Multimodal single-cell genomic and epigenomic analyses elucidate Alzheimer’s sexual dimorphism in human immune systems aging

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PROJECT SUMMARY Alzheimer’s disease (AD) is sexually dimorphic in its prevalence, incidence, symptomology, and neuropathology, but the mechanisms underlying these sex differences are not well understood. While sex differences in susceptibility to inflammation and AD progression have been reported, the relationship between local and systemic inflammation and sex differences remains to be determined. Our preliminary single-cell genomic analyses have identified sex-specific microglial gene signatures in AD patient brains. Bioinformatics analyses of single-cell transcriptomic data of human peripheral blood mononuclear cells (PBMCs) imply that multiple sex- specific, candidate pro-inflammatory genes are highly expressed in myeloid-derived suppressor cells (MDSCs) in AD. We therefore posit that an interplay between microglia and systematic inflammatory mechanisms (termed the “peripheral-central neuro-immune interactome”) exists and that understanding this system will be essential to improve the mechanistic elucidation of AD pathogenesis in a sex-specific manner. Recent advances of multimodal single-cell genomic and epigenomic analyses have shown the potential to provide a comprehensive understanding of the neuro-immune and peripheral immune systems underlying sex differences in AD. Integration of the single-cell transcriptome, epigenome, the human interactome, along with large-scale genetic loci from genome-wide association studies are essential for such identification. To address this hypothesis, our short-term goal is to identify next-generation immune modulators for AD sex differences and molecularly targeted treatments for male and female patients with AD. We will leverage large-scale single- cell genomic and epigenomic data generated from human brains and bloods with varying degrees of AD pathology available at our two National Institute of Aging (NIA)-funded Alzheimer's Disease Research Center (ADRCs) at the Cleveland Clinic and University of Washington. Aim 1 will test the hypothesis that central neuro- immune transcriptional networks mediate sex differences in AD using single-nucleus genomic and epigenomic analyses of human brains. Aim 2 will test the hypothesis that cell type-specific central neuro-immune and peripheral immune interactome network changes in AD pathogenesis act in a sex-specific manner. In parallel, we will utilize network-based, single-cell multi-omics analyses in AD transgenic mouse models to identify immune cell type-specific promoters and enhancers that encode sex-specific master gene regulatory networks for AD. Aim 3 will test the hypothesis that sex-specific, peripheral-central neuro-immune interactome networks in AD can be targeted via pharmacologic treatment to reduce AD progression. We will use our well-established network proximity methodologies to identify sex-specific repurposable drugs that influence the immune response using mouse models and validate preclinical findings in large patient databases using state-of-the-art retrospective cohort observations. We believe that this highly innovative and integrated approach offers the possibility of achieving our long-term goal of greatly accelerating personalized sex-specific treatments for AD.