Project 460524

Alzheimer's disease (AD) is the commonest cause of dementia, in which patients experience progressive deterioration of cognitive and physical abilities. Dementia affects ~50 million people worldwide, and AD contributes to 60-70% of the cases. Despite urgent demand for effective AD treatments worldwide, results from clinical trials have not been promising. People with living dementia due to AD typically have additional co-occurring pathologies, the commonest being disease of the brain's small vessel disease (SVD). This contributes to the complexity of the pathology and poses challenges to developing treatments. In the quest to understand the mechanisms underlying AD risk and progression, and to identify novel treatment targets, we take a genome-wide interaction approach to integrate genetic and neuroimaging characteristics of AD and SVD. While conventional genome-wide association studies (GWAS) that search for genetic markers of AD focus only on those with main statistical effects in analyses, the interaction approach examines conditional effects of genetic markers, that are likely missed in traditional GWAS. My approach asks how the combination of SVD and a person's genetic make-up conspire to increase risk of AD. Beginning with the Sunnybrook Dementia Study, a consecutive case series of dementia patients and controls, I seek to identify genetic markers that contribute to the risk of an AD diagnosis among people who have extensive SVD. These genetic vulnerability factors may identify molecular pathways that make a person more susceptible to dementia when they have SVD. In relation to these markers, I will also examine disease characteristics and extend this approach to other available resources for confirmatory analyses and meta-analysis of results across different populations to strengthen the evidence. Within these molecular pathways that determine a person's vulnerability vs. resilience to SVD may lie novel candidates to target for AD treatment and prevention.