Measuring blood levels of P-tau181 may allow doctors to diagnose Alzheimer’s before the onset of symptoms

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New research from NUI Galway and Boston University has identified a blood biomarker that could help identify people with the earliest signs of dementia, even before the onset of symptoms.

The study was published today (Tuesday 26 April) in the Journal of Alzheimer’s Disease.

The researchers measured blood levels of P-tau181, a marker of neurodegeneration, in 52 cognitively healthy adults, from the US-based Framingham Heart Study, who later went on to have specialised brain PET scans. The blood samples were taken from people who had no cognitive symptoms and who had normal cognitive testing at the time of blood testing.


P-tau181 (V2)

Threonine 181 is one of the phosphorylation sites of human tau protein (pTau-181). Tau is a microtubule- stabilizing protein primarily localized in neurons of the central nervous system but also expressed at low levels in astrocytes and oligodendrocytes. Tau consists of six isoforms in the human brain with molecular weights of 48,000 to 67,000 daltons, depending on isoform.

The Simoa pTau-181 Advantage V2 assay targets the proline rich region of the Tau protein which is highly conserved amongst these isoforms. Tau elevation is observed in the cerebrospinal fluid (CSF) of patients with neurodegenerative disease and severe head injuries, suggesting its extracellular release during neuronal damage and a role as a biomarker with specificity for brain injury.

In Alzheimer’s disease (AD) and related neurodegenerative diseases, including chronic traumatic encephalopathy, tau is abnormally phosphorylated and aggregated into bundles of filaments. pTau 181 has been found to be more strongly associated with markers of AD than total tau.


The analysis found that elevated levels of P-tau181 in the blood were associated with greater accumulation of ß-amyloid, an abnormal protein in Alzheimer’s disease, on specialised brain scans. These scans were completed on average seven years after the blood test.

Further analysis showed the biomarker P-tau181 outperformed two other biomarkers in predicting signs of ß-amyloid on brain scans.

Emer McGrath, Associate Professor at the College of Medicine Nursing and Health Sciences at NUI Galway and Consultant Neurologist at Saolta University Health Care Group was lead author of the study.

“The results of this study are very promising – P-tau181 has the potential to help us identify individuals at high risk of dementia at a very early stage of the disease, before they develop memory difficulties or changes in behaviour,” Professor McGrath said.

The research team said the identification of a biomarker also points to the potential for a population screening program.

Professor McGrath said: “This study was carried out among people living in the community, reflecting those attending GP practices. A blood test measuring P-tau181 levels could potentially be used as a population-level screening tool for predicting risk of dementia in individuals at mid to late-life, or even earlier.

“This research also has important potential implications in the context of clinical trials. Blood levels of P-tau181 could be used to identify suitable participants for further research, including in clinical trials of new therapies for dementia.

“We could use this biomarker to identify those at a high risk of developing dementia but still at a very early stage in the disease, when there is still an opportunity to prevent the disease from progressing.”

The research was funded in Ireland by a Health Research Board Clinician Scientist Award and in the US by an Alzheimer’s Association Clinician Scientist Fellowship, the National Heart Lung and Blood Institute, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke.


The findings in the present study supported our primary hypothesis that plasma p-tau181 levels increase over time with disease progression. Compared with CN groups, plasma p-tau181 levels was increased at baseline in patients with MCI and dementia. Besides, increasing levels over time were identified at preclinical (Aβ-positive cognitively normal), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stage of Alzheimer’s disease.

The secondary hypothesis that plasma p-tau181 were longitudinally associated with other AD-associated measures throughout the course of the disease was also supported. Associations between longitudinal plasma p-tau181 and biochemical, imaging, and cognitive measures at baseline were extensively found and were strongest in patients with MCI.

Besides, change of plasma p-tau181 correlated with change of cognitive measures in all diagnostic groups, with change of imaging measures in CN and MCI groups, and with change of CSF biomarkers in MCI and dementia groups. Importantly, all the significant associations identified in the whole sample were driven by the amyloid positive group.

Taken together, our analysis of longitudinal plasma p-tau181 suggest that the plasma p-tau181 is a dynamic biomarker along the course of the disease and may be used to track disease progression in AD.

Plasma p-tau181 may outperform other biomarkers in monitoring clinical change of AD. Although MRI was recognized to show neurodegeneration in AD [19], the presence of characteristic imaging features used in clinical settings such as hippocampus atrophy and their changes only merge at the later stage of the disease.

