Confounding factors of Alzheimer's disease plasma biomarkers and their impact on clinical performance

Binette, Alexa Pichet; Janelidze, Shorena; Cullen, Nicholas; Dage, Jeffrey L.; Bateman, Randall J.; Zetterberg, Henrik; Blennow, Kaj; Stomrud, Erik; Mattsson‐Carlgren, Niklas; Hansson, Oskar

doi:10.1002/alz.12787

Cited by 86 publications

(85 citation statements)

References 58 publications

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“…This is likely true for the ratios of other related proteins, which is supported by the findings of attenuated associations of CKD with Aβ42/40 compared with Aβ42 and Aβ40 in the present study and in previous publications. Interestingly, we also found that the correlations of eGFR with p-tau217 (but not p-tau181) were weaker in patients with cognitive impairment than in cognitively unimpaired participants. Further, we report that in patients with cognitive impairment, Aβ positivity was associated with considerably larger increases in p-tau217 levels compared with the increases observed in CKD.…”

Section: Discussionsupporting

confidence: 90%

“…Previous reports have suggested that CKD might influence plasma p-tau217 and p-tau181 concentrations determined using immunoassays . Here we corroborated these findings in cognitively unimpaired participants and 2 independent cohorts of patients with cognitive impairment using the IP-MS approach, which typically offers more accurate and reliable quantification of AD biomarkers in blood .…”

Section: Discussionsupporting

confidence: 88%

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

Janelidze

Barthélemy

et al. 2023

JAMA Neurol

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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 &lt; .004; cohort 2: R range, −0.18 to −0.53; P &lt; .02) and cognitively unimpaired individuals (cohort 2: R range, −0.44 to −0.50; P &lt; .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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 88%

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

Janelidze

Barthélemy

et al. 2023

JAMA Neurol

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“…Our results are in accordance with previous studies about the associations between renal function and plasma Aβ42/40 and NfL levels, which reported that eGFR was not associated with Aβ42/40 but negatively associated with NfL ( Akamine et al, 2020 ; Pichet Binette et al, 2022 ). However, none of them investigated the impact of renal function on the diagnostic performance of Aβ42/40 and NfL.…”

Section: Discussionsupporting

confidence: 93%

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer’s disease

Zhang

Zhang²,

Wang³

et al. 2023

Front. Aging Neurosci.

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BackgroundSeveral blood-based biomarkers are promising to be used in the diagnosis of Alzheimer’s disease (AD) including Aβ42/40, p-tau181, and neurofilament light (NfL). The kidney is associated with the clearance of proteins. It is crucial to evaluate the effect of renal function on the diagnostic performance of these biomarkers before clinical implementation, which is important for the establishment of reference ranges and the interpretation of results.MethodsThis study is a cross-sectional analysis based on ADNI cohort. Renal function was determined by the estimated glomerular filtration rate (eGFR). Plasma Aβ42/40 was measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma p-tau181 and NfL were analyzed by Single Molecule array (Simoa) technique. [18F] florbetapir-PET (Aβ-PET) was used as a reference standard to estimate the brain amyloid load. The cutoff of Aβ-PET positivity was defined as ≥1.11. Linear regression models were used to investigate the associations of continuous eGFR with each plasma biomarker separately. The diagnostic accuracies of plasma biomarkers for positive brain amyloid across different renal function groups were analyzed by Receiver operating characteristic (ROC) curve. Youden-Index was used to determine the cutoff levels.ResultsA total of 645 participants were included in this study. The levels and diagnostic performance of Aβ42/40 were not affected by renal function. eGFR was only found negatively associated with p-tau181 levels in Aβ-PET negetive sample (β = −0.09, p = 0.039). eGFR was found negatively associated with NfL levels both in whole sample and Aβ-PET stratified groups (β = −0.27, p < 0.001 in whole sample; β = −0.28, p = 0.004 in A−; β = −0.27, p < 0.001 in A+). The diagnostic accuracies of p-tau181 and NfL were not affected by renal function. But the cutoff values of p-tau181 and NfL changed in participants with mild to moderate eGFR decline compared to participants with normal eGFR.ConclusionPlasma Aβ42/40 was a robust biomarker for AD which was not affected by renal function. Plasma p-tau181 and NfL levels were affected by renal function, specific reference values of them should be considered in populations with different renal function stages.

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“…Adjusted models additionally included age at index visit, sex, race, APOE ε 4 status, and age × time interaction. We also included eGFR and body mass index (BMI) concurrent with plasma measurement as covariates given their associations with plasma biomarkers [30].…”

Section: Methodsmentioning

confidence: 99%

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

Bilgel

Walker

et al. 2023

Preprint

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IntroductionUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise disease progression assessment strategies for Alzheimer’s disease.MethodsWe examined the temporal order of changes in plasma amyloid-×βratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and two phosphorylated tau ratios (p-tau181/Aβ42and p-tau231/Aβ42) relative to11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199, Baltimore Longitudinal Study of Aging) were cognitively normal at index visit with a median 6.1-year follow-up.ResultsPiB− individuals exhibited longitudinal decline in Aβ42/Aβ40(β= ×−3.85 ×10−5, SE = 9.77 × 10−4,p= 1.96 × 10−4), whereas PiB+ did not exhibit change. Change in brain amyloid was correlated with change in GFAP (r= 0.5, 95% CI = [0.26, 0.68]) and NfL (r = 0.4 [0.13, 0.62]). Greatest relative decline in Aβ42/Aβ40(−1% per year) preceded brain amyloid positivity onset by 41 years (95% CI = [32, 53]).DiscussionPlasma Aβ42/Aβ40may begin declining decades prior to brain amyloid, whereas p-tau ratio, GFAP, and NfL increase closer in time to, and in parallel with, brain amyloid accumulation.HighlightsPlasma Aβ42/Aβ40declines over time among PiB− but does not change among PiB+p-tau to Aβ42ratios increase over time among PiB+ but do not change among PiB−Rate of change in brain amyloid is correlated with change in GFAP and NfLGreatest decline in Aβ42/Aβ40may precede brain amyloid positivity by decades

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Confounding factors of Alzheimer's disease plasma biomarkers and their impact on clinical performance

Cited by 86 publications

References 58 publications

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

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

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer’s disease

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

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