A large, multicohort study of cognitively unimpaired older adults has found that higher plasma p-tau217 levels are consistently associated with greater risk of progression to cognitive impairment and faster rates of cognitive decline, providing time-specific absolute risk estimates and supporting the potential of p-tau217 for prognostic model development.
In this pooled multicohort study of 2,684 cognitively unimpaired participants (median age, 69.6 years; female, 63 percent) across six longitudinal Alzheimer’s disease (AD) studies (based in North America, Japan and Australia), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up, 13.5 years). [JAMA 2026;doi:10.1001/jama.2026.12556]
Each 1-standard deviation (SD) increase in baseline p-tau217 level was associated with a 38 percent increased risk of progression to cognitive impairment (hazard ratio [HR], 1.38; 95 percent confidence interval [CI], 1.30–1.46), and the association remained significant after introducing β-amyloid PET scan Centiloids (Aβ-PET-CL) values as a covariate (HR, 1.32; 95 percent CI, 1.24-1.41; p<0.001).
Model-based estimates for the absolute risk of cognitive decline over 5 years were 24 percent in participants with high (1.1–2.4 SD) and 38 percent in those with very high (>2.5 SD) baseline p-tau217. The estimated risk for these participants was markedly higher over 10 years (62 and 78 percent, respectively). However, the authors noted that the 10-year absolute risk estimates should be treated with caution due to sparsity of data, as only 5 percent of the participants were followed up >10 years, and most were from only one out of the six studies (the Harvard Aging Brain Study).
Elevated p-tau217 was also associated with faster cognitive decline based on change in latent Preclinical Alzheimer Cognitive Composite (PACC) score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/year vs 0.03 units/year in the low p-tau217 group.
The study also found male sex to be a consistent predictor of progression to clinical impairment and faster rates of cognitive decline. “Although this finding appears counterintuitive given the higher lifetime prevalence of AD among females, some studies showed that females demonstrated greater cognitive resilience in preclinical stages and only greater incidence rates past the age of 90 years,” wrote the authors. [Alzheimers Dement 2024;20:5695-5719; J Alzheimers Dis 2023;91:1231-1241]
Although studies have demonstrated that elevated levels of plasma or serum p-tau217 are associated with increased relative risk of progression to incident mild cognitive impairment or dementia in individual cohorts, they did not provide absolute risk estimates over clinically relevant time horizons. The current study thus addressed this gap by quantifying the prognostic utility of plasma p-tau217 in older adults over 2-, 5- and 10-year windows, with and without covarying for Aβ-PET-CL, across the six longitudinal trial cohorts.
“By providing time-specific absolute risk estimates anchored in both plasma and imaging biomarkers, this study aims to inform preclinical AD prevention trials and potentially future clinical decision-making if AD therapeutics become available in the cognitively unimpaired older adult population,” stated the authors.