Specific Tau Protein Shows Potential as Blood Biomarker in Early Studies

A specific form of the tau protein, called phosphorylated-tau-217 or p-tau217, may function as a blood biomarker of Alzheimer’s disease, allow the development of blood tests to accurately diagnose the disease at earlier stages.

These are the findings of three studies presented during the recent Alzheimer’s Association International Conference (AAIC) 2020.

The brains of those with Alzheimer’s disease show accumulation of tau protein aggregates, which are thought to precede the loss of nerve cells, shrinkage of the brain, and cognitive impairment.

P-tau217, a modified form of tau which is phosphorylated at residue 217, seems to be the most specific to Alzheimer’s and the earliest to show measurable changes.

Researchers with the University of Lund, in Sweden, found evidence that blood levels of p-tau217 might serve as an early diagnostic biomarker for Alzheimer’s.

Their study, “Phospho-tau217 and phospho-tau181 in plasma and CSF as biomarkers for Alzheimer’s disease,” examined over 1,400 cases and blood p-tau217 distinguished Alzheimer’s from other neurodegenerative disorders with a diagnostic accuracy between 89 and 98 percent.

According to the team, “the diagnostic precision of blood p-tau217 was as high as established diagnostic methods, including positron-emission tomography (PET) imaging and cerebrospinal fluid biomarkers, which are invasive, costly and less available.”

Of note, the cerebrospinal fluid (CSF) is the liquid that surrounds the brain and spinal cord.

P-tau217 levels measured in both CSF and blood outperformed other experimental biomarkers, including p-tau181, neurofilament light chain, the amyloid beta 42/40 ratio and established magnetic resonance imaging (MRI) in differentiating Alzheimer’s dementia from non-Alzheimer’s neurodegenerative diseases.

The researchers also found that changes in p-tau217 seen in blood samples associated with Alzheimer’s-related brain changes — thought to be related to amyloid plaque accumulation — were also observed in tissue samples analyzed after death.

Importantly, in individuals with a particular Alzheimer’s-causing gene, PSEN1​, levels of p-tau217 began to increase about 20 years before the onset of cognitive impairment.

“This test, once verified and confirmed, opens the possibility of early diagnosis of Alzheimer’s before the dementia stage, which is very important for clinical trials evaluating novel therapies that might stop or slow down the disease process,” Oskar Hansson, the study’s principal investigator, in a press release from the Alzheimer’s Association.

In another study, “Mass spectrometry measures of plasma Aβ, tau and p-tau isoforms relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease,” researchers with Washington University School of Medicine in St. Louis suggested that a blood test measuring both amyloid and tau may lead to earlier and more accurate dementia diagnoses.

The team reported that only some p-tau variants measured in the blood correlated with levels found in cerebrospinal fluid (CSF) and measured by PET imaging.

Of these, p-tau217 correlated with the growth of amyloid plaques in the brain more than that of the better-known p-tau181.

They also found that measuring both the amyloid-beta 42/40 ratio and p-tau in the blood identified the stage of Alzheimer’s, as measured by the same proteins in the CSF and by PET.

These finding suggests that stages of Alzheimer’s progression might be better tracked by measuring levels of several different forms of p-tau in blood over time.

These data came from a study of 1,100 participants in the greater St. Louis area, to help guide development and validation of blood-based Alzheimer’s biomarkers.

Called the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia, or SEABIRD (NCT03899844), the study continues to recruit patients at its Missouri site. More information is available here.

Finally, researchers with the UCSF Memory and Aging Center presented their study ” Comparative diagnostic performance of plasma P-tau217 and P-tau181 in Alzheimer’s Disease and Frontotemporal Lobar Degeneration and correlations with [18F]Flortaucipir-PET uptake.”

They reported that blood plasma levels of both p-tau217 and p-tau181 could distinguish between Alzheimer’s and a neurodegenerative disease known as frontotemporal lobar degeneration (FTLD) or frontotemporal dementia.

Their retrospective study evaluated 617 participants, including 119 healthy controls, 74 biomarker-confirmed Alzheimer’s patients, and 294 people with FTLD.

They found that while blood p-tau181 levels were three times higher in people with Alzheimer’s compared with both controls and FTLD, blood p-tau217 levels were five times higher among Alzheimer’s patients compared to healthy controls and four times higher than FTLD patients.

Overall, p-tau181 demonstrated a 91% accuracy and p-tau217 a 96% accuracy in predicting whether a person had a tau positive brain scan, reflecting the results obtained through PET imaging of the brain.

“While these new reports are encouraging, these are early results, and we do not yet know how long it will be until these tests are available for clinical use. They need to be tested in long-term, large-scale studies, such as Alzheimer’s clinical trials,” said Maria Carrillo, the Alzheimer’s Association’s chief science officer.

“In addition, we need to continue research to refine and verify the tests that are the current state-of-the-art — including cerebrospinal fluid and PET imaging biomarkers.”