Stephanie Rainey-Smith

Background
Alzheimer's disease (AD) is a complex and multifactorial disease, defined by accumulation of Amyloid-Beta (Aβ) and tau, and ultimately cognitive decline leading to dementia. Plasma biomarkers offer an efficient and non-invasive method to detect either Aβ or tau pathology but have demonstrated substantially different accuracy. Assessment of how these plasma biomarkers change along the disease continuum (Aβ and tau) are needed.

Method
In the current study, we investigated 15 high performing plasma biomarkers (pTau217: Lumipulse, ALZpath, Elecsys@ NeuroToolKit [Roche Diagnostics International Ltd, Rotkreuz, Switzerland], Janssen; pTau181: Simoa, Elecsys, UGOT; pTau231: UGOT; Aβ42/40: Lumipulse, Elecsys@; GFAP: Simoa, Elecsys@, NFL: Simoa, Elecsys, BD-Tau: Simoa, Elecsys) against PET-Aβ Centiloid (CL) and meta-temporal CenTauR (CTR) across the AD continuum. Samples from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing were selected if they had both plasma and PET imaging for Aβ and tau (N = 272). Generalised additive models from biomarker Z-scores vs CL and CTR were computed, and receiver operating characteristic (ROC) analyses were performed to calculate area under the curve along with sensitivity, specificity, positive predictive value, negative predictive value and accuracy for both PET-Aβ and PET-tau positivity (CL>20 & CTR>24).

Result
Against both Centiloid and CenTauR, pTau217 had the largest increases over the disease continuum, with the Z-scores rising above the other biomarkers by 50CL for Aβ, and by 20 CTR for tau. From the point at which Aβ became positive to when tau became positive, pTau217 rose between 12% and 21%, whilst for all other markers rises of between 1% and 8% were seen. Highest correlations between biomarkers with CL and CTR were seen for pTau217 and optimal AUC values for CL and CTR reached approximate 0.95 and 0.91.

Conclusion
The findings from this research confirm that pTau217 is the strongest biomarker to predict either Aβ or tau across all the four assays analyzed. Unlike other plasma biomarkers which rise with increasing Amyloid burden and stay elevated, plasma pTau217 rises with increasing Amyloid, and then again with increasing Tau burden, indicating a dual response to different AD pathologies.

Background
With the increasing number of countries approving disease-modifying therapies (DMTs) for patients with either Mild Cognitive Impairment (MCI) or mild Alzheimer's disease (AD), it is vitally important to streamline treatment assessment processes. Blood-based biomarkers (BBMs) have been suggested as rivals to cerebrospinal fluid (CSF) biomarkers in their accuracy to detect neocortical Amyloid-Beta (Aβ). However, there is little consensus on potential thresholds and resulting confirmatory test performance for international use in target populations.

Method
Two separate sub-cohorts—the AD continuum cohort (ADCC) [cognitively impaired + unimpaired; N = 197] and the intention to treat cohort (ITTC) [cognitively impaired; N = 200]—from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging, were designed to test the accuracy and potential cut-offs of leading BBM Lumipulse assays from Fujirebio (pTau217 and Aβ42/40) to detect PET-Aβ (centiloid ≥25; amyloid prevalence ∼63%).

Result
Using the pTau217/Aβ42 ratio significantly improved the area under the curve (AUC) over pTau217 alone to detect PET-Aβ positivity in both the ADCC and ITTC (Figure 1A, ADCC p = 0.01; Figure 1B: ITTC p = 0.009). The Youden's Index cut-off for pTau217 was higher in the ITTC compared to the ADCC (0.25 pg/mL vs. 0.179 pg/mL). The highest accuracy observed for either single BBMs, the ratio of BBMs, or the linear combination of BBMs that included age, gender, and APOE ε4 was 93-95% in the ADCC (linear combination of pTau217, Aβ42/40, age, gender, and APOE ε4; pTau217/Aβ42 ratio) and 95-97% in the ITTC ( linear combination; pTau217/Aβ42 ratio). The lowest number of participants in the intermediate zone using dual cut-offs at 95% sensitivity and specificity was 9% and 14% for the pTau217/Aβ42 ratio in the ADCC and ITTC (92-93% accuracy), and 0% for the linear combination (pTau217, Aβ42/40, age, gender, and APOE ε4) in the ITTC (95% accuracy).

Conclusion
The general performance of the Lumipulse assays was similar across both the ADCC and ITTC, indicating strong repeatability independent of clinical stage. Focusing on only participants eligible for DMTs increased sensitivity and improved accuracy for the Aβ-containing pTau217/Aβ42 ratio and linear combination of markers, and resulted in small numbers of unclassified participants by the test.