Fluid biomarkers such as plasma neurofilament lights were also identified in the previous study that was capable of tracing disease progression [20]. However, these molecules were not as specific as p-tau181 to the AD pathology [21,22,23]. Other neurological comorbidity may interfere with the NLF levels to index AD severity for NLF levels would rise as long as the neuronal injury appear [20].

Thus, the plasma p-tau181 is competent as an indicator for AD progression. It is suggested that, once validated to regulatory standards, this easily-accessible biomarker would prompt the development of novel disease-modifying medicine and, possibly, offer guidance in clinical decisions once such treatments become available.

Besides, considering a rather close relation between the memory composite and the plasma p-tau181, it is promising that the memory function can be estimated objectively in future memory clinics. Additionally, the possible dual function of diagnosis and progression indication makes it a desirable biomarker for clinical use in primary care. For these purposes, we recommend that measurement of plasma p-tau181 should be included in future observational and therapeutic trials for AD to further investigate and validate its utility in clinical practice.

A recent work on the longitudinal plasma p-tau181 discovered that the level of plasma p-tau181 plateaued within the last four years prior to death in patients with AD neuropathology [24]. This appeared to be contradictory with our findings that plasma p-tau181 still increase at the stage of dementia.

The difference may attribute to the distinct clinical severity of included subjects. While the participants included in the literature reported a mean MMSE score of 17.7 at baseline, the mean MMSE score was 22.1 for individuals with AD dementia in our study. Thus, it might be the case that the level would keep increasing until the stage of mild dementia and then plateau at the end stage of AD course. In addition, we found no difference of change rate between different diagnostic groups for plasma p-tau181.

It seemed that the level of the blood biomarker increased in a linear fashion from the asymptomatic stage to mild dementia. Meanwhile, a positive association was clearly illustrated between the change rate of plasma p-tau181 and baseline AD-related outcomes such as Aβ-PET and ADAS-Cog score, which suggested that the rate of plasma p-tau181 change would be accelerated as the disease progressed.

One explanation would be insufficient sample size or follow up time to detect the minor signal as annual change of plasma p-tau181 was less than 1 pg/mL. We also noticed that participants in A-T-N- and A-T-N + showed elevating levels of plasma p-tau181. The analysis of longitudinal trajectories of plasma p-tau181 by Moscoso A might explained it as they found earliest elevations of plasma p-tau181 levels occurred before PET and CSF biomarkers of amyloid reached their respective abnormality thresholds [25]. Small sample sizes of certain groups (e.g. n = 13 in A-T-N + ) might also had an impact on analytical results, giving an inaccurate estimate.

Our study replicated some previous findings on plasma p-tau181 [6,7,] and comprehensively revealed its associations with other AD-related biological and clinical outcomes for the first time. Besides, by first using CSF Aβ42 (higher sensitivity and better linked to disease state compared to amyloid-PET [1,26,]) as a main approach and then including florbetapir-PET and data within 12 months of baseline as an auxiliary approach to determine amyloid positivity, we maximized the participants in AD continuum as well as the whole sample size, generating a sufficiently large, prospective cohort.

However, there are also several limitations to the present study. First, the participants enrolled in this research did not represent the totality of AD population. As mentioned above, the clinical severity is mild in dementia group according to the global cognitive measures. Thus, the analysis results cannot be extended to the population with moderate to severe dementia and future studies covering participants at advanced stage of AD would be necessary to examine the potential of plasma p-tau as progression biomarker.

Second, ADNI has a relatively pure AD population by mainly including amnestic patients. Reproducibility of findings with different phenotypes of AD and different participants from other cohorts would be beneficial. Third, for tau pathology, only CSF tau biomarkers not tau PET were investigated.

As tau PET was introduced in 2015 at the phase of ADNI-3, the baseline interval between plasma p-tau181 and tau PET was quite long (more than 6 years). It would be valuable for future researches with different study designs to include PET data and to analyze the association between different modalities of tau biomarkers.

Forth, there were high drop-out rates in each diagnostic group after 5 years since baseline that lead to a rather short-term follow-up data. This might affect the estimates of longitudinal plasma p-tau181 change and its association with other variables.

In conclusion, our findings suggest that plasma p-tau181 level can be used as a noninvasive biomarker to track disease progression in AD and therefore may be candidate tool to monitor effects in trials of disease-modifying therapeutics.

reference link: https://www.nature.com/articles/s41398-021-01476-7


Original Research: Closed access.
“Blood Phosphorylated Tau 181 as a Biomarker for Amyloid Burden on Brain PET in Cognitively Healthy Adults” by Emer McGrath et al. Journal of Alzheimer’s Disease

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