Associations of plasma GFAP and P-tau217 with imaging ATN markers and cognitive decline across Centiloid scales

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.

This study involved 1346 participants who underwent [18F]florbetapir PET, plasma P-tau217 and GFAP measurements, structural MRI (sMRI), and cognitive assessments. A subset of 604 participants additionally completed [18F]MK6240 PET. CL values were stratified into three scales: CL ≤ 10, 10 < CL ≤ 30, and CL > 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.

Plasma levels of P-tau217 and GFAP exhibited a progressive increase across the groups of CL ≤ 10, 10 < CL ≤ 30, and CL > 30 (P < 0.0001), and were most positively associated with CL values within the 10 < CL ≤ 30 range (β = 0.236, P = 0.016; β = 0.206, P = 0.027, respectively). Plasma P-tau217 effectively differentiated between CL > 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 < CL ≤ 30 range. Elevated GFAP levels were correlated with reduced cortical thickness and poorer cognitive performance in the CL ≤ 10 group, while increased P-tau217 levels were associated with atrophy and non-executive cognitive deficits in the CL > 10 group.

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.

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).