Fig. 4

Spatial transcriptomic changes between different stages of ADNC. a Frontal cortex stained for amyloid plaque (green) and p-tau (red). NP and non-NP is determined by anti-tau antibody 7F2 positivity around the amyloid plaque. Amyloid plaque (green) with 7F2 positivity is considered NP. Amyloid plaque without 7F2 positivity is considered non-NP. Control is ROI without amyloid plaque. A total of 23 250- μm diameter ROI (10 NP, 10 non-NP, and 3 control) were selected per sample. 12 brain samples – low AD (n = 4), intermediate AD (n = 4) and high AD (n = 4) were used. However, 1 low AD case and 2 high AD cases failed to pass the quality control for analysis. b UMAP dimension reduction of spatial transcriptomic changes in different ADNC and plaque types. The biggest transcriptomic changes are seen between stages of ADNC. c Volcano plot and pathway analysis of different stages of ADNC – Low AD vs. Intermediate AD, Low AD vs. High AD, and Intermediate AD vs. High AD. Left panel: Volcano plot and pathway analysis showing spatial transcriptomic differences between Low AD and Intermediate AD cases. Top 20 pathways that are upregulated in both Low AD and Intermediate AD microenvironment. The blue color represents pathways that are upregulated in Intermediate AD or downregulated in Low AD. The red color represents pathways that are upregulated in Low AD or downregulated in Intermediate AD. Integration of energy metabolism (adj p-value = 0.014), Cellular response to heat stress (adj p-value = 0.014), and Hemostasis (adj p-value = 0.024) are upregulated in Intermediate AD. Middle panel: Volcano plot and pathway analysis showing spatial transcriptomic differences between Low AD and High AD. Top 20 pathways that are upregulated in both Low AD and High AD microenvironments. The blue color represents pathways that are upregulated in High AD or downregulated in Low AD. The red color represents pathways that are upregulated in Low AD or downregulated in High AD. Developmental Biology (adj p-value = 0.003), Cellular response to stress (adj p-value = 0.003), and Axon guidance pathways (adj p-value = 0.003), are upregulated in High AD. Right panel: Volcano plot and pathway analysis showing spatial transcriptomic differences between Intermediate AD and High AD. Top 20 pathways that are upregulated in both Intermediate AD and High AD microenvironment. The blue color represents pathways that are upregulated in High AD or downregulated in Intermediate AD. The red color represents pathways that are upregulated in Intermediate AD or downregulated in High AD. Extracellular matrix organization (adj p-value = 0.005) is upregulated in High AD while, neuronal system pathway (adj p-value = 0.005), is upregulated in Intermediate AD