July 29, 2020 -- An elevated level of the protein tau phosphorylated at threonine 217 (p-tau-217) is an accurate biomarker for the early detection of Alzheimer's disease (AD) and appears to be specific to the pathology, according to studies reported July 28 at the annual Alzheimer's Association International Conference (AAIC).
One study was conducted at the lab of Dr. Randall Bateman, a Charles F. and Joanne Knight distinguished professor of neurology at Washington University in St. Louis. Researchers evaluated a mass spectrometry test for assessment of p-tau-217 and other tau fragments using small blood samples -- as small as 4 mL.
"To our knowledge, this is the lowest concentration ever measured by mass spectrometry for a protein marker in human blood plasma," said Nicolas Barthélemy, PhD, an assistant professor in Bateman's laboratory, in a statement about the data.
The study involved a discovery cohort with 36 participants and a validation cohort with another 92. Nano liquid chromatography was paired with tandem mass spectrometry for plasma testing. Results were presented at the AAIC meeting, which was held in a virtual format this year due to the COVID-19 pandemic, and published in the Journal of Experimental Medicine on July 28.
P-tau-217 and another tau protein that has been under investigation called p-tau-181 were both highly specific for amyloid pathology evident on positron emission tomography (PET) scans, with an area under the receiver operating characteristic (AUROC) curve of 0.99 and 0.98, respectively, in the discovery cohort, the investigators reported. In the validation cohort, p-tau-217 was still specific for amyloid pathology, with an AUROC of 0.92, which was better than p-tau-181, with an AUROC of 0.75. The analysis included an evaluation of p-tau-217 in cerebrospinal fluid (CSF).
"Importantly, CSF and plasma p-tau-217 measures distinguished amyloid-positive, tau PET-negative participants from controls," Barthélemy and colleagues wrote in J Exp Biol. "This suggests that p-tau biomarkers are changed before detectable tau aggregation and reflect abnormal soluble tau metabolism occurring concomitantly with brain [beta-amyloid] pathology."
The results suggest that plasma tau could be developed as a highly sensitive screening tool for individuals at risk of having amyloid pathology and a lower-cost alternative to PET imaging, the researchers suggested. Tau blood tests could also be complementary to beta-amyloid 42/40 ratio blood tests.
"The use of plasma p-tau biomarkers in combination with direct measurement of plasma amyloid 42/40 ratio would improve the specificity of the test and enable differential diagnosis of pure tauopathies versus diseases with mixed pathologies," the authors wrote.
The promise of presymptomatic detection
A second AAIC study also bolstered the case for p-tau-217 as a blood-based biomarker for early Alzheimer's disease. Results were published by Dr. Oskar Hansson, PhD, a professor of neurology at Lund University, and colleagues in the Journal of the American Medical Association on July 28.
Hansson and colleagues evaluated p-tau-217 in three cohorts of patients. In a total of 1,402 participants in the three cohorts, plasma p-tau-217 discriminated Alzheimer's disease from other neurodegenerative conditions "with significantly higher accuracy than established plasma- and MRI-based biomarkers," the authors reported. Furthermore, its performance was not significantly different from key CSF or PET-based measures, the team noted.
The study provides evidence that p-tau-217 levels are elevated early in the disease process during the presymptomatic phases and could be useful for detecting preclinical Alzheimer's disease, the authors reported. P-tau-217 in plasma and CSF is an early marker of Alzheimer's pathophysiology, whereas PET studies of tau mainly detect changes that occur later in the course of the disease, Hansson et al wrote.
|Summary of 3-cohort study results for p-tau-217|
|Cohort description||Highlights of findings|
|Arizona-based cohort: Neuropathologically classified participants from antemortem-postmortem donor cohort. Included 34 participants with AD and 47 without AD.||Antemortem plasma p-tau-217 differentiated neuropathologically defined AD from non-AD, AUC 0.89, with significantly higher accuracy than plasma p-tau-181 and neurofilament light chain (AUC range, 0.50-0.72).|
|Participants in prospective Swedish BioFinder-2 study. Included participants with no cognitive impairment (n = 301), mild cognitive impairment (n = 178), Alzheimer's dementia (n = 121), and other neurodegenerative diseases (n = 99).||Plasma p-tau-217 accuracy for differentiating clinical AD dementia vs. other neurodegenerative diseases (AUC, 0.96) was significantly higher than plasma p-tau-181, plasma neurofilament light, and MRI measures (AUC range, 0.50-0.81). Similar performance as p-tau-217 in CSF, p-tau-181 in CSF, and tau-PET.|
|Columbian Autosomal-Dominant AD Registry. Included 365 participants who were carriers of PSEN1 E280A mutations and 257 age- and sex-matched nonmutation carriers.||Plasma p-tau-217 levels were significantly greater in PSEN1 mutation carriers, compared with noncarriers, from 25 years and up (20 years prior to estimated onset of mild cognitive impairment in mutation carriers).|
Potential applications of a blood test for detecting early disease include use in establishing a correct diagnosis and differentiating the condition from other neurodegenerative diseases. Blood testing could also enable recruitment in Alzheimer's prevention trials, with potential to speed up the development of treatments.
More research is needed to optimize the p-tau-217 blood test and validate findings in diverse populations, Hansson and colleagues wrote. It's possible that in the future it could find a role in facilities where access to CSF and PET scans is limited, such as in primary care settings and/or low- and middle-income countries, they suggested.
Data from populations more representative of real-world clinical practice are needed as the research populations tend to be pretty homogenous -- with participants who are highly educated and with a high socioeconomic status, said Dr. Suzanne Schindler, an instructor in neurology at Washington University, during a July 28 press briefing held by the AAIC. That's in contrast with people who are seen in the clinic, who have a lot of medical comorbidities and present challenges for diagnosis, she said.
Research with tau blood tests is in the discovery stage, and it takes time to develop assays into a commercial product, Bateman suggested during the press briefing. Further validation steps are needed, and it could take several years to get a test approved by regulatory agencies and reimbursed by insurance companies to enable widespread use.