Multimodal omics analytic framework identifies microglial immunometabolism endophenotypes underlying sex differences in Alzheimer’s disease

Abstract

AbstractBackgroundAlthough Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying AD sex differences are incompletely understood.MethodIn this study, we investigated the interplay between cellular metabolism and immune responses (termed the “immunometabolism endophenotype”) by unique integration of single nuclei transcriptomics (snRNA‐seq) and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer’s Disease Research Center. We conduced pathway activity score (PAS) to investigate metabolic alteration in microglia and astrocytes from brain cortex, with PAS > 0 indicating a specific cell type with higher average gene expression within a pathway, relative to all remaining cell types.ResultWe found that female AD subjects had a reduced PAS score within the TNFR2 non‐canonical NF‐kB pathway in microglia compared to male AD subjects, indicating reduced anti‐inflammatory effects of microglia in women. In addition, women with AD also showed lower PAS score within the branched chain amino acid pathway. Integrative sc/snRNA‐seq data analysis also shows sex‐specific metabolic cell‐cell communications among microglia, astrocytes and neurons. For example, male AD subjects have higher metabolic communication between astrocytes and excitatory neurons. In particular, astrocytes show lower PAS distribution across 84 metabolic pathways in women with AD, compared to men with AD. Astrocytes in female AD subjects showed deceased PAS within creatine metabolism pathways and increased PAS within threonine catabolism pathways.ConclusionThis study demonstrates proof‐of‐concept of microglial immunometabolism underlying sex differences in AD.