Plasma p-tau217 and p-tau217/Aβ1–42 ratios associate with medial temporal lobe subfield atrophy in normal aging and mild cognitive impairment

Early diagnosis of Alzheimer's disease (AD), particularly during its preclinical and prodromal phases, remains a major challenge. Plasma biomarkers such as phosphorylated tau at threonine 217 (p-tau217), amyloid-β (Aβ) isoforms, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) show promise for early detection; however, their relationships with medial temporal lobe (MTL) subfield atrophy and potential inter-biomarker pathways remain unclear. This study aimed to address this gap by investigating the associations between plasma biomarkers and MTL subfield atrophy, and by assessing potential mediation pathways. We conducted a cross-sectional study using data from 330 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) and mild cognitive impairment (MCI) groups. High-resolution coronal T2-weighted MRI quantified MTL subfield volumes using the ASHS protocol. Plasma biomarkers were measured using ultrasensitive immunoassays. The cohort included 209 CN participants (mean age [SD] = 69.3 [6.9] years; 64.2% women; 24.4% APOE ε4 carriers) and 121 MCI participants (mean age [SD] = 71.3 [7.3] years; 48.8% women; 27.9% APOE ε4 carriers). MCI individuals showed significantly higher plasma concentrations of p-tau217, p-tau217/Aβ_1-42 ratio, NfL, and GFAP, and greater MTL atrophy. Higher plasma p-tau217 and p-tau217/Aβ_1-42 were associated with reduced bilateral hippocampal and CA1 volumes in MCI (β = - 0.37 to - 0.28; FDR p < 0.02). In CN, these biomarkers were positively associated with left hippocampal volume (β ≈ 0.19; FDR p = 0.04), and GFAP correlated with larger sulcal volume (FDR p = 0.03). Mediation analysis demonstrated that in CN individuals, the relationship between p-tau217/Aβ_1-42 and left sulcal volume was partially mediated by GFAP (indirect β = 0.11; FDR p = 0.048). This study reveals stage-specific plasma biomarker-MTL relationships across the Alzheimer's continuum. In MCI, plasma p-tau217 and its ratio to Aβ_1-42 closely track hippocampal subfield atrophy, reflecting tau-related neurodegeneration. In CN individuals, higher p-tau217 and p-tau217/Aβ_1-42 levels relate positively to hippocampal integrity, partly mediated by GFAP, suggesting early astroglial activity preceding structural loss. These findings underscore dynamic biomarker interactions and support integrating plasma and imaging markers for early AD characterization.