Grant: CIHR Fellowship

Dementia due to Alzheimer's disease currently affects over 500 000 Canadians and is expected to reach 1.1 million within a generation. Delaying the onset of symptoms by only two years would result in a savings of $15 billion in health care over the next decade. Approximately 30% of cognitively normal elderly are found to have Alzheimer's disease pathology in their brains at autopsy. Understanding the mechanisms behind this cognitive resilience - which may be influenced by an individual's genetic makeup, the pattern of expression of their genes, and the functioning of their immune system - is of paramount importance. Our primary goal is to model, compare, and contrast the roles of potential resilience genes in both the brain and immune system. In addition to genetic variation and gene expression, the three-dimensional structure of DNA and associated proteins, known the epigenome, is also different in brain tissue and immune cells (e.g. monocytes). A "residual cognitive score" representing the difference between cognitive performance and several types of brain pathology will be our main outcome. We will combine four layers of data simultaneously from the same set of over 600 individuals: genetics, epigenetics, gene expression, and residual cognitive score. We will also examine genetics and gene expression dynamics in monocytes derived from 300 of these same subjects. This will allow us to understand which genetic and epigenetic modifications affect cognitive reserve and if this effect is driven by gene expression. We will then test how neurons and immune cells derived from human induced pluripotent stem cells respond to changing expression levels of implicated resilience genes. Understanding these mechanisms behind may provide molecular targets for clinical intervention with the potential to slow or prevent cognitive decline in elderly who are affected by Alzheimer's disease pathology.