High-resolution ex-vivo MRI reveals layer-specific atrophy of hippocampal subregions to the earliest tau pathology

Background Tau deposition targets the medial temporal lobe (MTL), making this region essential for understanding the earliest stages of Alzheimer’s disease (AD). Although in-vivo MRI can detect MTL atrophy, the link between structural alterations and underlying tau pathology during the preclinical phase remains unclear. This study aimed to identify the anterior MTL subregions affected by early tau pathology (Braak stages I–II) using ultra-high-resolution ex-vivo MRI combined with quantitative histopathology. Methods High-resolution ex-vivo MRI (50 µm) of the anterior MTL was obtained from 15 donors using an 11.7 T scanner. Twelve subfields were manually segmented, and landmark-based cortical thickness was estimated. Corresponding tissue blocks were paraffin-embedded for ipsilateral neuropathology, with quantification of neuropil threads and (pre)tangles. Cortical thickness was compared between Braak I and II using contrast analyses, and partial Spearman correlations assessed associations with tau pathology. All analyses were adjusted for age, sex, and co-pathologies (TDP-43/α-synuclein). Results Compared with Braak I, Braak II individuals showed significantly reduced thickness of the anterior CA1 pyramidal layer (β = –0.22mm; p