Local and distant atrophy mediate the relationship between tau pathology and cognition in temporoparietal region in Alzheimer's disease

Background Tau pathology is closely associated with brain atrophy and cognitive decline, but how it specifically influences local and distant gray matter volume (GMV) and cognitive function remains unclear. Objective This study aims to explore the spatial relationships between tau pathology, GMV and cognition using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Methods Twenty amyloid-β (Aβ)-positive Alzheimer's disease (AD) patients, 14 mild cognitive impairment (MCI) patients, and 22 Aβ-negative normal controls (NC) underwent standardized neuropsychological assessments and 18 F-fortaucipir PET/MRI scans. We investigated the associations between regional tau standardized uptake value ratio (SUVR) and GMV in AD signature regions. Mediation analyses were conducted to explore the potential mediating effects of local and distant GMV in the relationship between tau pathology and cognition. Results The study indicated that increased 18 F-fortaucipir SUVR and decreased GMV were related to cognitive performance in MCI and AD patients. Compared to NC group, the number of brain regions with local and distant correlations between GMV and SUVR was greater in AD/MCI group. Mediation analysis revealed that GMV served as a significant mediator between tau pathology and cognition in local regions. Furthermore, distant effects were also observed, with hippocampal atrophy partially mediated the relationship between entorhinal cortex tau pathology and cognition. Meanwhile, medial parietal lobe atrophy partially mediated the relationship between medial temporal lobe tau deposition and cognition. Conclusions Our findings provide an anatomically detailed insight into relationships between tau, GMV and cognition, especially in entorhinal cortex-hippocampus, temporal-parietal lobe cortical circuits.