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

Abstract

ImportanceChronic 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).ObjectiveTo investigate associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD.Design, Setting, and ParticipantsThis 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.ExposuresP-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 MeasuresAssociations between plasma-soluble p-tau and CKD.ResultsA 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 RelevanceIn 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.

Diagnostic performance of plasma Aβ1-42, Aβ1-40and pTau181in the LUMIPULSE automated platform for the detection of Alzheimer disease

“…The effect of comorbidities as CKD on plasma biomarker concentrations points in the same direction as recently published studies [29] in which the use of ratios, in this case different isoforms of pTau with their corresponding unphosphorylated peptides, even analyzed on different platforms, could attenuate the effect of CKD.…”

Fully automated measurement of plasma Aβ42/40 and p‐tau181: Analytical robustness and concordance with cerebrospinal fluid profile along the Alzheimer's disease continuum in two independent cohorts

“…On the contrary, impaired renal function will likely generate false positive results on plasma p-tau181. 11 Following the results obtained by Bellaver et al, 12 we considered BBB permeability (reflected by CSF/serum albumin ratio levels) as another potential confounder. The highest agreement between CSF and plasma biomarkers -both Aβ42/40 and p-tau181 -was observed in patients with the highest CSF/serum albumin ratio.…”

“…The presence of KD was defined if the glomerular filtration rate was < 60 mL/min/1.73 m 2 . 11 With respect to CSF/serum albumin ratio, patients were categorized into those with low, medium, and high ratio based on the tertile partition of the cohort as previously described by Bellaver et al. 12 Detailed information about how patients with AD, PD, PD with dementia (PDD), DLB, and FTD were diagnosed is present in the Supplementary Material.…”

“…The presence of KD was defined if the glomerular filtration rate was < 60 mL/min/1.73 m 2 . 11 With respect to CSF/serum albumin ratio, patients were categorized into those with low, medium, and high ratio based on the tertile partition of the cohort as previously described by Bellaver et al 12 Detailed information about how patients with AD, PD, PD with dementia (PDD), DLB, and FTD were diagnosed is present in the Supplementary Material. The UNIPG cohort was used to determine the distribution of plasma Aβ42/40 and p-tau181 in the different A/T categories and clinical groups, to evaluate the impact of KD and BBB permeability on the concordance between CSF and plasma biomarkers, and for model training.…”

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry‐based test with algorithm combining %p‐tau217 and Aβ42/40 ratio to identify presence of brain amyloid

“… 40 Our current dataset lacked the necessary variables to carefully assess the effect of kidney disease as well as other comorbidities; however, that work is currently ongoing in other studies. Published data by others 41 using an LC‐MS/MS method akin to that used herein for protein quantitation have revealed that kidney disease as measured by lower levels of estimated glomerular filtration rate is associated with higher plasma levels of soluble tau, including p‐tau217 and p‐tau181, in individuals with and without cognitive impairment. The confounding effect of kidney disease was markedly diminished with the %p‐tau217 measurement, suggesting that the p‐tau217/np‐tau217 ratio is a more reliable measure of brain p‐tau pathology in individuals across the AD spectrum and, thus, may be more diagnostically robust for implementation in real‐world clinical practice.…”