T+ were defined as ≥ 2 SD above the CU reference mean. Positivity frequencies for p-tau217 and PET biomarkers were modeled using logistic and multinomial logistic regression as a function of age, sex, cohort, and Aβ PET status when applicable.
Results: The frequency of p-tau217 positivity increased with age in both CU (β = 0.09, p < 0.01) and CI (β = 0.05, p < 0.01), and was mainly associated with Aβ PET status (CU: β = 2.51, p < 0.01; CI: β = 3.33, p < 0.01) (Figure 1). Among CU A+ participants, most individuals were p-tau217− between ages 50-70 and p-tau217+ between ages 70-90 (Figure 2A). In CI A+ participants, p-tau217 positivity was predominantly observed in the A+/T+ group across ages 50-90 (Figure 2A-B). Overall, p-tau217 positivity was more associated with A+/T− in CU individuals and with A+/T+ in CI individuals across ages (Figure 2B).
Conclusion: Notably, we demonstrated for the first time that the implications of p-tau217 positivity differ by cognitive status and age, predominantly indexing A+/T− states in CU individuals and A+/T+ states in CI individuals. This pattern supports p-tau217 positivity—rather than serving merely as a proxy for Aβ or tau PET—as marking an intermediate biomarker stage between the onset of Aβ PET abnormality and subsequent tau PET positivity in the AD continuum.