High-field MRI correlates with immunohistochemical analysis of the normal and Alzheimer's disease anterior olfactory nucleus

The human anterior olfactory nucleus (AON) is one of the earliest brain regions affected by tau and beta amyloid pathology in Alzheimer's disease, potentially serving as a conduit for the spread of aggregated proteins to downstream cortical regions. However, the architecture of the human AON remains poorly understood. Here, we applied a multimodal imaging framework combining ultra-high-field magnetic resonance (MR) microscopy, thin-section immunofluorescence, and whole-mount tissue clearing with confocal and light-sheet microscopy to characterise the three-dimensional architecture of the AON and its involvement in Alzheimer's disease (AD). In neurologically normal cases, we identified tear-shaped AON clusters using MR microscopy that aligned with cytoarchitectural boundaries defined by PGP9.5, CNPase, and UEA lectin immunolabelling in serial sections, confirming the validity of AON segmentation in intact bulbs. In AD cases, MR microscopy, immunofluorescence, and light-sheet imaging revealed concentrated tau and beta-amyloid pathology within the AON clusters. Despite this pathology burden, neither total olfactory bulb volume nor AON volume differed significantly between neurologically normal and AD groups, and pathology load did not correlate with either volumetric measure. These findings refine our understanding of the human olfactory bulb and AON structure and demonstrate that high-resolution MR microscopy is a reliable tool for investigating substructural changes in the olfactory system.