Nissl-stained sections and FIB/SEM images of the neuropil from Alzheimer’s disease cases showing different neuropathological stages. (A and B) Nissl-stained coronal sections of the human CA1 field of the hippocampus from Cases VK22 (A) and VK16 (B) (Braak/CERAD stage: V/C and VI/C, respectively; see Supplementary Table 1 for further details). Note in B that this case shows a dramatic neuronal loss (hippocampal sclerosis), in comparison to the other Alzheimer’s disease case shown in A. (C and D) FIB/SEM images of the neuropil of Cases VK22 (C) and VK16 (D). Some asymmetric synapses are marked with white arrowheads in C. Some bundles of thick electron-dense filaments inside neuronal processes are pointed out with white arrows in D. A dystrophic neurite has been pseudo-coloured in brown. (E–H) Asymmetric synapses shown at higher magnification from Cases VK22 (E and F) and VK16 (G). While the synapse observed in E–G are morphologically normal-looking, the synapse observed in H presents a presynaptic terminal virtually lacking synaptic vesicles and with intracellular thick electron-dense filaments (white arrow). These abnormal-looking synapses were only observed in Case VK16 (see also Supplementary Fig. 9). Lac-Mol = stratum lacunosum-moleculare; Pyr = stratum pyramidale; Rad = stratum radiatum. Scale bar in H = 350 µm in A and B; 762 nm in C and D; 354 nm in E–H.