Associations of plasma phosphorylated tau217 with cognitive impairment and brain microstructural alterations in Alzheimer's disease

Abstract Introduction Plasma phosphorylated tau217 (p‐tau217) is a promising biomarker for Alzheimer's disease (AD) risk detection. Its relationship with brain microstructure and cognitive impairment remains unclear. Multi‐component T2‐relaxometry is an MRI technique sensitive to myelin content, axonal degeneration, and neuroinflammation. Methods A total of 229 participants classified by p‐tau217 levels into p‐tau217– ( n = 176), p‐tau217+ ( n = 26), and intermediate ( n = 27) underwent neuropsychological testing and MRI. Voxel‐wise general linear models controlling for age, sex, education, apolipoprotein E ( APOE , and white matter lesions were performed for total water content (TWC), myelin water fraction (MWF), intra‐/extracellular water fraction (IEWF), geometric mean of intra‐/extracellular water (T2 IE ), and free/quasi‐free water fraction (FQFWF). Results The p‐tau217+ participants showed poorer cognition, increases in FQFWF and TWC, and reductions in IEWF and T2 IE across cortical and subcortical regions and white matter tracts. Discussion High p‐tau217 level associates with brain microstructure alterations and poorer cognition, supporting it as a biomarker of AD‐related neuropathology and the utility of T2‐relaxometry for detecting tissue integrity.