Grant: Project Grant

Over 700,000 Canadians live with Alzheimer's disease (AD) or another dementia, and this is projected to exceed one million by 2030. 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 behavioural deficits. Recent promising drug trials targeting the removal of amyloid have reached modest effect sizes. However, up to 30% of patients were at increased risk for brain swelling and bleeding following drug intake. Preclinical and autopsy studies have suggested that these at-risk patients have amyloid deposition in the vessel wall (cerebral amyloid angiopathy or CAA). While the biological pathways underlying CAA remain not well understood, inflammation has recently emerged as a potential key mediator in the stages between vascular amyloid (CAA) and vascular dysfunction. However, to study the link between inflammation and CAA in living humans, we need biomarkers that reflect CAA in the early stages of abnormality. The goal of this work is to identify inflammatory and cognitive differences across the spectrum between early-stage CAA and AD dementia. To this end, we leverage existing large dementia cohorts. To estimate early-stage CAA, we employ structural and functional magnetic resonance imaging to measure the enlarged spaces around our vessels and vessel function, both at high- and ultra high-resolution MRI. We will evaluate these early-stage CAA-related markers in relation to select inflammation markers and cognitive decline. Identifying biomarkers of CAA and related inflammation will open up new directions on: 1) biological pathways underlying the risk of drug-induced side-effects, 2) novel targets for treatment beyond cortical amyloid and tau, and 3) informing upcoming clinical trials that enroll AD participants with combined vascular disease, by developing a patient stratification approach based on vascular, immune, and AD biomarkers.