Kidney Disease Skews Alzheimer's Biomarker Testing

Megan Brooks

April 05, 2023

New research provides more evidence that tau plasma biomarkers associated with Alzheimer's disease (AD) can be skewed by chronic kidney disease (CKD) and suggests that using ratios of these biomarkers can attenuate the skewed results.

In a cross-sectional study of adults with and those without cognitive impairment, CKD was associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and 181.

However, there were no associations between CKD and the ratio of p-tau217 to unphosphorylated tau 217 (pT217/T217), and the associations with p-tau181 to unphosphorylated tau 181 (pT181/T181) were attenuated in patients with cognitive impairment.

"These novel findings suggest that plasma measures of the phosphorylated to unphosphorylated tau ratios are more accurate than p-tau forms alone as they correlate less with individual difference in glomerular filtration rate or impaired kidney function," the investigators, led by Oskar Hansson, MD, PhD, with Lund University in Sweden write.

"Thus, to mitigate the effects of non-AD-related comorbidities like CKD on the performance of plasma AD biomarkers, certain tau ratios, and specifically pT217/T217, should be considered for implementation in clinical practice and drug trials," they add.

The study was published online March 29 in JAMA Neurology to coincide with a presentation at the International Conference on Alzheimer's and Parkinson's Diseases (AD/PD 2023) in Gothenburg, Sweden.

Skewed Tau Levels

Plasma biomarkers of amyloid-beta (Aβ) and tau pathologies, and in particular variants in p-tau217 and p-tau181, have shown promise for use in AD diagnosis and prognosis.

However, previous reports have suggested that CKD might influence plasma p-tau217 and p-tau181 concentrations, potentially decreasing their usefulness in the diagnostic workup of dementia.

Researchers investigated associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD.

The data came from 473 older adults, with and without cognitive impairment, from the Swedish BioFinder-2 study who had plasma tau assessments and CKD status established within 6 months of plasma collection.

The researchers found that lower eGFR levels (indicative of kidney dysfunction) were associated with higher plasma concentrations of phosphorylated and unphosphorylated tau peptides measured simultaneously using the tau immunoprecipitation mass spectrometry (IP-MS) assay.

However, the correlations with eGFR were nonsignificant for the pT217/T217 ratio in individuals with cognitive impairment and were significantly attenuated for pT217/T217 in cognitively unimpaired individuals and for pT181/T181 in both cognitively unimpaired and impaired individuals.

"Importantly, we demonstrate that there were no significant associations between CKD and the pT217/T217 ratio and changes in plasma pT181/T181 associated with CKD were small or nonsignificant," the researchers note.

"Our results indicate that by using p-tau/tau ratios we may be able to reduce the variability in plasma p-tau levels driven by impaired kidney function and consequently such ratios are more robust measures of brain p-tau pathology in individuals with both early- and later-stage AD," they add.

The researchers believe this is likely true for the ratios of other related proteins ― a view that is supported by findings of attenuated associations of CKD with Aβ42/40 compared with Aβ42 and Aβ40 in the current study and in previous studies.

Important Clinical Implications

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer's Association senior director of scientific engagement, noted that research continues to indicate that blood biomarkers have "promise for improving, and possibly even redefining, the clinical workup for Alzheimer's.

"Many of the Alzheimer's blood tests in development today have focused on core blood biomarkers associated with amyloid accumulation and tau tangle formation in the brain," Edelmayer told Medscape Medical News.

"Before these tests can be used more broadly in the clinic, we need to understand all of the variables that may impact the results of various blood biomarkers, including differences that may be driven by race, ethnicity, sex, and underlying health conditions, such as chronic kidney disease.

"This study corroborates other research suggesting that some Alzheimer's-associated markers can be affected by chronic kidney disease, but by using ratios of amyloid or tau markers, we may be able to minimize these differences in results caused by underlying disease," Edelmayer said.

Also weighing in on the findings for Medscape Medical News, Howard Fillit, MD, co-founder and chief science officer at the Alzheimer's Drug Discovery Foundation, said, "Using these ratios makes a lot of sense because the ratios wouldn't change with kidney function. I think this is an important advance in clinical utilization of these tests."

Fillit noted that older people often have declining kidney function, which can be easily measured by GFR. Changes in blood levels of these markers with declining kidney function are "not unexpected, but [it's] important that it's been demonstrated.

"As we go forward, maybe the future utilization of these tests will be not only recording the ratios but also reporting the ratios in the context of somebody's GFR. You could imagine a scenario where when the test is done, it's automatically done alongside of GFR," Fillit told Medscape Medical News.

The study was supported by Coins for Alzheimer's Research Trust, the Tracy Family Stable Isotope Labeling Quantitation Center, and the National Institute of Neurological Disorders and Stroke. Hansson has received support to his institution from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche; consultancy/speaker fees from Amylyx, Alzpath, Biogen, Cerveau, Fujirebio, Genentech, Novartis, Roche, and Siemens; and personal fees from Eli Lilly and Company, Eisai, Bioarctic, and Biogen outside the submitted work. Edelmayer and Fillit have disclosed no relevant financial relationships.

JAMA Neurol. Published online March 29, 2023. Full text

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.