Traditional AD tau Braak staging, based largely on the presence/absence of tau in serial autopsies, described a stereotypical progression of tau pathology in HIPPsf. Many younger AD patients present with non-amnestic syndromes (naAD) during life, suggesting relative sparing of the hippocampus, but patterns of tau in HIPPsf in these patients are understudied. We used digital pathology to test the hypotheses that 1) severity of tau pathology measured by digital pathology in HIPPsf will reflect traditional Braak staging in aAD and 2) naAD patients have lower hippocampal tau than aAD.

We selected autopsy-confirmed naAD (n=41) and an age/sex-matched autopsy aAD reference cohort (n=40) for study. Hippocampal sections were stained for phosphorylated-tau (AT8), scanned on a digital slide scanner and digital images analyzed using HALO software. Hippocampal subfields [Entorhinal Cortex (ERC) and Cornu Ammonis (CA) regions: CA2/3, CA1/Subiculum and CA4/dentate gyrus (DG)] were manually segmented using cytoarchitectural features according to a previously validated approach and percent-area occupied (%AO) tau measured in each subfield. We used a linear mixed-effects model to test HIPPsf regional and clinical-group differences in ln-transformed %AO tau.

We found a significant effect of subfield region, with lower tau %AO in later-affected subregions, including  CA2/3 and CA4/DG compared to early-affected ERC (β=-0.5,-1.6, p<0001), whereas earlier-affected CA1/Subiculum had similar high-level tau %AO to ERC (β=-0.03, p>0.1). We also found a significant “clinical group x subfield” interaction, with lower tau %AO in naAD in CA4/DG (β=-0.5, p<0.04).

Digital measure of tau pathology in postmortem HIPPsf appear to recapitulate traditional Braak stages in aAD, where early regions (CA1/Subiculum and ERC) have higher tau than later-affected subfields (CA 2/3, CA4/DG). Tau pathology in naAD may relatively spare later-stage HIPPsf.