Biomarkers

Chronic kidney disease (CKD) is associated with increased blood-based biomarker concentrations, potentially confounding their utility in Alzheimer's disease (AD) evaluation. While plasma phosphorylated tau217 (p-tau217) is elevated in the presence of amyloid related pathology, amyloid beta 1-42 (Aβ42) is decreased. We investigated the association of plasma p-tau217, non-phosphorylated tau217 (np-tau217), Aβ42, Aβ40, as well as the Aβ42/Aβ40 and p-tau217/Aβ42 ratios, versus decreased estimated glomerular filtration rate (eGFR in mL/min/1.73 m²) in individuals without amyloid pathology.

This study included participants with CKD stages 1-2 (eGFR 60-98, n = 50), and stages 3-4 (eGFR 25-59, n = 33), who were Pittsburgh ¹¹C-Compound B amyloid-PET negative (Centiloid of < 25). Plasma p-tau217, np-tau217, Aβ42, and Aβ40 were measured by immunoprecipitation mass spectrometry (C₂N Diagnostics). %p-tau217 [(p-tau217/np-tau217) x100], Aβ42/Aβ40 ratio, and p-tau217/Aβ42 ratio were calculated. Log-Log (power function) best-fit regression analysis was used to quantitatively predict effects of changes in eGFR (2021 CKD-EPI equation) versus each single analyte or ratio (Figure 1).

Selected best-fit analyte equations versus eGFR are shown in Table 1. The predicted percent increase of p-tau217 as eGFR decreases from 60 to 45 was 52% (95% CI: 30-78%). Significantly smaller increases of 16% were predicted for Aβ42 (95% CI: 12-21%), and 19% for Aβ40 (95% CI: 16-23%) over the same eGFR range. The best-fit predicted increase for the p-tau217/Aβ42 ratio and %p-tau217 as eGFR decreases from 60 to 45 was 31% (95% CI: 12-53%), and 19% (95% CI: 2-38%), respectively. While not recommended for assessment of amyloid pathology, the Aβ42/Aβ40 ratio did not exhibit a predicted increase (-2.3% decrease, 95% CI: -5.2-0.6%) versus decreasing eGFR from 60 to 45.

The use of either %p-tau217 or the p-tau217/Aβ42 ratio (to a lesser degree) reduced the confounding effects of decreasing eGFR as compared to p-tau217 alone. Aβ42 and Aβ40 exhibited similar reduced predicted increases versus decreasing eGFR as compared to p-tau217. Relative to the predicted effects of decreasing eGFR on p-tau217 measurements, the p-tau217/Aβ42 ratio relative increase was reduced by 40%, while the relative increase was reduced by 63% for %p-tau217 measurements.