Researchers have found that plasma pTau181 can predict Alzheimer’s in real-world patients, giving clinicians a less invasive way to screen for disease progression and improve early intervention in memory clinics.

Study: Clinical value of plasma pTau181 to predict Alzheimer’s disease pathology in a large real-world cohort of a memory clinic. Image Credit: Kateryna Kon / Shutterstock

In a recent study published in the journal eBioMedicine, a group of researchers evaluated the clinical utility of plasma Phosphorylated Tau at threonine 181 (pTau181) as a predictive biomarker for Alzheimer’s disease (AD) (A progressive brain disorder that leads to memory loss and cognitive decline) pathology in a large, real-world memory clinic cohort. 

Background 

Dementia (a general term for conditions causing impaired memory, thinking, and behavior, often seen in older adults) epidemic presents significant economic and social challenges, with AD being the leading cause.

Early detection is critical, as current treatments cannot reverse the irreversible neuronal damage. While costly and invasive biomarkers like Positron emission tomography (PET) and cerebrospinal fluid (CSF) are standard, plasma biomarkers like pTau181 offer a promising, less invasive alternative.

However, the study underscores that further research is still required to validate the widespread clinical use of plasma biomarkers, especially in diverse populations and longitudinal assessments, to ensure their reliability across different settings.

About the study 

Participants were informed of the study’s goals and procedures before providing written consent in accordance with Spain’s Data Protection Law. Patient privacy and data confidentiality were ensured throughout the study.

The study protocols were approved by the Clinical Research Ethics Commission of the Hospital Clinic in Barcelona, Spain, in compliance with the Declaration of Helsinki and Spanish biomedical research regulations. 

Samples from the paired CSF/plasma collection, registered with the Instituto de Salud Carlos III (Spanish National Institute of Health) (ISCIII), were included. Participants were real-world patients from the Ace Alzheimer Center Barcelona memory clinic, primarily referred by primary care centers in the Barcelona area.

A multidisciplinary team assigned diagnoses, and lumbar punctures were offered to individuals with dementia, mild cognitive impairment (MCI), or subjective cognitive decline (SCD) who consented to participate.

The study included three independent cohorts: the modeling cohort (n = 991), the testing cohort (n = 642), and the validation cohort (n = 441), with demographic and clinical characteristics detailed in the accompanying tables.

Plasma and CSF samples were collected and processed on the same day, following Alzheimer’s Biomarkers Standardization Initiative protocols. Biomarker quantification was performed using Lumipulse or Enzyme-Linked Immunosorbent Assay (ELISA) platforms.

Statistical analyses, including receiver operating characteristic (ROC) curve analysis and Cox proportional hazards Model (Cox) regressions, were used to evaluate biomarker levels and their predictive value for AD conversion. 

Study results 

The correlation between plasma and CSF pTau181 was strongest in patients with MCI who were amyloid-beta positive (Aβ+) and in those with AD dementia. In contrast, no correlation was observed in individuals with SCD or other dementias.

The comparison of two different CSF analytical techniques confirmed that this variability did not affect the CSF/plasma pTau181 correlation.

When examining the distribution of plasma pTau181 across the Alzheimer’s continuum, clear clusters of data emerged, particularly with elevated levels in AD dementia patients and lower levels in those with SCD.

Significant differences in plasma pTau181 levels were found between MCI Aβ(+) and the healthiest populations but not between MCI Aβ(−) and other dementia subjects. Plasma pTau181 levels were notably higher in MCI patients with at least one positive biomarker, suggesting increased neurodegeneration compared to those with negative profiles.

Age played a significant role in influencing plasma pTau181 levels, particularly in patients over 70 with MCI Aβ(+), while the presence of APOE ε4, amyloidosis, and cognitive status were also influential. However, unlike other variables, sex was found to have no effect on biomarker levels.

ROC curve analyses revealed a robust ability of plasma pTau181 to differentiate between AD dementia and other groups. In a real-world scenario, a cut-off value of 1.36 pg/ml was identified for detecting Alzheimer’s pathology, with high sensitivity but moderate specificity. In MCI patients, a cut-off of 1.30 pg/ml exhibited a strong capacity to differentiate between prodromal and non-prodromal AD, with a high positive predictive value and negative predictive value.

Plasma pTau181 levels were also able to predict the conversion from MCI to dementia. Individuals with plasma pTau181 levels above the established cut-off had a significantly higher conversion rate to dementia than those below it.

Follow-up analysis showed that 50.8% of individuals with plasma pTau181 levels above the cut-off in the testing cohort converted to dementia, compared to only 13.4% of those with lower levels.

This trend was consistent across both the testing and validation cohorts, with MCI patients displaying an 84% higher risk of conversion to AD dementia when plasma pTau181 levels were elevated.

These findings were further supported by Cox regression analyses, which revealed no differences between age-sex adjusted models and were consistent across multiple cohorts.

Study limitations

While plasma pTau181 holds promise as an AD screening tool, the study emphasized several important limitations. Firstly, the absence of longitudinal measurements means the biomarker’s performance over time is yet to be evaluated, limiting conclusions about its long-term predictive value.

Secondly, the need for further validation in independent cohorts, particularly those from different geographic and demographic backgrounds, was highlighted as essential for broader clinical application.

Additionally, the potential for pre-analytical variability—such as differences in sample collection and processing across multiple centers—may impact the generalizability of the findings.

Lastly, the study notes that plasma pTau181 alone may not be sufficient to detect AD pathology in patients with SCD, indicating that additional biomarkers or a combination of them might be necessary for these earlier stages.

Conclusions 

To summarize, Plasma pTau181 correlated with CSF pTau181 in patients with MCI and AD dementia but not in those with SCD or other dementias. Plasma pTau181 levels rose with disease progression and effectively predicted conversion from MCI to AD dementia. Plasma pTau181 holds potential as an AD screening tool, but confirmatory tests remain essential for diagnosis.