Fig. 4

Cellular and proteopathy composition of hippocampal neuroanatomy. a Representation of the three imaged hippocampi to identify differences in AD pathological changes. Included are samples from people who were diagnosed as cognitively normal (CN), cognitively impaired, no dementia (CIND), or Alzheimer’s Disease dementia (ADD). LFB and H&E histochemical staining of a serial section of each hippocampal slice imaged (Top). Pseudo-color overlay of CALRETININ (CR), CALBINDIN (CB), MAP2, and Histone H3 (HH3) acquired in each sample representing high-level neuronal morphology (Bottom). b Mask overlays of the cells and proteopathies collected by the segmentation methods described in Fig. 2, broken down by hippocampal neuroanatomy (Top) and cell or proteopathy subtype (Bottom). c Relative composition of each cell and proteopathy subtype within each anatomical subregion of each individual. d Ratio of proteopathy-associated cells to proteopathy-free cells in each anatomical region of each individual. Ratio of 1 indicates an equal number of proteopathy-associated cells to proteopathy-free cells, where PHF1-TAU NFT-NTs cell associations are shown in the top-panel and Aβ plaque cell associations in the bottom-panel. Callout indicates ADD, CA1 microglia with a high number of NFT-NTs associated microglia (green circle). e Normalized mean expression of microglia phenotyping channels in CA1 region of each individual, broken down by microglia with NFT-NTs association or those without. f Normalized mean expression of microglia phenotyping channels in CA1 region of each individual, broken down by microglia with Aβ plaque association or those without. g UMAP projections of CA1 microglia phenotyping channels in ADD. Gray represents CA1 microglia from CN, CIND samples (S4K-L for CN, CIND expression maps). Projection was calculated using Iba1, CD45, CD33, APOE, PHF1-TAU, Aβ42, Aβ40, and Pan Aβ markers. CIND and ADD are subsampled so that all conditions are represented by 447 microglia, the total number of CA1 microglia in the CN condition. h Image representation of tau-tangle and amyloid associated phenotypes described in E and F found in ADD CA1 microglia. Masks of microglia (yellow), tau NFT-NTs (cyan), and Aβ plaques (pink) (Left). Inset of microglia expressing phenotypic and proteopathy markers (Right). Abbreviations: CN, cognitively normal; CIND, cognitive impairment no dementia; ADD, AD dementia; DG, Dentate Gyrus CA1-4, Cornu Ammonis 1–4