50µm ex vivo MRI reveals distant layer-specific hippocampal atrophy in early Alzheimer's disease

Tau pathology is a major driver of neurodegeneration in Alzheimer's disease, yet its earliest structural correlates remain poorly understood because of the limited resolution of in vivo magnetic resonance imaging (MRI). We studied 19 postmortem brains spanning Braak neurofibillary tangle (NFT) stages I ( N  = 9) and II ( N  = 10) using ultra-high-resolution ex vivo MRI of the medial temporal lobe (MTL) at 50 × 50 µm² in-plane resolution and 100 µm slice thickness. MTL subregions and layers were delineated across the anterior and posterior MTL, including layers of cornu ammonis (CA)1 and CA3, subiculum, dentate gyrus, transentorhinal cortex (Brodmann area 35 [BA35]), and entorhinal cortex (ERC). Associations between AT8-positive NFT density and regional thickness were assessed using nonparametric models controlling for demographic factors and co-pathologies. Ultra-high-resolution MRI enabled visualization of previously inaccessible mesoscopic features, including dentate gyrus lamination, subicular boundaries, and the internal organization of the stratum radiatum/lacunosum-moleculare. Compared with Braak stage I, Braak stage II cases showed significantly lower thickness of the anterior CA1 pyramidal cell layer and anterior subicular stratum lacunosum-moleculare, with findings remaining robust across sensitivity analyses. Anterior CA1 and subicular thinning were strongly associated with NFT burden in early Braak-affected regions (ERC/BA35), rather than with local tau pathology, supporting a distant effect of tau on neurodegeneration. Interaction analyses further suggested that the association between tau pathology and CA1 atrophy differed according to TDP-43 status. These findings demonstrate that tau-related atrophy is detectable as early as Braak stage II and preferentially affects anterior CA1 and subiculum at the laminar level, supporting a network-level mechanism of early neurodegeneration.