Plasma P-Tau181 Biomarker May Be Accessible, Scalable Test for Alzheimer Disease

Tharick A. Pascoal, MD, Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging

Tharick A. Pascoal, MD

Analysis of data from a number of cohorts suggests that the validated an ultrasensitive blood immunoassay for cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (p-tau181) can predict both tau and amyloid-ß pathologies, differentiate Alzheimer disease from other disorders, and identify it across the clinical spectrum. Researchers noted that the blood biomarker could serve as a simple, accessible, and easily scalable test for the screening and diagnosis of Alzheimer.

The findings showed that plasma p-tau181 gradually increased along the Alzheimer continuum, with the lowest concentrations observed in amyloid β-negative young adults and cognitively unimpaired older adults, higher concentrations shown in the amyloid β-positive cognitively unimpaired older adults and mild cognitive impairment (MCI) groups, and the highest concentrations reported in the amyloid β-positive MCI and Alzheimer disease groups (P <.001 for Alzheimer vs all other groups).

The study included 37 individuals from the discovery cohort, 226 from the first validation cohort (dubbed TRIAD), 763 in the second validation cohort (dubbed BioFINDER-2), and 105 in the primary care cohort, totaling 1131 individuals. The analysis was conducted by co-first authors Tharick A. Pascoal, MD, Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, and Thomas K. Karikari, PhD, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, and colleagues.

“CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools,” Pascoal et al. detailed. “CSF p-tau181 is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.”

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Plasma p-tau181 distinguished Alzheimer disease dementia from young adults who were amyloid β-negative (area under the curve [AUC], 99.40%) and cognitively unimpaired older adults (AUC, 90.21—98.24% across cohorts). Additionally, it differentiated from other neurodegenerative disorders, including frontotemporal dementia (FTD; AUC, 82.76–100% across cohorts), vascular dementia (AUC, 92.13%), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS; AUC, 88.47%), and Parkinson's disease or multiple system atrophy (MSA; AUC, 81.90%).

Additionally, the biomarker was linked with positron emission tomography (PET) measured cerebral tau (AUC, 83.08—93.11% across cohorts) as well as amyloid β (AUC, 76.14–88.09% across cohorts) pathologies. It was also associated with 12-month cognitive decline (P = .0015) and hippocampal atrophy (P = .015). In the primary care cohort, plasma p-tau181 was able to distinguish Alzheimer disease from young adults (AUC, 100%) and cognitively unimpaired older adults (AUC, 84.44%), though it did not distinguish from MCI (AUC, 55.00%).

“The blood p-tau181 test showed high accuracy for predicting in-vivo tau tangles and a predictive power to detect amyloid β plaque-positive individuals that was similar to high-performance mass spectrometry-based amyloid β plasma assays,” Pascoal and colleagues wrote, noting that blood p-tau181 can identify those with brain tau and amyloid β pathology with an AUC of up to 90%.

“The strong correlation between plasma p-tau181 and amyloid β PET, together with the increased plasma p-tau181 in amyloid β PET-positive and tau PET-negative (Braak 0) individuals suggests that this new test detects Alzheimer disease type pathology in the very early disease stages,” they wrote.

All told, the discovery cohort included cognitively unimpaired older adults (n = 18) and those with Alzheimer (n = 19), while the primary care cohort included young adults (n = 11), cognitively unimpaired older adults (n = 72), those with MCI (n = 12), and those with Alzheimer (n = 10). TRIAD also included young adults (n = 27), cognitively unimpaired older adults (n = 113), and those with MCI (n = 45), Alzheimer’s disease (n=33), and FTD (n = 8). The BioFINDER-2 cohort included cognitively unimpaired older adults (n = 337), those with MCI (n = 191) and Alzheimer (n = 126), those with behavioral variant FTD or primary progressive aphasia (PPA; n = 18), Parkinson or multiple system atrophy (n = 36), vascular dementia (n = 12), and PSP or CBS (n = 21).

This technology has applications for diagnosis and recruitment for disease-modifying trials. The blood p-tau181 assay has the potential to be incorporated into clinical practice as a rapid screening test to rule out Alzheimer’s disease pathophysiology and to guide therapy and clinical management of patients with dementia,” Pascoal et al. concluded.

Howard Fillit, MD, founding executive director and chief science officer, Alzheimer’s Drug Discovery Foundation (ADDF), which aided in the funding for this study, has previously explained the priority of identifying biomarkers in blood in an interview with NeurologyLive. “The advantage of the blood test is that it’s noninvasive and, hopefully, will be much cheaper than the neuroimaging technologies that are out there right now and the spinal fluid tests that require, obviously, a spinal tap, but are also quite expensive,” he said.

REFERENCE

Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modeling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-433. doi: 10.1016/S1474-4422(20)30071-5