A-112 Differential effects of chronic kidney disease on circulating concentrations of phosphorylated tau and beta amyloid Alzheimer’s Disease blood biomarkers

Abstract Aims Blood biomarkers (BBMs) are promising minimally invasive tools for the evaluation of Alzheimer’s disease (AD). However, recent studies have demonstrated that comorbidities, such as severe chronic kidney disease (CKD), may elevate circulating concentrations of various BBMs including amyloid-ß (Aß) and phosphorylated tau proteins (p-tau). Previous work has found that the effects of CKD on BBM plasma concentrations could be partially mitigated through use of biomarker ratios (e.g., the proportion of p-tau217 to non-phosphorylated tau217 (np-tau217)). In this work, we quantitatively evaluate how different combinations of BBM ratios and single biomarkers are affected in the context of decreased kidney function. Methods Participants (n=83, >57 years of age) with CKD stages 1-2 (eGFR 60-98, n = 50), and stages 3-4 (eGFR 25-59, n = 33) and without amyloid pathology (A-) were included. eGFR (mL/min/1.73 m2) was calculated using the 2021 CKD-EPI equation based on serum-paired creatinine measurements. Plasma p-tau217, np-tau217, p-tau181, np-tau181, Aß42, and Aß40 were measured by mass spectrometry (MS) (C2N Diagnostics). %p-tau217 [(p-tau217/np-tau217) x 100], %p-tau181 [(p-tau181/np-tau181) x 100], Aß42/Aß40 ratio, and p-tau217/Aß42 ratio were calculated. Log-Log (power function) best-fit regression analysis was used to quantitatively predict the relationship of BBM changes as a function of eGFR. Results Median concentrations of p-tau217, np-tau217, p-tau181, np-tau181, Aß42, and Aß40 were all significantly elevated in individuals with eGFR <60 mL/min/1.73 m2 compared to those with eGFR > or =60 (all p < 0.05). There were no differences in the %p-tau217 and Aß42/Aß40 median values between these two groups (eGFR <60 versus > or =60) (p > 0.05); whereas the proportions %p-tau181 and p-tau217/Aß42 median values were higher in the eGFR > or =60 group versus the <60 subset. Observed best-fit analyte regression equations of eGFR versus BBM concentrations predict that an eGFR decrease from 60 to 45 results in p-tau217 and p-tau181 increases of 52% (95% confidence interval (CI): 30–78%) and 40% (95% CI: 29–53%), respectively. A 16% (95% CI: 12–21%), and a 19% (95% CI: 16–23%) increase was predicted in response to the same eGFR decline for Aß42 and Aß40. Furthermore, increases of 19% (95% CI: 2–38%) for %p-tau217, 6% (95% CI: -0.02–13%) for %p-tau181 and 31% (95% CI: 12–53%) for p-tau217/Aß42 were predicted as eGFR declined from 60 to 45, while a minor decrease of 2.3% (95% CI: -5.2–0.6%) was predicted for Aß42/Aß40. Conclusions: Reduction in eGFR is associated with significant elevations in plasma concentrations of p-tau217, p-tau181, Aß42, and Aß40, which may affect the interpretations of these biomarkers. However, the use of %p-tau217, %p-tau181, or p-tau217/Aß42 could partially attenuate this effect. Although the Aß42/Aß40 ratio is not considered an effective diagnostic BBM for AD, this ratio was relatively unaffected by CKD. For example, in comparison to p-tau217 alone, using %p-tau217 or p-tau217/Aß42, the relative increase in analyte values associated with decreased eGFR was reduced by 63% and 40%, respectively. These findings provide a better understanding of the effect of reduced eGFR on AD BBM interpretation in the presence of CKD.