Impact of preanalytical delay on the performance of plasma Aβ42, Aβ42/40, p‐tau217, and p‐tau217/Aβ42 in detecting brain amyloidosis in the ALZAN cohort

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BACKGROUND: Alzheimer disease (AD), the leading cause of dementia, has increased interest in the development of blood-based biomarkers for early diagnosis and monitoring. The plasma amyloid beta (Aβ)42/Aβ40 ratio and phosphorylated tau (p-tau) isoforms closely align with cerebrospinal fluid and positron emission tomography markers. The recent approval of the plasma p-tau217/Aβ42 ratio marks a key step toward non-invasive diagnostics. However, known Aβ42's preanalytical and analytical challenges raise concerns about the reliability of this ratio in routine clinical practice. METHODS: Using the ALZAN prospective cohort of cognitively impaired individuals, we examined how delays between blood collection and laboratory processing affected the performance of plasma biomarkers in detecting. RESULTS: The preanalytical delay has a significant impact for Aβ40 and Aβ42. However, the performance of p-tau217 and p-tau217/Aβ42 ratio were similar, thereby supporting the use of the ratio as a robust and efficient marker for AD diagnosis. DISCUSSION: Our findings reinforce the high diagnostic accuracy of the p-tau217/Aβ42 ratio in AD, regardless of preanalytical delays. HIGHLIGHTS: Blood-based biomarkers are playing an increasingly important role in the routine clinical management of AD. A significant advancement in this field was marked by the FDA's recent approval of the Lumipulse immunoassay, which measures the plasma p-tau217/Aβ42 ratio for AD diagnosis. However, this development has sparked notable concern among researchers. One major issue is that the p-tau217/Aβ42 ratio has not been extensively investigated. Only recently have studies begun to show that it offers slightly better diagnostic performance than p-tau217 alone (https://doi.org/10.1101/2024.12.07.24318640). In addition, the known instability of Aβ42 under different preanalytical conditions could potentially compromise the reliability of the ratio in routine clinical settings. Using data from the ALZAN cohort, where we previously confirmed the enhanced diagnostic value of the p-tau217/Aβ42 ratio, we specifically examined how preanalytical factors, specifically delays in blood sample processing, might affect its performance. Our results highlight the limited effect of this preanalytical parameter on clinical performance of the ratio, thereby supporting its robustness and practical value for routine use in AD diagnostic and care.

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