Hippocampal atrophy starts in CA1 pyramidal layer from NFT Braak stage II : a post-mortem 11.7T MRI study

Background Tau deposition primarily targets the medial temporal lobe (MTL), making this region critical for understanding preclinical Alzheimer’s disease (AD). While in-vivo MRI has been used to measure MTL atrophy, the relationship between structural MRI and underlying tau pathology at early stages remains poorly understood. We aimed to identify MTL subregions affected by early tau pathology using high-resolution ex-vivo MRI combined with histopathology. Methods Fifteen high-resolution (50 µm in-plane) ex-vivo MRI scans of the human MTL were acquired using an 11.7T Bruker MRI scanner. For each specimen, anterior MTL was manually segmented into 12 subfields to extract cortical thickness (Figure 1). Specimens were then paraffin-embedded for immunohistochemistry to quantify tangle and pretangles density per mm² in the anterior section. Statistical analyses included group comparisons of cortical thickness between NFTs Braak stage I and II, and partial correlations between cortical thickness and (pre)tangle measures. All analyses were adjusted for age, sex, and co-pathologies. Results Group comparisons showed that Braak stage II individuals exhibited thinner anterior CA1 pyramidal layers compared to Braak stage I donors (β= -0.22mm; p < 0.01, Figure 2). Notably, anterior CA1 pyramidal cell layer thickness was the only measure significantly correlated with tangle density in the same region, with 84.6% of the thickness variability explained by neurofibrillary tangles (R= -0.92; p < 0.01, Figure 3). It also showed a trend towards association with pretangle density (R= -0.74; p = 0.06). Discussion By combining high-field ex-vivo MRI with tau histopathology, we demonstrate that early tau pathology in AD is associated with selective atrophy of the CA1 pyramidal layer. These findings highlight the CA1 subfield as a priority target for in-vivo studies aimed at detecting preclinical AD.