Here, we seek to overcome this limitation by directly profiling changes in the circuitry of neurons and other brain cell types during Alzheimer’s disease, and examining how genetic variants are affecting that circuitry. Numerous high-profile attempts and hopes at therapeutics have consistently failed, and it is increasingly thought that the secret to success may be early intervention in pre-symptomatic individuals or those with mild cognitive impairment (MCI). However, such early interventions require detailed knowledge of the genes, pathways and cell types altered during the early stages of MCI and AD progression. To guide targeted therapeutic development that modulates these pathways, and to recognize the progression of Alzheimer’s disease at the molecular level across different brain regions and stages, we proposed single-cell profiling to dissect transcriptomic and epigenetic signatures. In addition, we also use contributions of combinations of genetic variants to uncover the expression changes resulting from their joint interactions.
Our ongoing work suggests microglial cells (immune cells in the brain) are likely to yield important insights in early diagnosis and interventions of AD, so we will classify subtypes of microglial cells according to different states, which will guide biomarker development and new therapeutic strategies for early intervention. We also will develop computational tools to systematically search for the candidates from the convergence of common, rare and somatic mutations in AD. Furthermore, we will functionally validate the candidates to support our hypothesis and predictions.
Alzheimer’s disease is a devastating neurodegenerative disorder affecting 1 in 3 dying seniors and costing $236 billion annually in the United States alone. Its prevalence is increasing rapidly in an aging population, and there currently is no cure. Recent genetic studies provide new hope for therapeutic avenues, but translating genetic results into therapeutics has been remarkably difficult, due primarily to the fact that most genetic mutations do not alter protein function directly, but instead affect the expression of nearby genes in subtle ways.
Here, we seek to overcome this limitation by directly profiling changes in the circuitry of neurons and other brain cell types during Alzheimer’s disease, and how genetic variants are affecting that circuitry. In the first funding period of the award, we generated thousands of transcriptional and epigenomic maps of gene expression and control region activity across individuals at single-cell resolution. We integrated the resulting datasets to decipher the mechanistic basis of genetic variants associated with disease, and to discover new therapeutic targets, and the pathways and cell types where they act.
In the next period of the award, we expand these studies with a spatiotemporal single-cell map of disease progression across brain regions and disease stages, detailed analyses of genetic effects by APOE and other strong-effect variants on gene expression at single-cell resolution, a high-resolution characterization of microglia subtypes, and integration of common, rare and somatic mutations to predict target genes, regulatory regions and regulators, which we systematically perturb using highly parallel reporter assays.