A blood-based biomarker could predict a person’s risk of developing Alzheimer’s disease years before any symptoms arise, research suggests.
Plasma levels of phosphorylated tau 217 (p‑tau217) may one day help identify at-risk individuals before overt signs of dementia, enabling the pre-emptive use of disease-modifying therapies.
Higher plasma p‑tau217 levels were associated with a greater risk of progressing to cognitive impairment in previously unaffected older adults, and they also predicted faster levels of decline.
The research findings appear in JAMA and were simultaneously presented this week at the annual Alzheimer’s Association International Conference in London.
“In this longitudinal study of several selected cohorts, plasma p-tau217 provided long-term prognostic information for individuals who were cognitively unimpaired at baseline, laying the groundwork for possible future development of individualized risk prediction scores,” proposed Rachel Buckley, PhD, from Mass General Brigham, and co-workers in their published work.
“By providing absolute risk estimates of progression to cognitive impairment, this article moves the field closer to presymptomatic risk stratification with p-tau217, supporting trial design.”
The large, pooled multicohort study included 2684 cognitively unimpaired older adults from six longitudinal studies, who were followed for a median of 5.4 years. Their median age was just short of 70 years, and 63% were women.
Results showed that higher baseline p-tau217 was significantly associated with an increased risk of progression to cognitive impairment during up to 13.5 years of follow up, with a hazard ratio of 1.38 per standard deviation (SD) increase.
This remained significant after accounting for age, sex, education, apolipoprotein E ε4 status, cohort, as well as amyloid positron emission tomography—known to accurately detect Alzheimer’s disease brain pathology.
The researchers report that the absolute risk of cognitive decline at five years was “meaningfully elevated” in the group with very high p-tau217 levels (≥2.5 SD) at 38%, versus just 12% in group with low levels.
Estimated 10-years risks were substantially higher at between 40% and 78% for the low and high p-tau217 groups, respectively. However, just 139 participants—or one in every 20—were followed up for at least a decade and the researchers say these risk estimates should be treated with caution.
Elevated p-tau217 was also associated with faster decline on the harmonized latent Preclinical Alzheimer Cognitive Composite assessment tool.
In an editorial accompanying the published study, Suzanne Schindler, PhD, from Washington University in St Louis school of medicine, and David Wolk, MD, from the University of Pennsylvania, note that cognitive impairment likely reflected multiple etiologies, not just Alzheimer’s disease.
“Indeed, even the low p-tau217 group, in which Alzheimer disease pathology was minimal or absent, still had a 12% risk of progression to cognitive impairment at five years, suggesting the importance of other drivers of cognitive decline in this population and the likelihood that in the higher p-tau217 groups, some proportion of individuals who declined may have primarily been driven by other processes,” they pointed out.
“Notably, discordance between plasma p-tau217 and amyloid PET (especially at intermediate or low amyloid levels) highlights that biomarkers beyond p-tau217 could further improve risk prediction.”
Nonetheless, overall they summarized: “The study by Buckley et al. represents a significant advance. It demonstrates that plasma p-tau217 can provide a time-specific absolute risk estimate for development of cognitive impairment.”
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