Grant: Project Grant

Over 500,000 Canadians are currently living with dementia, and this is predicted to reach one million in the next two decades. Alzheimer's disease (AD) is the most common form of dementia and remains one of the most feared consequences of aging. AD is characterized by the abnormal accumulation of two proteins in the brain (amyloid and tau), which leads to neuronal death and eventually cognitive and memory deficits. There are currently no approved disease-modifying therapies for AD and recent drug trials targeting clearance of amyloid alone have been unsuccessful, motivating the need of studying therapies targeting both proteins. In addition to protein accumulation, human and animal work has demonstrated widespread brain networks dysfunction in AD. Specifically, the connectivity between the entorhinal cortex (one of the first sites of abnormal tau accumulation in the brain) and the hippocampus (a key brain region for memory formation) is selectively abnormal in early AD. The overall goals of our work are to study altered entorhinal-hippocampal connectivity and its effect on cognitive function, and determine the efficacy of a combinatory treatment (that targets abnormal buildup of both amyloid and tau) in recovering normal connectivity and normal cognition. To perform this study, we will leverage our expertise in animal models of AD that we have previously characterized, computational tools that we have developed, novel histological techniques, functional brain recordings and cognitive testing. Compelling preliminary data from our prior work supports this proposal. Our proposed study will establish signatures of abnormal hippocampal network function and enhance our understanding of the direct effects of these signatures on cognition. This research also has the potential to establish network dysfunction as a secondary, intermediate outcome measure of treatment response in clinical trials, a critical need given the difficulty of achieving cognitive rescue in AD.