PURPOSE: This study aimed to investigate the correlation between subcortical tau-positron emission tomography (Tau-PET) and plasma glial fibrillary acidic protein (GFAP) levels and cognitive function in participants with cognitively unimpaired (CU), mild cognitive impairment (MCI) and Alzheimer's disease (AD) conditions. METHODS: 105 participants with amyloid (Aβ) PET and Tau-PET scans were enrolled. Region of interest (ROI) level and voxel-wise comparisons were performed between those three groups. Correlations between standardized uptake value ratio (SUVR) and cognitive performance were analyzed. The diagnostic performance of Tau-PET, Aβ-PET, and plasma GFAP, both individually and combined, was evaluated by calculating the area under the curve (AUC) from receiver operating characteristic (ROC) analyses. RESULTS: Plasma GFAP levels in the AD and MCI groups were higher than those in the CU group. The AD and MCI groups showed higher Tau-PET load at the amygdala, accumbens, putamen, pallidum, hippocampus, para-hippocampus and olfactory tubercle than the CU group (p <
0.05). In the MCI group, the mean tau SUVR in the combined subcortical ROI negatively correlated with cognitive scores (r = -0.38, p = 0.02). The combination of Tau-PET, Aβ-PET and plasma GFAP provided optimal diagnostic accuracy for classifying AD from MCI, with an AUC of 0.82, a sensitivity of 0.69 and a specificity of 0.81. CONCLUSIONS: Subcortical tau deposition and increased plasma GFAP levels are associated with cognitive impairment in MCI patients.