Researchers have found that plasma pTau181 can predict Alzheimer’s disease in real patients, giving doctors 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 memory clinic cohort. Image credits: Kateryna Kon / Shutterstock
This is evident from 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 leading to memory loss and cognitive decline) in a large, real-world cohort memory clinic .
Background
The dementia epidemic (a general term for conditions that cause impaired memory, thinking and behavior, often seen in older adults) poses significant economic and social challenges, with AD being the leading cause.
Early detection is critical because current treatments cannot reverse irreversible neuronal damage. While costly and invasive biomarkers such as positron emission tomography (PET) and cerebrospinal fluid (CSF) are standard, plasma biomarkers such as pTau181 offer a promising, less invasive alternative.
However, the study underlines that further research is still needed to validate the widespread clinical use of plasma biomarkers, especially in diverse populations and longitudinal assessments, to ensure their reliability in different settings.
About the study
Participants were informed of the objectives and procedures of the study before providing written consent in accordance with the Spanish Data Protection Act. 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 accordance with the Declaration of Helsinki and the Spanish Regulations for Biomedical Research.
Samples from the paired CSF/plasma collection registered at the Instituto de Salud Carlos III (Spanish National Institute of Health) (ISCIII) were included. Participants were real patients of the memory clinic Ace Alzheimer Center Barcelona, referred mainly from primary care centers in the Barcelona area.
A multidisciplinary team established diagnoses and lumbar punctures were offered to individuals with dementia, mild cognitive impairment (MCI), or subjective cognitive decline (SCD) who agreed 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, according to 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 Hazard 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 patients with AD dementia. In contrast, no correlation was observed in individuals with SCD or other forms of dementia.
The comparison of two different CSF analysis techniques confirmed that this variability did not affect the CSF/plasma pTau181 correlation.
When examining the distribution of plasma pTau181 across the AD continuum, clear clusters of data emerged, especially with elevated levels in AD dementia patients and lower levels in patients with SCD.
Significant differences in plasma pTau181 levels were found between MCI Aβ(+) and the healthiest populations, but not between MCI Aβ(-) and other individuals with dementia. Plasma pTau181 levels were notably higher in MCI patients with at least one positive biomarker, indicating increased neurodegeneration compared to those with a negative profile.
Age played an important role in influencing plasma pTau181 levels, especially in patients over 70 with MCI Aβ(+), while the presence of APOE ε4, amyloidosis and cognitive status also had an influence. However, unlike other variables, sex was found to have no effect on biomarker levels.
ROC curve analyzes revealed a robust ability of plasma pTau181 to discriminate 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 cutoff value of 1.30 pg/ml showed a strong ability to distinguish between prodromal and non-prodromal AD, with a high positive predictive value and a negative predictive value.
Plasma pTau181 levels were also able to predict conversion from MCI to dementia. Individuals with plasma pTau181 levels above the established cutoff had a significantly higher conversion rate to dementia than those below.
Follow-up analysis found that 50.8% of individuals with plasma pTau181 levels above the cutoff in the test cohort progressed to dementia, compared with only 13.4% of those with lower levels.
This trend was consistent across both the test and validation cohorts, with MCI patients showing 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- and sex-adjusted models and were consistent across multiple cohorts.
Limitations of the study
Although plasma pTau181 shows promise as a screening tool for AD, the study highlighted several important limitations. First, the lack of longitudinal measurements means that the biomarker’s performance over time has yet to be evaluated, limiting conclusions about its long-term predictive value.
Second, the need for further validation in independent cohorts, especially those from different geographic and demographic backgrounds, was highlighted as essential for broader clinical application.
Furthermore, the potential for pre-analytical variability – such as differences in sample collection and processing across multiple centers – may impact the generalizability of the findings.
Finally, 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 thereof may be necessary for these earlier stages.
Conclusions
In summary, plasma pTau181 correlated with CSF pTau181 in patients with MCI and AD dementia, but not in patients with SCD or other dementias. Plasma pTau181 levels increased with disease progression and effectively predicted conversion from MCI to AD dementia. Plasma pTau181 has potential as a screening tool for AD, but confirmatory testing remains essential for diagnosis.