Fig. 1

Aberrant expansion of functionally compromised microglial populations in female subjects with LOAD. A T-SNE plot of 70,634 nuclei derived from 48 age- and sex-matched prefrontal cortex samples harvested from both nondementia [N = 24 (male N = 12; female N = 12)] and LOAD [N = 24 (male N = 12; female N = 12)] patients from the Mathys et al. dataset. Different cell types are abbreviated as follows: excitatory neurons, Ex; oligodendrocytes, Oli; inhibitory neurons, In; astrocytes, Ast; microglia, Mic; endothelial cells, En; and oligodendrocyte progenitor cells, Opc. B Cells were further subclustered and colored based on subcluster numbering. C Cell number distribution statistics according to sex and disease status within different subclusters. Bars on the right represent − log10(p value). D Trends of changes in the scaled female:male cell ratio against disease status. ***P < 0.05. E T-SNE plots showing how female and male nuclei from Clusters 13 and 21 are distributed in different stages of the disease. F, G Relative cell ratio of Cluster 13 in different F stages of disease or G status of cognitive functions (Cogdx scores). H Disease status of samples of the ROSMAP study was defined based on multiple clinicopathological parameters (x-axis). I, J Relative microglial cell ratio changes in ROSMAP samples calculated by the Scaden deep learning algorithm. Comparisons were made between various I disease statuses and J stages of cognitive function (Cogdx scores). K Number of DEGs identified from sex-specific comparisons made between LOAD and ND samples of the ROSMAP dataset. L Gene Ontology: biological process pathway enrichment analysis of downregulated DEGs in female LOAD samples. M Volcano plots illustrating DEGs curated from the comparison between Cluster 13 nuclei originating from LOAD versus ND samples in a sex-specific manner [females (top panel) and males (bottom panel)]. N UpSet plot illustrating how DEGs shown in M overlapped and were related to one another. O. Metascape enrichment network of DEGs shown in M and corresponding boxes indicating how different pathways manifested in LOAD samples of different sexes. Pathways that shared similar trends of changes in a particular sex are grouped together in dashed boxes. Color code: light pink (downregulated pathways in female LOAD); dark pink (upregulated pathways in female LOAD); dark blue (upregulated pathways in male LOAD)