Plasma p-tau217 Clock Models Estimate Time to Symptomatic Alzheimer Disease
A single plasma % phosphorylated tau217 (%p-tau217) measurement may estimate not only risk but also timing of symptomatic Alzheimer disease (AD) onset, according to a longitudinal cohort study published in Nature Medicine. In 2 independent cohorts, clock models based on plasma %p-tau217 (ratio of phosphorylated to nonphosphorylated tau at position 217) predicted age at symptom onset with a median absolute error (MdAE) of approximately 3 to 4 years.
In the study, investigators analyzed longitudinal plasma %p-tau217 data from the Knight Alzheimer Disease Research Center (ADRC) (n=258 for clock development) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n=345). Participants had longitudinal plasma samples collected ≥1 year apart within a defined interval of consistent change in plasma %p-tau217 (1.06% to 10.45%). Plasma positivity was defined at 4.06%, corresponding to amyloid PET Centiloid 20. Two modeling approaches—Temporal Integration of Rate Accumulation (TIRA) and Sampled Iterative Local Approximation (SILA)—estimated age at %p-tau217 positivity and were used to model time to symptomatic AD (CDR>0 with AD syndrome).
Key findings include the following:
- Estimated age at %p-tau217 positivity correlated with observed conversion age (Knight ADRC TIRA adjusted R², 0.733; ADNI TIRA adjusted R²=0.815).
- Cox models demonstrated good discrimination for progression to symptomatic AD (Knight ADRC TIRA C-index, 0.784; 95% CI, 0.720 to 0.843).
- Age at %p-tau217 positivity was moderately associated with age at symptom onset (Knight ADRC TIRA adjusted R², 0.599; SILA Knight ADRC adjusted R², 0.612).
- Models predicting symptom onset demonstrated an MdAE of 3.0 to 3.7 years.
Older age at biomarker positivity was associated with shorter time to symptom onset (eg, 20.5 years if positive at age 60 years vs 11.4 years at age 80 years).
Source: Petersen, K.K., Milà-Alomà, M., Li, Y. et al. Predicting onset of symptomatic Alzheimerʼs disease with plasma p-tau217 clocks. Nat Med (2026). https://doi.org/10.1038/s41591-026-04206-y