Physiological variability in key Alzheimer's biomarkers in amyloid-positive clinical trial cohorts and the mechanistic basis of biomarker ratios

The study examined how physiological differences between individuals contribute to variability of Alzheimer's biomarkers in blood and cerebrospinal fluid. Researchers analyzed data from four Phase III clinical trials (GRADUATE I and II, CREAD and CREAD2) and found that a large portion of biomarker variability, including A-beta40, A-beta42, p-tau181, t-tau, NfL, GFAP, sTREM2, and YKL-40, originates from physiological differences. Normalization of biomarkers using A-beta40 or A-beta42 reduced physiological variability for some biomarkers, but the effect was dependent on sample type and patient cohort. The research identified two conditions when biomarker ratio normalization is most effective: when the target and reference biomarkers share physiological variability and maintain independent biological variability. These findings help clarify when and why ratio-based approaches are most informative for biomarkers.