Target Audience and Goal Statement: Neurologists, hematologists, radiologists
The goal of this study was to assess the application of a new ultrasensitive blood immunoassay for tau phosphorylated at threonine 181 (p-tau181) for the detection of Alzheimer’s disease pathology.
Question Addressed:
Two proteinopathies that define Alzheimer’s disease — deposits of aggregated amyloid β and deposits that contain a mixture of three-repeat and four-repeat tau isoforms — can be detected in vivo. However, detecting these biomarkers has either been expensive, as with positron emission tomography (PET) scans, or invasive, as with cerebrospinal fluid (CSF) sampling, which requires a lumbar puncture.
Blood testing has the potential to be used in a variety of relevant settings, including primary care, community-based medicine centers, or even in a patient’s home, and at repeated intervals. However, detection of plasma amyloid β (ratio of amyloid β1-42 to amyloid β1-40), which reflects brain amyloidosis, via mass spectrometry is complicated by assay limitations and the fact that 10-30% of cognitively unimpaired individuals also exhibit brain amyloidosis.
Tau is a microtubule-associated protein that regulates the assembly and stability of microtubules in the axons of neurons. It is a major component of neurofibrillary tangles — an Alzheimer’s hallmark — and has more than 40 phosphorylation sites. CSF p-tau181 is known to be a highly specific pathological marker of Alzheimer’s disease, which remains normal in other dementias.
In a new study published in Lancet Neurology, Canadian and Swedish researchers reported on the development and validation of an ultrasensitive blood test for p-tau181 for the detection of Alzheimer’s disease pathology.
Traditional immunoassays are conducted in a relative large reaction volume of 50-100 μL (e.g., wells in 96-well plates) and detect signal molecules in the picomolar range (i.e., 10-12 M). Kaj Blennow, MD, of the University of Gothenburg in Sweden, and colleagues adapted an assay based on measurement of p-tau181 in ordinary blood samples using a more sensitive single molecule array technique, which can detect proteins in blood at sub-femtomolar concentrations (i.e., 10-16 M).
Evidence from the literature has suggested that tau in blood and CSF might be processed differently, with mainly N-terminal forms of tau present in measurable quantities in blood. Blennow’s group focused on a novel N-terminal form of tau that is distinct from the mid-region forms targeted by the established CSF assays.
Blennow and colleagues evaluated their immunoassay in 1,131 people across four independent samples: a discovery cohort of 37 Alzheimer’s patients and age-matched controls, two observational research cohorts of 226 (TRIAD, which included younger participants and people with frontotemporal dementia) and 763 people (BioFINDER2, which included people with other neurodegenerative disorders), and a primary care cohort of 105 patients in the Canadian National Health Service who were referred to a dementia specialist but did not have biomarker assessment or neurologic diagnosis. A subset of TRIAD participants had MRI and cognitive testing at 1 year.
Linear regression models tested the associations between plasma p-tau181 at baseline and a 1-year change in cognition (using the Mini Mental State Examination score) and structural imaging (using hippocampus grey matter density). Linear regressions were corrected for age, sex, APOE4 genotype, and years of formal education.
Blennow and team showed that the assay was specific for the p-tau181 site, did not capture non-phosphorylated tau species, and showed good diagnostic performance for Alzheimer’s disease in both plasma and serum. In all cohorts, plasma p-tau181 concentrations increased progressively from amyloid β-negative young adults to amyloid β-positive cognitively unimpaired older adults to amyloid β-positive patients with dementia, suggesting that the assay is sensitive along the entire Alzheimer’s disease continuum.
The blood test also showed the capacity to distinguish Alzheimer’s from other brain diseases. Plasma p-tau181 distinguished Alzheimer’s dementia from amyloid β-negative young adults (area under the curve [AUC] 99.40%) and cognitively unimpaired older adults (AUC 90.21%-98.24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC 82.76%-100% across cohorts), vascular dementia (AUC 92.13%), progressive supranuclear palsy or corticobasal syndrome (AUC 88.47%), and Parkinson’s disease or multiple systems atrophy (AUC 81.90%).
Specific p-tau181 in the blood also corresponded very closely with the level of tau tangles in the brain observed on a PET scan.
