On 2 March, two articles published back-to-back in Nature Medicine demonstrated the diagnostic and prognostic value of blood tests that measure pTau181 in Alzheimer’s disease. The two studies were carried out by research groups based in the US and in the EU, with first authors Shorena Janelidze and Niklas Mattsson (first study), and Elisabeth Thijssen (second study).
The accumulation of disordered Tau proteins in the brain is a defining neuropathological feature of Alzheimer’s disease (AD). In healthy individuals, Tau is a fairly simple, filamentous protein that supports microtubules, molecular tracks that transport cargo inside brain cells. However, in AD, Tau becomes misfolded and misshaped, accumulating in squash racket-shaped knots called neurofibrillary tangles. One of the causes of Tau tangling in AD is a process called “phosphorylation”, thought to happen as a knock-on effect of increased amyloid beta levels in the brain. Accumulating amyloid beta creates a microenvironment which favours Tau hyperphosphorylation, and this in turn alters Tau shape and function - leading to aggregation and tangling. One of the sites within the Tau protein that is particularly prone to hyperphosphorylation is residue 181 in the Tau protein chain: Tau that is hyperphosphorylated at this site is denoted as “pTau181”. Research has shown that hyperphosphorylated forms of Tau such as pTau181 are released into the blood stream, and can be detected in blood plasma using antibody-based tests. Importantly, studies indicate that blood tests for pTau181 are correlated with PET imaging scans for amyloid beta and Tau, suggesting that blood tests for pTau181 may represent a minimally invasive and less costly way to diagnose AD. However, it is not yet known whether plasma pTau181 can differentiate between AD and other neurodegenerative diseases - or whether it can accurately identify healthy individuals at risk for progression to AD.
To answer these questions, the two research teams studied plasma pTau181 across several different cohorts of healthy individuals, people with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. In the first study, Shorena Janelidze, Niklas Mattsson and colleagues compared plasma pTau181 levels to measures of pTau181 in cerebrospinal fluid (CSF) and Tau PET brain imaging scans. Studying two prospective cohorts with 526 individuals, as well as a cohort of 63 individuals with autopsy-confirmed AD, the researchers found that plasma pTau181 was increased in the presymptomatic stages of AD, continuing to increase as disease progressed. In contrast, pTau181 was not increased in individuals with non-AD dementia, showing the utility of this blood test to differentiate AD from non-AD conditions, and to track disease progression – and disease risk - in AD.
In clinical practice, it can be hard to determine whether a patient has AD or frontotemporal lobar degeneration (FTLD) as both conditions are similarly prevalent in certain age groups and share several clinical features. In the second study, Dr. Thijssen and colleagues therefore focused on the ability of pTau181 plasma tests to distinguish between individuals with FTLD and AD. To do this, the researchers evaluated a cohort of 362 participants with MCI, AD or non-AD forms of dementia, including FTLD-associated conditions such as corticobasal syndrome and behavioural variant frontotemporal dementia. Comparing plasma pTau181 tests to other biomarkers, PET and MRI, the researchers showed that plasma pTau181 was increased 3.5-fold in participants with AD compared to individuals without AD. Plasma pTau181 tests were able to discriminate between AD and FTLD at a level of accuracy similar to CSF pTau181 tests, which are much more invasive than plasma tests due to the requirement for spinal taps to obtain the CSF. Similar to the first study, Dr. Thijssen and colleagues found that plasma pTau181 measurements were correlated with the amounts of Tau protein in the brain, as measured by Florbetapir Tau-PET brain scans.
Together, these two studies highlight the utility of minimally-invasive plasma tests for pTau181 as a surrogate measure of Tau accumulation in the brain. Each study overcomes a limitation of the other; the small size of the non-AD disease subgroup in the first study, and the low number of controls and participants with MCI/AD in the second study. Importantly, both studies consistently show that plasma pTau181 measurements can predict the risk of developing AD dementia, providing a way for researchers and clinicians to identify those who may most benefit from therapeutic interventions at an early stage.