Untitled Paper

As disease-modifying therapies for Alzheimer's disease (AD) become available, identifying at-risk individuals during the preclinical phase—when they remain cognitively unimpaired—is a clinical priority. This study investigated whether the ratio of phosphorylated to non-phosphorylated tau at threonine 217 (%p-tau217) in blood plasma can effectively predict long-term cognitive and neurodegenerative trajectories in healthy older adults.

The researchers followed 982 cognitively unimpaired older adults from the Vallecas Project in Madrid for up to 12 years. Baseline %p-tau217 levels were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Participants were categorized into four risk strata based on established cut-offs. The study analyzed longitudinal data regarding cognitive performance, hippocampal volume, functional impairment, and progression to clinical diagnosis. Findings were validated using immunoassay-based p-tau217 in the original cohort and an independent primary care cohort of 1204 individuals.

The study demonstrated that elevated and high levels of %p-tau217 are strong prognostic markers. Participants in these high-risk groups showed significantly accelerated hippocampal atrophy and sharper declines in cognitive composites compared to those with low baseline levels. Notably, the 'High' group reached risks of progression to dementia more than 21 times higher than the 'Low' group. Conversely, the 'Low' group exhibited a 92.2% negative predictive value for any progression over 10 years, suggesting that this biomarker is excellent for ruling out imminent risk in community settings. While immunoassays also performed well, the %p-tau217 ratio provided more granular risk stratification at the upper range of pathology.

These findings suggest that plasma %p-tau217 is a highly effective, non-invasive tool for population-based risk stratification in preclinical AD. By identifying individuals at minimal risk, it allows for more efficient screening, while elevated levels help identify those who may benefit from closer monitoring or inclusion in clinical trials for early intervention.