“P-tau181 levels in blood samples are increased in individuals who have a positive amyloid scan but not yet a positive tau PET scan, suggesting that plasma p-tau181 becomes positive before tau PET,” Blennow said.
“These findings show p-tau181 in blood samples works very well to identify Alzheimer’s pathology,” and could serve as an easily accessible, cheap test for Alzheimer’s disease in primary care, he told MedPage Today.
The researchers acknowledged that the primary care cohort had no CSF or PET imaging assessments, precluding an etiological diagnosis of individuals with mild cognitive impairment and identification of preclinical Alzheimer’s-type pathophysiology in cognitively normal older adults. Although their findings suggest that baseline plasma p-tau181 has potential clinical applications for prognosis and longitudinal monitoring, the researchers stated that the “relatively short duration of the longitudinal evaluations and the small number of individuals with longitudinal cognition and imaging biomarkers limits the interpretation of these results.”
Source References: Lancet Neurology 2020; DOI: 10.1016/S1474-4422(20)30071-5
Editorial: Lancet Neurology 2020; DOI: 10.1016/S1474-4422(20)30112-5
Study Highlights and Explanation of Findings:
Plasma p-tau181 provided high diagnostic accuracy for Alzheimer’s disease in four independent cohorts, discriminated amyloid β-positive cognitively unimpaired older adults and amyloid β-positive individuals with mild cognitive impairment from amyloid β-negative cognitively unimpaired older adults and young adults, and identified clinically diagnosed Alzheimer’s patients with unknown brain amyloid status, according to Blennow and team. The test also predicted cognitive decline/hippocampal atrophy over a period of 1 year, and could differentiate Alzheimer’s from other neurodegenerative diseases with high performance.
“Furthermore, plasma p-tau181 performed better than the most well-known Alzheimer’s disease risk factors (age, APOE4 genotype, or both) and other plasma biomarkers (total-tau, amyloid β1-42, amyloid β1-42 to amyloid β1-40 ratio, and total-tau to amyloid β1-42 ratio) in predicting Alzheimer’s disease diagnosis, increased tau PET, and increased amyloid β PET,” the team wrote.
“It was a challenge because these proteins are in very low amounts in the blood,” explained co-author Tharick Pascoal, MD, of the McGill University Research Centre for Studies in Aging in Montreal.
“If you compare with the fancier tests, such as PET or cerebrospinal fluid, we saw that they are almost the same for several applications,” he added. “The results were amazing. We were very surprised, to be honest, and very excited. We didn’t expect that a simple blood test could give very similar results to the PET technique.”
“This is a game changer,” agreed co-author Serge Gauthier, MD, also of the McGill University Research Centre for Studies in Aging.
He pointed out that the test, used at this early stage, will identify a risk factor, but is not a diagnosis (much like a cholesterol test can identify a risk factor for heart disease). “There is no treatment for mild cognitive impairment except for lifestyle changes, especially lowering blood pressure, keeping the mind and body busy — all the good things you’re supposed to do,” he said in a statement. “But people will be more motivated to do it if they know they have elevated proteins and are at risk.”
“Plasma p-tau181 is an important advance that could transform the diagnosis of Alzheimer’s disease,” wrote Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.
The assay has potential use in both clinical practice and disease-modifying trials, though “how plasma p-tau181 would perform as an indicator of target engagement is unclear,” he observed.
Many aspects need further study, including the assay’s longitudinal stability and precision, how it evolves over time in individuals, and how it relates to cognitive impairment development and changes in tau PET, he added. “A thoughtful approach will be needed concerning application of plasma p-tau181 in asymptomatic individuals, and recommended use guidelines by expert panels are likely to be required,” he continued.
In addition, CSF studies have “indicated that other pathological phosphorylation sites might also be diagnostically useful, particularly tau phosphorylated at threonine 217 (p-tau217), and studies comparing the diagnostic performance of plasma p-tau181 and p-tau217 will be important,” Jack noted.
The goal of this study was to assess the application of a new ultrasensitive blood immunoassay for tau phosphorylated at threonine 181 (p-tau181) for the detection of Alzheimer’s disease pathology.
Question Addressed:
- Could plasma p-tau181 help indicate the pathophysiological status of Alzheimer’s disease?
