On 22 April, Dr Thomas Karikari and colleagues published a paper in the Lancet Neurology journal, reporting on the clinical validation of a blood-based assay for p-Tau181, a biomarker for Alzheimer’s disease (AD). The accumulation of disordered, phosphorylated Tau proteins in the brain is a defining neuropathological feature of AD. Previous studies have shown that measurement of phosphorylated Tau proteins in cerebrospinal fluid (CSF) can help diagnose AD, distinguishing between dementias caused by AD and those caused by other neurodegenerative diseases such as Parkinson’s or Lewy Body disease. However, CSF-based tests are reliant on invasive, time-consuming and costly lumbar punctures, unlike plasma-based assays that measure the presence of protein biomarkers in blood. In the present study, Dr Karikari and colleagues report on the development of an ultrasensitive plasma immunoassay for phosphorylated Tau-181 (p-Tau181), which they validate in four independent prospective cohorts.
The new p-Tau181 immunoassay was first evaluated in a discovery cohort consisting of 18 cognitively unimpaired older adults and 19 individuals with AD. Here, the average p-Tau181 concentrations were three times higher in plasma from individuals with AD compared to matched controls. When the immunoassay was evaluated in the first validation cohort (TRIAD; including younger adults, cognitively unimpaired older adults, people with MCI, AD or frontotemporal dementia), p-Tau181 levels were highest in individuals with AD compared to all other groups. p-Tau181 plasma tests were also able to distinguish between amyloid-positive and amyloid-negative cognitively unimpaired older adults, showcasing the ability of this test to selectively identify at-risk individuals. Similar results were observed in the second validation cohort (BioFINDER; n=763) and a primary care cohort of 1131 individuals.
Across all cohorts, plasma p-Tau181 was detected at increasing levels along the AD continuum, from healthy young adults at the lower end to amyloid-positive, cognitively impaired individuals with AD at the upper end. In addition, the immunoassay was able to distinguish between AD dementia and dementias associated with other neurodegenerative disorders, such as Parkinson’s disease, vascular dementia and multiple systems atrophy. The researchers also reported that the p-Tau181 assay performed better than many well-known risk factors in predicting AD diagnosis, including age and ApoE4 genotype. Together with two recent studies published in Nature Medicine, this study underlines the utility of blood-based p-Tau assays for the diagnosis of AD, and for the recruitment of at-risk individuals to interventional clinical trials. This article was published in Lancet Neurology and can be found here:
https://www.sciencedirect.com/science/article/pii/S1474442220300715#bib14
