Associations of ¹⁸F‐RO‐948 Tau PET with Fluid AD Biomarkers, Centiloid, and Cognition in the Early AD Continuum

Abstract Background Fluid biomarkers provide a convenient way to predict AD pathophysiology. However, few studies have focused on determining associations with tau neurofibrillary tangle pathology in the early preclinical AD continuum, relevant to prevention strategies. Methods Ninety‐nine cognitively unimpaired individuals from the ALFA+ cohort with valid 18 F‐RO‐948 and 18 F‐flutemetamol PET, T1‐weighted MRI, cognition, CSF, and plasma biomarkers were included. Participants were initially categorized into AT stages using CSF‐based pre‐established cut‐off values [1]. Regional SUVR of 18 F‐RO‐948 PET was calculated in entorhinal(BraakI/II), limbic(BraakIII/IV), and neocortical(BraakV/VI) regions using the inferior cerebellum as reference region as well as with the CenTAUR z . Regional positivity thresholds per Braak stage were calculated as the median+2SD of the CSF A‐T‐ group. Amyloid PET was quantified using Centiloids. Pearson correlations were calculated between regional 18 F‐RO‐948 SUVRs and AD biomarkers. ROC analyses adjusted for age, sex, and APOE‐ε4 performed to evaluate the capacity of biomarkers in predicting BraakI/II Positive . Four progressive PET‐derived AT groups were defined using Centiloid and tau PET positivity cut‐offs (A‐T‐, A GZ T‐, A+T‐ and A+T+; with A‐ CL<12, 12≤A GZ <38 and A+ CL≥38 [2], and T+ BraakI/II>1.35) and between‐stage differences in z‐scored biomarkers evaluated using a Kruskal‐Wallis tests. Results Table 1 shows demographic information of participants. Nine(9.09%) participants were BraakI/II Positive , seven(7.07%) BraakIII/IV Positive and one(1.01%) BraakV/VI Positive . Two BraakIII/IV Positive participants were BraakI/II Negative , deviating from the Braak hierarchical model. CSF biomarker correlations with BraakI/II SUVR (Figure 1‐A) ranged from r=0.24(ttau) to r=0.57(ptau217) and plasma (Figure 1‐B) from r=0.30(ptau217) to r=0.49(ptau181). Correlations survived adding age+sex+APOE‐ε4 in the model (Figure 1‐C&D). CSF ptau181/Aβ42, ptau217 and ptau205 showed an AUC≥0.93 to predict BraakI/II Positive , and plasma ptau181, ptau181/Aβ42 and ptau217 had an AUC≥0.84. Centiloid positivity threshold for BraakI/II Positive was 38.14CL. Plasma ptau181, ptau181/Aβ42, and CSF ptau205, ptau217, and ptau235 reached a mean z‐score>2 for the PET‐derived A+T+ group (Figure 2) which was associated with lower cognitive scores for executive function (p=0.03), attention (p=0.05), and the PACC (p=0.01). Conclusion 18 F‐RO‐948 PET conformed to the Braak hierarchical model for most tau‐positive participants. Fluid AD biomarkers showed moderate associations with tau PET SUVR. Plasma biomarkers showed good capacity to predict BraakI/II Positive and track fibrillary amyloid and tau pathological changes in the early preclinical AD continuum.