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Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests

Medicine and Health

Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests

N. R. Barthélemy, G. Salvadó, et al.

This groundbreaking study conducted by Nicolas R. Barthélemy and colleagues reveals a plasma blood test that outperforms traditional cerebrospinal fluid tests in detecting Alzheimer's disease pathology. With an impressive accuracy of up to 95% in identifying amyloid-β and tau pathology, this innovative approach could revolutionize AD diagnosis and treatment access.

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Playback language: English
Introduction
Alzheimer's disease (AD) is a major global health concern, affecting over 40 million people worldwide and projected to rise to 130 million by 2050. AD accounts for 60-70% of dementia cases and is characterized by amyloid-β (Aβ) plaques and tau tangles in the brain. The development of disease-modifying therapies necessitates accurate and accessible diagnostic tools to identify patients who could benefit. Current methods, such as positron emission tomography (PET) and cerebrospinal fluid (CSF) assays, are costly, invasive, and require specialized expertise, limiting widespread use. Recent advancements in blood-based markers (BBMs) offer a potential solution. Plasma phosphorylated tau (p-tau), particularly p-tau217, has shown promise in detecting AD pathology. However, the performance of plasma p-tau217 compared to established CSF tests remains to be definitively determined. This study directly compares the diagnostic accuracy of plasma %p-tau217, using a mass spectrometry approach, with FDA-approved CSF assays in detecting Aβ and tau pathology in independent cohorts. The primary focus is on individuals with cognitive impairment (mild cognitive impairment (MCI) and mild dementia), the target population for currently available disease-modifying treatments, as accurate identification of these patients is critical to ensure appropriate application of these therapies.
Literature Review
Existing literature highlights the strong association between plasma p-tau levels and AD pathology, as shown by various studies using different p-tau variants. Among these, p-tau217 has demonstrated the highest accuracy in detecting AD pathology and predicting future cognitive decline. Previous research has demonstrated the association of plasma p-tau with PET and CSF biomarkers of AD pathology, neuropathological changes, and the subsequent development of AD dementia. However, confounding factors like kidney disease can affect plasma p-tau levels. Using the ratio of p-tau217 to non-phosphorylated tau (%p-tau217) helps mitigate this issue. While some countries utilize blood-based markers in clinical practice, their equivalence to established CSF and PET methods needs further validation before they can be widely recommended as standalone diagnostic tests. The current study aimed to address this gap by comparing plasma %p-tau217 to clinically used and FDA-approved CSF assays in independent cohorts.
Methodology
This study employed a comparative design using data from two independent observational cohorts: the Swedish BioFINDER-2 cohort (n=1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n=337). Both cohorts included participants with varying cognitive statuses, ranging from cognitively unimpaired to those with MCI or dementia. Participants underwent Aβ PET and tau PET scans, along with CSF collection and blood sampling. CSF samples were analyzed using either Roche Elecsys (BioFINDER-2) or Fujirebio Lumipulse (Knight ADRC) automated immunoassays for Aβ42/40 and p-tau181/Aβ42. Blood plasma was analyzed by mass spectrometry to determine %p-tau217. The primary outcome was the detection of Aβ pathology, as determined by Aβ PET imaging, crucial for initiating anti-amyloid immunotherapies. Secondary outcomes included classification of tau pathology (tau PET) and agreement with clinical AD diagnosis. The primary analyses focused on cognitively impaired individuals, the target population for anti-amyloid therapies. Statistical analyses included receiver operating characteristic (ROC) curve analysis to assess the area under the curve (AUC) for each biomarker in classifying Aβ and tau PET status. Clinically relevant diagnostic metrics, such as accuracy, positive predictive value (PPV), and negative predictive value (NPV), were also calculated for the cognitively impaired subgroup using both single-cutoff and two-cutoff approaches. Sensitivity analyses, including out-of-bag statistics and external cutoff derivation, were performed to validate the findings. Furthermore, the researchers explored the concordance of the visual read for Aβ PET positivity with the quantitative Aβ PET data. In additional analyses, the accuracy of the plasma %p-tau217 was evaluated for clinical diagnosis of symptomatic AD against other neurodegenerative diseases. Finally, the consistency across time was investigated in a subcohort of the Knight ADRC, with available longitudinal plasma %p-tau217 data.
Key Findings
Plasma %p-tau217 demonstrated high accuracy in classifying both Aβ and tau PET status, with AUCs ranging from 0.95 to 0.98 across both cohorts. Compared to FDA-approved CSF tests, plasma %p-tau217 showed clinically equivalent performance in classifying Aβ PET status and superior performance in classifying tau PET status. In the cognitively impaired subgroups, plasma %p-tau217 predicted Aβ PET status with an accuracy, PPV, and NPV of approximately 90% using a single-cutoff approach. This performance was comparable to CSF tests. Applying a two-cutoff approach significantly improved the accuracy to approximately 95%, with a PPV and NPV of 95% for Aβ PET status, and a smaller percentage of participants falling into the intermediate category. Similar results were obtained for tau PET status, with plasma %p-tau217 demonstrating superior performance to CSF tests in the classification of tau PET positivity. The performance of plasma %p-tau217 was consistent across different analysis methods, including out-of-bag estimations and external cut-offs. The results were robust regardless of whether quantitative or visual read assessment methods were used for Aβ PET positivity. Furthermore, the analysis showed that plasma %p-tau217 accurately predicted clinical diagnosis of symptomatic AD with an AUC similar to CSF-based tests. Sensitivity analyses further supported the robustness of the findings. The longitudinal analysis in the Knight ADRC subcohort showed that the plasma %p-tau217 biomarker status remains highly consistent across time, indicating its reliability for repeated testing.
Discussion
This study's findings demonstrate that plasma %p-tau217, measured by mass spectrometry, offers a highly accurate and readily accessible method for detecting AD pathology. Its performance is comparable to, or surpasses, that of currently used CSF tests in classifying Aβ and tau pathology, particularly in individuals with cognitive impairment. The high accuracy, especially with the two-cutoff approach, suggests that plasma %p-tau217 could be used as a reliable replacement for CSF tests or Aβ PET, particularly in clinical settings where these methods may be less accessible or feasible. The superior performance of plasma %p-tau217 in classifying tau PET status suggests its potential value in determining whether cognitive impairment stems from AD. The widespread availability of blood collection makes this blood test particularly attractive for large-scale screening and the improved accuracy could help accelerate clinical trial enrollment. The findings strongly support the potential of plasma %p-tau217 as a valuable tool for improved diagnosis and patient selection for disease-modifying therapies.
Conclusion
This study demonstrates the high accuracy of a blood-based plasma %p-tau217 test in detecting Alzheimer's disease pathology, comparable to or exceeding that of established CSF tests. The ease of blood collection and high performance suggest that this blood test could significantly improve AD diagnosis and treatment access globally. Further research should investigate the performance of this test in diverse populations and compare it directly to other blood-based assays to fully assess its clinical utility and cost-effectiveness. Investigating the test's performance in large-scale primary care settings will be crucial for practical implementation.
Limitations
The study's limitations include the relatively small number of cognitively impaired participants in the Knight ADRC cohort and the lack of a large enough group with both antemortem and postmortem data for correlation. While mass spectrometry is highly accurate, it is currently more expensive and requires more expertise than immunoassays, potentially limiting its scalability. The representation of minoritized populations in the study cohorts was also limited, necessitating further research to investigate the generalizability of the results across diverse populations. Finally, the study relied on PET scans as a gold standard, which has limitations for assessing amyloid positivity.
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