Two proteinopathies that define Alzheimer’s disease — deposits of aggregated amyloid β and deposits that contain a mixture of three-repeat and four-repeat tau isoforms — can be detected in vivo. However, detecting these biomarkers has either been expensive, as with positron emission tomography (PET) scans, or invasive, as with cerebrospinal fluid (CSF) sampling, which requires a lumbar puncture.
Action Points
- An ultrasensitive blood immunoassay for tau phosphorylated at threonine 181 (p-tau181) identified Alzheimer’s disease across a continuum of cognitive impairment and predicted tau and amyloid β pathologies, according to an analysis of four independent cohorts.
- Note that plasma p-tau181 shows promise as a simple, accessible, and scalable test for the screening and diagnosis of Alzheimer’s disease.
Blood testing has the potential to be used in a variety of relevant settings, including primary care, community-based medicine centers, or even in a patient’s home, and at repeated intervals. However, detection of plasma amyloid β (ratio of amyloid β1-42 to amyloid β1-40), which reflects brain amyloidosis, via mass spectrometry is complicated by assay limitations and the fact that 10-30% of cognitively unimpaired individuals also exhibit brain amyloidosis.
Tau is a microtubule-associated protein that regulates the assembly and stability of microtubules in the axons of neurons. It is a major component of neurofibrillary tangles — an Alzheimer’s hallmark — and has more than 40 phosphorylation sites. CSF p-tau181 is known to be a highly specific pathological marker of Alzheimer’s disease, which remains normal in other dementias.
In a new study published in Lancet Neurology, Canadian and Swedish researchers reported on the development and validation of an ultrasensitive blood test for p-tau181 for the detection of Alzheimer’s disease pathology.
Traditional immunoassays are conducted in a relative large reaction volume of 50-100 μL (e.g., wells in 96-well plates) and detect signal molecules in the picomolar range (i.e., 10-12 M). Kaj Blennow, MD, of the University of Gothenburg in Sweden, and colleagues adapted an assay based on measurement of p-tau181 in ordinary blood samples using a more sensitive single molecule array technique, which can detect proteins in blood at sub-femtomolar concentrations (i.e., 10-16 M).
Evidence from the literature has suggested that tau in blood and CSF might be processed differently, with mainly N-terminal forms of tau present in measurable quantities in blood. Blennow’s group focused on a novel N-terminal form of tau that is distinct from the mid-region forms targeted by the established CSF assays.
Blennow and colleagues evaluated their immunoassay in 1,131 people across four independent samples: a discovery cohort of 37 Alzheimer’s patients and age-matched controls, two observational research cohorts of 226 (TRIAD, which included younger participants and people with frontotemporal dementia) and 763 people (BioFINDER2, which included people with other neurodegenerative disorders), and a primary care cohort of 105 patients in the Canadian National Health Service who were referred to a dementia specialist but did not have biomarker assessment or neurologic diagnosis. A subset of TRIAD participants had MRI and cognitive testing at 1 year.
Linear regression models tested the associations between plasma p-tau181 at baseline and a 1-year change in cognition (using the Mini Mental State Examination score) and structural imaging (using hippocampus grey matter density). Linear regressions were corrected for age, sex, APOE4 genotype, and years of formal education.
Blennow and team showed that the assay was specific for the p-tau181 site, did not capture non-phosphorylated tau species, and showed good diagnostic performance for Alzheimer’s disease in both plasma and serum. In all cohorts, plasma p-tau181 concentrations increased progressively from amyloid β-negative young adults to amyloid β-positive cognitively unimpaired older adults to amyloid β-positive patients with dementia, suggesting that the assay is sensitive along the entire Alzheimer’s disease continuum.
The blood test also showed the capacity to distinguish Alzheimer’s from other brain diseases. Plasma p-tau181 distinguished Alzheimer’s dementia from amyloid β-negative young adults (area under the curve [AUC] 99.40%) and cognitively unimpaired older adults (AUC 90.21%-98.24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC 82.76%-100% across cohorts), vascular dementia (AUC 92.13%), progressive supranuclear palsy or corticobasal syndrome (AUC 88.47%), and Parkinson’s disease or multiple systems atrophy (AUC 81.90%).
Specific p-tau181 in the blood also corresponded very closely with the level of tau tangles in the brain observed on a PET scan.
