Accurate detection of Alzheimer’s disease (AD) pathophysiological changes is crucial for research and clinical practice. While positron emission tomography (PET) imaging is an established reference standard for detecting brain amyloid and tau deposition, cerebrospinal fluid (CSF) biomarkers offer a more accessible alternative. This study aimed to identify optimal CSF biomarkers and thresholds for predicting tau and amyloid PET positivity in a memory clinic population.
This cross-sectional, observational study included 220 participants from a memory clinic who underwent amyloid or tau PET scans and CSF biomarker analysis using either Fujirebio INNOTEST or LUMIPULSE assays. CSF biomarker performance was assessed via receiver operating characteristic (ROC) analysis. Double-threshold approaches were implemented to address classification uncertainty.
Ratios combining biomarkers of both amyloid and tau, such as Aβ42/pTau, consistently outperformed individual biomarkers in detecting amyloid and tau PET positivity. For amyloid PET, the Aβ42/pTau ratio achieved an AUC of 0.93 (95% CI: 0.86–0.99) with INNOTEST and an AUC of 0.89 (95% CI: 0.8–0.98) with LUMIPULSE. For tau PET, the Aβ42/pTau ratio achieved an AUC of 0.85 (95% CI: 0.77–0.93) with INNOTEST and an AUC of 0.97 (95% CI: 0.9-1.00) with LUMIPULSE. Double thresholds enabled classification based on predefined sensitivity and specificity, and can be used by clinicians to quickly assess a subject’s likelihood of positivity based on their biomarker levels.
CSF biomarker ratios such as Aβ42/pTau provide high predictive accuracy for brain amyloid and tau deposition. Implementing double thresholds enhances clinical utility by highlighting ambiguous cases requiring further assessment.
Sophie Mutel, F. Ribaldi, Augusto J. Mendes et al.· Alzheimer's Research & T...· 0 citations
Importance
Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used.
Objective
To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads.
Data Sources
PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025).
Study Selection
Studies were included if they provided Centiloids, radiotracer, age, and sex.
Data Extraction and Synthesis
Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis.
Main Outcomes and Measures
Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available.
Results
This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I2 = 80%).
Conclusions and Relevance
In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.
Ganna Blazhenets, David N Soleimani-Meigooni, Konstantinos Chiotis et al.· Journal of the American Medi...· 2 citations
