Alzheimer’s disease is emerging as a crucial problem in our society, raising the need for new therapeutic targets. One of the challenges in the study of the disease is that the course of the disease is highly variable across individuals, due to multiple different risk factors, including age and sex. Moreover, the aging process has overlapping molecular features with Alzheimer’s disease that might be masking the mechanism of disease. We hypothesized that age- and sex- dependent cellular and molecular changes in the brain are key drivers of the development of Alzheimer’s disease and of the memory impairment, and that the dynamics of this cellular cascade in the brain, determines the risk and resilience levels of individuals. In this project we aim to expand the traditional resolution in the study of Alzheimer’s disease from tissues to entire cellular environments, and to untangle overlapping molecular signatures of sex and aging, in order to unmask the true molecular mechanism of Alzheimer’s. The complexity of the brain tissue has been hampering the investigation of the different brain cells and their role in Alzheimer’s disease. Here, we are harnessing recent complementary technological advancements - in genomics: mapping RNA molecules with single cell resolution, in imaging: multiplexing imaging of hundreds of RNA molecules, as well as in machine learning and computational modeling.
Our specific goals for this project are to: 1) Map brain cells, molecular profiles and cellular environments that are unique to Alzheimer’s disease brains compared to healthy aging. 2) Chart the cellular cascade that leads to disease and how it differs from healthy aging. 3) Predict key cells and molecules that drive the increased risk for Alzheimer’s disease in women compared to men, and the key cells and molecules that drive cognitive resilience with age. 4) Investigate the key driver molecules to uncover the mechanism of disease and new drug targets. Overall, our innovative proposal has the potential to advance us toward novel and more effective therapeutic targets for Alzheimer’s disease.
