Sex-Specific Single Cell Expression Profiles, Genetic Risk and Drug Responsiveness in Alzheimer's Disease

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PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by progressive cognitive decline coupled with accumulation of brain amyloid-ß and tau aggregates. Despite being the most common neurodegenerative disease, there is no effective treatment available to slow or halt the fatal progression of AD. Two thirds of AD patients are females, and women have a higher risk of developing AD. Women with AD have more extensive brain histological changes than men with AD, more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects female and male brains differentially. Despite evident AD sex variance, the mechanisms and pathways are still poorly understood. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions and to develop sex-specific therapies. We hypothesize that female and male brains present critically distinct disease susceptibilities and responses to AD pathology, specifically with regard to immune architecture and CNS synapse plasticity. Our Preliminary single nucleus RNA sequencing (snRNA-seq) profiles of post-mortem human AD brains revealed sex-specific differences in cellular composition and neuroinflammatory features. We identified marker gene sets for AD- associated female-specific microglia subpopulations and assessed these gene sets through re-analysis of genome wide association study (GWAS) data. The proposed additional human data collection and statistical assessments will delineate the molecular architecture of the diverse brain cell responses affected by AD and sex, and is expected to identify multiple sex-specific candidate AD risk genes. The Preliminary studies have already revealed known female-biased and novel female-specific AD risk genes, such as APOE and MERTK. We will define the sex-specific role of MERTK in the determination of AD risk and neuroinflammation using conditional mouse MERTK alleles and AD knock-in mice. In mouse models, we will define at single cell resolution the extent to which sex-specific expression responses to knock-in of FAD mutations overlap with human Late Onset AD sex-specific expression patterns, as well as sex-dependent differences in gene expression profiles responding to treatment with a synapse-preserving therapeutic. The results from our study will identify sex- specific genes and pathways for AD onset, progression, and treatment response, offering new biological insights for AD prevention and therapy.