SummaryBackground The Centiloid (CL) value offers a standardized metric for quantifying amyloid-β (Aβ) levels in the brain. We aimed to investigate the associations of plasma phosphorylated tau 217 (P-tau217) and glial fibrillary acidic protein (GFAP) with Aβ (A) deposition, Tau (T) accumulation, cortical atrophy (N), and cognitive decline across varying CL scales. Methods This study involved 1346 participants who underwent 18Fflorbetapir PET, plasma P-tau217 and GFAP measurements, structural MRI (sMRI), and cognitive assessments. A subset of 604 participants additionally completed 18FMK6240 PET. CL values were stratified into three scales: CL ≤ 10, 10 30. ROC analyses assessed the discriminative abilities of plasma P-tau217 and GFAP across various CL scales. Adjusted regression models examined their associations with Aβ/Tau burden, cortical atrophy, and cognitive decline among different CL scales. Findings Plasma levels of P-tau217 and GFAP exhibited a progressive increase across the groups of CL ≤ 10, 10 30 (P 30 and CL ≤ 30 in cognitively normal (CN) and mild cognitive impairment (MCI) participants (AUC = 0.919 and 0.926, respectively), whereas in dementia participants, it more effectively separated CL > 10 from CL ≤ 10 (AUC = 0.959). A sequential mediation model indicated that CL values influenced the MK6240-SUVR (temporal-meta-ROI) through plasma GFAP, followed by P-tau217, with the most significant effects observed within the 10 10 group. Interpretation Plasma P-tau217 and GFAP track early Aβ accumulation, downstream Tau pathology, neurodegeneration, and cognitive deterioration across different CL scales. These biomarkers may provide valuable information for risk stratification and therapeutic targeting of AD within specific CL contexts. Funding National Natural Science Foundation of China (Grant No. 82171198, 82501892), Shanghai Municipal Commission of Health Research Project (Grant No. 202440009, 202440010), Shanghai Municipal Science Technology Major Project (Grant No. 2018SHZDZX01), STI2030-Major Projects (Grant No. 2022ZD0213800), and Shanghai Medical Innovation and Development Foundation "Brain Health Youth Fund–Precision Diagnosis and Treatment Research on Alzheimer's Disease" (Grant No. SMIDF-150-2025A30).
Huang et al. (2026) studied this question.