Impact of sex differences on the trajectory of interactome dysfunctions across the AD spectrum

ABSTRACT The impact of sex differences in Alzheimer's disease (AD) remains poorly understood, especially in the context of protein-protein interactions within vulnerable regions that drive dysfunction. Despite growing appreciation of the clinical course, presentation, and severity of AD, studies of sex impacting AD development and progression

are lacking. Although recent high-throughput and bioinformatics technologies help to understand molecular and genetic basis of sex differences in aging and AD, reliance on static `omics data representing a descriptive inventory of biomolecules measuring changes in their stoichiometry at a given time and condition limits functional

insights. Another roadblock is translating these complex datasets into biological insights requires sophisticated computational algorithms, diminishing access and impact to the biomedical community at large. To address these limitations this proposal introduces epichaperomics, an unbiased state-of-the-art `omics

approach we invented to generate direct access to interactome perturbations and to the functional outcome of such changes in native biological systems. We posit by applying epichaperomics to well-characterized postmortem human brains that i) capture the disease trajectory, ii) encompass AD vulnerable and less affected

regions, and iii) have robust parallel information on patient-specific correlates, will enable rigorous hypothesis- generating analyses on potential impact of stressors and vulnerabilities on disease trajectory, and on interactome as well as connectome dysfunctions as they occur in sex-dependent manner. Through this novel approach we

expect to derive mechanistic innovation on specific dysfunctions impacted by sex differences leading to insights into sex-phenotype relationships not available through other `omics platforms. By evaluating, understanding, and anticipating interactome changes through epichaperome formation in relation to sex impact (Aim 1) and

subsequent straightforward computational analysis with web-based output (Aim 2), first-of-a-kind proteome-wide insights into the impact of sex differences on interactome networks vulnerabilities and dysfunctions within the hippocampus and regions of the default mode network in relation to the relatively spared cerebellum, both on

their nature and trajectory, in vulnerable cells and brain regions will be generated. Information how stressors and vulnerabilities (e.g., genes, environment, hormonal status) interact at cell and brain connectome levels to produce heterogeneous phenotype mapping of disease vulnerability will be produced. We posit a whole new

treatment paradigm avenue will open, providing a previously unavailable sex-specific precision medicine approach to AD by understanding and targeting the interactome across the AD spectrum of no cognitive impairment, mild cognitive impairment, and AD dementia through stressor and vulnerability analysis. Raw

datasets and data analytics from interactome network studies will be deposited into free-access portals accessible by the scientific community for additional mining and hypothesis testing studies. A web-based user- interface will also be designed facilitating data processing and visualization.