Mitigating the Associations of Kidney Dysfunction With Blood Biomarkers of Alzheimer Disease by Using Phosphorylated Tau to Total Tau Ratios

Abstract

Importance: Chronic kidney disease (CKD) has been associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and p-tau181, which potentially decreases their usefulness in the diagnostic workup of Alzheimer disease (AD).

Objective: To investigate associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD.

Design, setting, and participants: This cross-sectional study included patients with mild cognitive impairment (cohort 1; enrollment in 2000-2005) and replication in cohort 2 from the Swedish BioFINDER-2 study, including both cognitively unimpaired individuals and those with cognitive impairment (enrollment in 2017-2022). All participants were from 2 memory clinics in Sweden and had plasma tau assessments and CKD status established within 6 months of plasma collection.

Exposures: P-tau217 and p-tau181, unphosphorylated peptides (Tau212-221 and Tau181-190), and the ratios (pT217/T217 and pT181/T181) as well as estimated glomerular filtration rate (eGFR) as an indicator of CKD.

Main outcomes and measures: Associations between plasma-soluble p-tau and CKD.

Results: A total of 141 participants from cohort 1 (mean [SD] age, 72.2 [7.7] years; 82 [58.2%] women) and 332 participants from cohort 2 (172 with cognitive impairment and 160 cognitively unimpaired individuals; mean [SD] age, 69.8 [9.4] years; 169 [50.9%] women) were included. Higher eGFR was associated with increased levels of plasma p-tau217, p-tau181, Tau212-221, and Tau181-190 in individuals with cognitive impairment (cohort 1: R range, -0.24 to -0.59; P < .004; cohort 2: R range, -0.18 to -0.53; P < .02) and cognitively unimpaired individuals (cohort 2: R range, -0.44 to -0.50; P < .001). However, eGFR did not correlate with the pT217/T217 ratio in patients with cognitive impairment (cohort 1: R, -0.11; P = .19; cohort 2: R, -0.02; P = .78), and the correlations with pT217/T217 ratio were significantly attenuated in cognitively unimpaired individuals (difference: R, -0.14 [95% CI, -0.22 to -0.007]; P = .001). For p-tau217 and pT217/T217, the mean fold increases in amyloid-β positive (Aβ+) compared with Aβ- groups ranged from 2.31 (95% CI, 1.86-2.77) to 4.61 (95% CI, 3.39-5.83) in participants with cognitive impairment and from 1.26 (95% CI, 0.98-1.55) to 1.27 (95% CI, 0.94-1.59) in cognitively unimpaired individuals and were clearly higher than the mean fold increases in those with CKD compared with those without CKD, ranging from 0.05 (95% CI, -0.28 to 0.38) to 0.72 (95% CI, 0.25-1.19) in participants with cognitive impairment and from 0.09 (95% CI, -0.08 to 0.26) to 0.36 (95% CI, 0.19-0.52) in cognitively unimpaired individuals.

Conclusions and relevance: In this study, CKD was associated with increased plasma levels of soluble tau, but for p-tau217 the associations were considerably lower than the association with Aβ positivity. Importantly, the ratios, and especially pT217/T217, were less associated with CKD than p-tau forms alone and therefore are likely to more accurately reflect AD-related pathological changes.

Figure 1.. Associations of Plasma of Phosphorylated Tau (p-tau) 217, Tau212-221, and pT217/T217 With Chronic Kidney Disease (CKD) and Amyloid-β (Aβ) Status

Fold increase in plasma biomarker levels in participants with CKD (CKD+) compared with those without CKD (CKD−) in cohort 1 (mild cognitive impairment, n = 141) and cohort 2 (cognitively unimpaired, n = 146 and cognitive impairment, n = 154) and in participants with abnormal compared with normal Aβ status in cohort 1 (mild cognitive impairment, n = 141) and cohort 2 (cognitively unimpaired, n = 146 and cognitive impairment, n = 154). Data are coefficients with 95% CI from linear regression models. Different x-axis scales in panels A and B reflect different magnitudes in fold changes for CKD and Aβ status. Aβ status was defined using cerebrospinal fluid Aβ42/40.

Figure 2.. Associations of Plasma of Phosphorylated Tau (p-tau) 181, Tau181-190, and pT181/T181 With Chronic Kidney Disease (CKD) and Amyloid-β (Aβ) Status

Fold increase in plasma biomarker levels in participants with CKD (CKD+) compared with those without CKD (CKD−) in cohort 1 (mild cognitive impairment, n = 141) and cohort 2 (cognitively unimpaired, n = 146 and cognitive impairment, n = 154) and in participants with abnormal compared with normal Aβ status in cohort 1 (mild cognitive impairment, n = 141) and cohort 2 (cognitively unimpaired, n = 146 and cognitive impairment, n = 154). Data are coefficients with 95% CI from linear regression models. Aβ status was defined using cerebrospinal fluid Aβ42/40.