Comparative performance of plasma pTau181/Aβ42, pTau217/Aβ42 ratios, and individual measurements in detecting brain amyloidosis
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Background
Early detection of brain amyloidosis (Aβ+) is crucial for diagnosing Alzheimer’disease (AD) and optimizing patient management, especially in light of emerging treatments. While plasma biomarkers are promising, their combined diagnostic value through specific ratios remains underexplored. In this study, we assess the diagnostic accuracy of plasma pTau isoform (pTau181 and pTau217) to Aβ42 ratios in detecting Aβ+ status.
Methods
This study included 423 participants from the multicenter prospective ALZAN cohort, recruited for cognitive complaints. Aβ+ status was determined using cerebrospinal fluid (CSF) biomarkers. The confirmatory cohort comprises 1,176 patient samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with Aβ+ status determined by positron emission tomography (PET) imaging. Plasma biomarkers (pTau181, pTau217, Aβ40, Aβ42) were measured using immunoassays and mass spectrometry, with specific ratios calculated. In the ALZAN cohort, the impact of confounding factors such as age, renal function, ApoE4 status, body mass index, and the delay between blood collection and processing was also evaluated to assess their influence on biomarker concentrations and diagnostic performance. The primary outcome was the diagnostic performance of plasma biomarkers and their ratios for detecting Aβ+ status. Secondary outcomes in the ALZAN cohort included the proportion of patients classified as low, intermediate, or high risk for Aβ+ using a two-cutoff approach.
Findings
In ALZAN the pTau181/Aβ42 ratio matched the diagnostic performance of pTau217 (AUC of 0.911 (0.882-0.940) vs. 0.909 (0.879-0.939), P=0.85). The pTau217/Aβ42 ratio demonstrated the highest diagnostic accuracy, with an AUC of 0.927 (0.900-0.954). Both ratios effectively mitigated confounding factors, such as variations in renal function, and were also efficient in identifying Aβ+ status in individuals with early cognitive decline. Diagnostic accuracy of ratios vs. individual measurement was confirmed in the ADNI cohort. In ALZAN, using two-cutoff workflows with pTau217/Aβ42 instead of pTau217 alone reduced the intermediate-risk zone from ∼16% to ∼8%, enhancing stratification for clinical decision-making.
Interpretation
The pTau217/Aβ42 ratio demonstrated improved diagnostic performance for detecting Aβ+ compared to individual biomarkers, potentially reducing diagnostic uncertainty. These findings suggest that plasma biomarker ratios could be useful; however, further validation in independent and diverse clinical settings is necessary before broader clinical implementation.
Funding
Fondation Research Alzheimer (ALZAN projet), AXA Mécénat Santé (INTERVAL Project), Fondation pour la Recherche Médicale (FRM, team Proteinopathies).
Research in Context
Evidence before this study
Blood biomarkers of Alzheimer’s disease are receiving increasing attention, as they have great potential for non-invasive detection of the presence of cerebral amyloidosis (Aβ+), one of the key elements in the diagnosis of the disease. Among these biomarkers, the phosphorylated isoforms of the tau protein, principally the pTau217 form, show performances that suggest major interest for clinical use. In addition, a number of studies have demonstrated the value of calculating ratios such as Aβ42/40 or pTau181/Aβ42 in CSF and blood, thereby eliminating the variability associated with pre-analytical or physiological confounding factors, such as renal failure. However, studies directly comparing ratios with individual markers remain limited.
Added value of this study
In the prospective real-life ALZAN cohort of cognitively impaired participants we show that plasma pTau181/Aβ42 and pTau217/Aβ42 ratios outperform individual biomarkers for the detection of Aβ+ status established from CSF. This result was confirmed for pTau217/Aβ42 in the ADNI cohort in which detection of Aβ+ status is done with PET. The ratios also show greater resistance to confounding factors such as impaired renal function or delays in sample processing. Finally, by using an approach based on the use of two cutoffs enabling effective population Aβ+ risk stratification, the ratios help to reduce the number of inconclusive situations.
Implications of all the available evidence
Taking previous studies into account, our results strengthen the case for using tau and amyloid ratios, and in particular the plasma pTau217/Aβ42 ratio, in the detection of Aβ+ status. These ratios not only improve detection accuracy but also help to take confounding factors into account. Ultimately, they could encourage wider use of routine blood tests, making diagnosis earlier, guiding therapeutic decisions while potentially reducing the use of procedures such as lumbar punctures or PET imaging.
