Abstract
Abstract IMPORTANCE Early detection of brain amyloidosis (Aβ+) is pivotal for diagnosing Alzheimer’s 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. OBJECTIVE To evaluate the diagnostic accuracy of plasma pTau isoform (pTau181 and pTau217) to Aβ42 ratios in detecting Aβ+ status. DESIGN, SETTING, AND PARTICIPANTS This study included 423 participants from the multicenter prospective ALZAN cohort, recruited for cognitive complaints. Aβ+ status was determined using cerebrospinal fluid (CSF) biomarkers. Validation of the key findings was performed in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, where Aβ+ status was determined using PET imaging. EXPOSURES 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. MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic performance of plasma biomarkers and their ratios for detecting Aβ+ status. Secondary outcomes included the proportion of patients classified as low, intermediate, or high risk for Aβ+ using a two-cutoff approach. RESULTS The pTau181/Aβ42 ratio matched the diagnostic performance of pTau217 with AUC of 0.911 (0.880-0.936). The pTau217/Aβ42 ratio demonstrated the highest diagnostic accuracy in the ALZAN cohort, with an AUC of 0.927 (0.898-0.950), outperforming individual biomarkers. Both ratios effectively mitigated confounding factors, such as variations in renal function, and were particularly excellent in identifying Aβ+ status in individuals with early cognitive decline. Validation in the ADNI cohort confirmed these findings, with consistent performance across different measurement methods. The two-cutoff workflow using pTau217/Aβ42 reduced the intermediate-risk zone from 16% to 8%, enhancing stratification for clinical decision-making. CONCLUSIONS AND RELEVANCE The pTau217/Aβ42 ratio offers superior diagnostic accuracy for detecting Aβ+ compared to individual biomarkers and reduces diagnostic uncertainty. These findings highlight the clinical utility of plasma biomarker ratios for early AD detection, paving the way for broader implementation in clinical and research settings.