Plasma Aβ42/Aβ40 ratio is independent of renal function

Abstract

Letter to the Editor in response to Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities, J.A. Syrjanen, M.R. Campbell, A. Algeciras-Schimnich, P. Vemuri, J. Graff-Radford, M.M. Machulda, G. Bu, D.S. Knopman, C.R. Jack, Jr., R.C. Petersen, M.M. Mielke, Alzheimer's & dementia: the journal of the Alzheimer's Association 18(6) (2022) 1128-1140. https://doi.org/10.1002/alz.12466 We read with great interest the recent article by Syrjanen et al., who reported the association of comorbidities with amyloid and neurodegeneration plasma biomarkers.1 Their main conclusion was that a history of chronic kidney disease was associated with significant elevations of all Alzheimer's disease (AD) biomarkers in a large population of cognitively unimpaired participants, that is, that chronic kidney disease is a confounding factor that needs to be taken into account. This important contribution complemented their work focusing on plasma phosphorylated tau (P-Tau) levels in AD patients.2 We also recently investigated the interest of plasma amyloid beta peptides (Aβ) in a large cohort of cognitively impaired patients, where history of kidney disease was available.3 Our cohort had the further benefit of onsite measurement of blood creatinine as a proxy for and estimate of glomerular filtration rate (eGFR).4 This gave us an opportunity to test Syrjanen's findings, in another population and using biological results to estimate renal function. By having access not only to kidney disease history but also to continuous numerical values of renal function, one can expect more accurate results and more clinically relevant conclusions. As illustrated in Figures 1A,C, plasma Aβ40 and Aβ42 levels are higher with chronic kidney disease history, as well as in high-blood-creatinine and low-eGFR subjects. Importantly, however, unlike the individual components, the plasma Aβ42/Aβ40 ratio is not associated with any of these factors and therefore is independent of impaired renal function. This was also reported recently in cohorts with longitudinal measures of kidney function.5 We then split our population into categories of decreasing kidney function following the KDIGO staging system6 based on eGFR (<45, 45–60, or 60–90 ml/min/1.73m2). As illustrated in Figures 1D,F, altered kidney function progressively impacted plasma Aβ40 and Aβ42 levels for all categories, but not the Aβ42/Aβ40 ratio. Correlative scatter plots for all the included subjects confirmed this association (Figures 1G,I) The rationale for the “resistance” of the Aβ42/Aβ40 plasma ratio to altered renal function is likely linked to the fact that the two peptides are equally affected by this comorbidity. Further work, including the study of the renal clearance of the different Aβ isoforms, will be needed to confirm this hypothesis. Irrespective of the causes, our cohort reveals that computing the Aβ42/Aβ40 ratio dissects away the confounding effect of renal dysfunction. It is noteworthy that studies evaluating cerebrospinal fluid7 and blood Aβ rely primarily on this Aβ42/40 ratio rather than on the individual levels of Aβ40 or Aβ42. In cerebrospinal fluid, the ratio largely overrides preanalytical biases of the individual peptides since it takes into account individual variations in Aβ production and amplifies the synergistic effect of Aβ40 increase8 and Aβ42 decrease in AD. In blood, we propose that calculating the Aβ42/40 ratio will also reduce biases linked to altered renal function, which nevertheless needs to be taken into account for other biomarkers in future large population screens.9 It will also reduce the risk of false positives in elderly people who have a high prevalence of AD and renal dysfunction; over 70 years of age the proportion of people with a GFR < 60 ml/min/1.73 m2 varies from 38% to 62% depending on the estimation equation used.10 The independence of Aβ42/Aβ40 plasma ratio to renal dysfunction will also be useful to confirm the association between this comorbidity and prevalence of dementia.11 The fact that computing the ratio between Aβ42 and Aβ40 reduced biases is an example that could be followed for other blood biomarkers. We have in mind Tau, which exists in multiple phosphorylated and nonphosphorylated isoforms.12 In conclusion, the fact that the plasma Aβ42/Aβ40 ratio is independent of renal function adds greatly to its value for AD diagnosis and prognosis compared with blood P-Tau and Nfl, which are strongly affected by this comorbidity.1 Sylvain Lehmann and Olivier Hanon contributed equally to this work. We acknowledge the contribution of the BALTAZAR study group in the cohort creation and analysis. The French ministry of Health (Programme Hospitalier de Recherche Clinique), Grant/Award Numbers:PHRC2009/01-04,PHRC-13-0404; The Foundation Plan Alzheimer; Fondation pour la Recherche Médicale (FRM); The Gerontopôle d'Ile de France (GERONDIF). None of the funding bodies had any role in study design, in the collection, analysis, and interpretation of data, in the writing of the report or in the decision to submit the paper for publication. The authors have declared no conflicts of interest. Author disclosures are available in the supporting information. Data and informed consent form are available upon request after publication (APHP, Paris). Requests will be considered by each study investigator based on the information provided by the requester regarding the study and analysis plan. If the use is appropriate, a data sharing agreement will byhhn e put in place before a fully de-identified version of the dataset, including the data dictionary used for analysis with individual participant data, is made available. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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