Biomarkers

The objective of this study was to determine the predictive value of amyloid-PET versus plasma %p-tau217 (defined as the ratio of phosphorylated to non-phosphorylated Tau217 × 100), Aβ42/40, and the amyloid probability score (APS2; which combines of Aβ42/40 and %p-tau217) in tau-PET transitions (T- to T+).

Participants included were from the Mayo Clinic Study of Aging (MCSA) and had plasma markers measured by mass spectrometry (IP-MS; C2N), had an amyloid-PET scan, and had a tau-PET negative scan (SUVR<1.29, temporal meta-ROI) at the baseline, along with one or more follow-up tau-PET scans. Cox proportional hazard models were used to evaluate the relationship between C2N plasma %P-Tau217 and APS2 and incident tau-PET positivity (SUVR>=1.29) adjusting for age, sex, and APOE ε4. An analysis was also performed using amyloid-PET centiloid as the predictor. Both the plasma markers and amyloid-PET centiloid were scaled so that a one-unit change corresponds to the respective interquartile range (IQR) for comparability of hazard ratios (HR). The analyses were repeated in the BioFINDER-2 cohort for validation.

255 MCSA participants (122 female [47.8%] were included with a median age of 71.9 (IQR: 65.8, 78.8) years old, of which 37 progressed to tau-PET positivity. At baseline, 238 (93.7%) were cognitively unimpaired. Higher baseline %p-tau217 (HR: 1.52 [95% CI: 1.28, 1.8]), amyloid-PET centiloid (HR: 1.47 [95% CI: 1.20, 1.79]), and APS2 (HR: 1.62 [95% CI: 1.22, 2.16]) were associated with an increased risk of progressing to tau-PET positive (Figure 1). Aβ42/40 (HR: 1.06 [95% 0.604-1.867] was not associated with incident tau positivity Among 605 participants who were tau negative at index date in BioFINDER-2 (316 (52.2%) cognitively unimpaired), with a median age of 70.2 (IQR: 60.5-76.4), 33 progressed to tau positivity with higher %p-tau217 (HR: 1.8 [95% CI: 1.5, 2.17]), amyloid-PET centiloid (HR: 2.3 [95% CI: 1.77, 2.97]), and lower Aβ 42/40 (HR: 0.42 [95% CI: 0.21, 0.85]) at index date all associated with an increased risk of progressing to tau-PET positive.

In two independent cohorts, %p-tau217 provides predictive information about those who will convert from tau negative to tau positive on PET scan with the associations being similar to amyloid-PET.