“P-tau181 levels in blood samples are increased in individuals who have a positive amyloid scan but not yet a positive tau PET scan, suggesting that plasma p-tau181 becomes positive before tau PET,” Blennow said.
“These findings show p-tau181 in blood samples works very well to identify Alzheimer’s pathology,” and could serve as an easily accessible, cheap test for Alzheimer’s disease in primary care, he told MedPage Today.
The researchers acknowledged that the primary care cohort had no CSF or PET imaging assessments, precluding an etiological diagnosis of individuals with mild cognitive impairment and identification of preclinical Alzheimer’s-type pathophysiology in cognitively normal older adults. Although their findings suggest that baseline plasma p-tau181 has potential clinical applications for prognosis and longitudinal monitoring, the researchers stated that the “relatively short duration of the longitudinal evaluations and the small number of individuals with longitudinal cognition and imaging biomarkers limits the interpretation of these results.”
Source References: Lancet Neurology 2020; DOI: 10.1016/S1474-4422(20)30071-5
Editorial: Lancet Neurology 2020; DOI: 10.1016/S1474-4422(20)30112-5
Study Highlights and Explanation of Findings:
Plasma p-tau181 provided high diagnostic accuracy for Alzheimer’s disease in four independent cohorts, discriminated amyloid β-positive cognitively unimpaired older adults and amyloid β-positive individuals with mild cognitive impairment from amyloid β-negative cognitively unimpaired older adults and young adults, and identified clinically diagnosed Alzheimer’s patients with unknown brain amyloid status, according to Blennow and team. The test also predicted cognitive decline/hippocampal atrophy over a period of 1 year, and could differentiate Alzheimer’s from other neurodegenerative diseases with high performance.
“Furthermore, plasma p-tau181 performed better than the most well-known Alzheimer’s disease risk factors (age, APOE4 genotype, or both) and other plasma biomarkers (total-tau, amyloid β1-42, amyloid β1-42 to amyloid β1-40 ratio, and total-tau to amyloid β1-42 ratio) in predicting Alzheimer’s disease diagnosis, increased tau PET, and increased amyloid β PET,” the team wrote.
“It was a challenge because these proteins are in very low amounts in the blood,” explained co-author Tharick Pascoal, MD, of the McGill University Research Centre for Studies in Aging in Montreal.
“If you compare with the fancier tests, such as PET or cerebrospinal fluid, we saw that they are almost the same for several applications,” he added. “The results were amazing. We were very surprised, to be honest, and very excited. We didn’t expect that a simple blood test could give very similar results to the PET technique.”
“This is a game changer,” agreed co-author Serge Gauthier, MD, also of the McGill University Research Centre for Studies in Aging.
He pointed out that the test, used at this early stage, will identify a risk factor, but is not a diagnosis (much like a cholesterol test can identify a risk factor for heart disease). “There is no treatment for mild cognitive impairment except for lifestyle changes, especially lowering blood pressure, keeping the mind and body busy — all the good things you’re supposed to do,” he said in a statement. “But people will be more motivated to do it if they know they have elevated proteins and are at risk.”
“Plasma p-tau181 is an important advance that could transform the diagnosis of Alzheimer’s disease,” wrote Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.
The assay has potential use in both clinical practice and disease-modifying trials, though “how plasma p-tau181 would perform as an indicator of target engagement is unclear,” he observed.
Many aspects need further study, including the assay’s longitudinal stability and precision, how it evolves over time in individuals, and how it relates to cognitive impairment development and changes in tau PET, he added. “A thoughtful approach will be needed concerning application of plasma p-tau181 in asymptomatic individuals, and recommended use guidelines by expert panels are likely to be required,” he continued.
In addition, CSF studies have “indicated that other pathological phosphorylation sites might also be diagnostically useful, particularly tau phosphorylated at threonine 217 (p-tau217), and studies comparing the diagnostic performance of plasma p-tau181 and p-tau217 will be important,” Jack noted.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
Primary Source
Lancet Neurology
Secondary Source
Lancet Neurology
Additional Source
MedPage Today
Source Reference: George J “Alzheimer’s Blood Test Predicts Pathology” 2020.
https://www.medpagetoday.org/neurology/alzheimersdisease/86649?_ga=2.34068133.503806516.1590619765-265074527.1569866268
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