Association of Cortical Free Water With Brain Tau Tangle Load in the Alzheimer Disease Continuum

Neurofibrillary tangles (NFTs) progressively damage gray matter in Alzheimer disease (AD). Resulting cortical microstructural alterations might not be detectable using macrostructural metrics but may be studied using isotropic water diffusion, as it reflects extracellular free water content. The aim of this study was to examine the effect of NFTs on cortical microstructure by investigating whether cortical free water increases as a function of tau load. We also investigated whether phosphorylated tau in blood plasma also indicated cortical microstructural abnormalities.

For this cross-sectional study, we sampled participants with T1 MRI, multishell diffusion-weighted MRI, amyloid PET ([¹⁸F]AZD4694), tau PET, and plasma phosphorylated tau 217+ (p-tau217) from the Translational biomarkers in Aging and Dementia cohort at McGill University; participants were recruited between 2017 and 2024. We used the Neurite Orientation Dispersion and Density Imaging algorithm to calculate isotropic free water images ("free water"). FreeSurfer was used to calculate cortical thickness in the entorhinal, fusiform, inferior temporal, and middle temporal gyri regions of interest ("meta-ROI"); Automatic Segmentation of Hippocampal Subfields was used to calculate hippocampal volumes. We grouped participants by amyloid PET positivity (A), plasma p-tau217 positivity (T1), and tau PET positivity (T2). We performed voxel-wise correlation analyses between free water and these proteinopathy markers, as well as ROI-based analyses in the meta-ROI.

A total of 303 participants (mean age 67 years, 58.7% female) were included in this study (168 cognitively normal individuals, 43 with mild cognitive impairment, 23 with AD dementia, 68 not diagnosed). Tau PET was positively correlated with free water in gray matter predominantly in the temporal lobe (partial R² = 0.39, p < 0.001), and the correlation of p-tau217 with the meta-ROI free water was entirely mediated by tau PET (p < 0.001). In addition, medial temporal and hippocampal free water was negatively correlated with Montreal Cognitive Assessment scores in the A-T₁+ and A+T₂+ groups. The strongest ROI-based multilinear models for predicting temporal gray matter and hippocampal tau PET burden used both cortical thickness and free water as predictors (temporal gray matter partial R² = 0.62; hippocampal partial R² = 0.64).

In AD-relevant regions, increased free water correlates with tau load independently of macrostructural metrics or amyloid load. Free water may serve as an imaging marker for microstructural changes in gray matter resulting from NFT accumulation, complementary to macrostructural metrics.