Imaging the pathways towards Alzheimer’s disease: The value of MRI-derived phenotypes in its earliest stages

MRI bears great potential for advancing our knowledge of the early pathological substrates of Alzheimer’s disease and can add valuable information for the disease diagnosis and understanding. Biologically characterizing MRI-derived features will provide us with non-invasive in vivo information about the pathophysiological processes that interact with early Aβ deposition and promote pathogenesis of AD from its preclinical asymptomatic stages. The overall aim of this thesis was therefore to characterize the value of MRI-derived phenotypes in preclinical AD research. To this end, the following questions were addressed: 1. How can we address the methodological challenges of performing large neuroimaging multicenter studies with preclinical AD cohorts? 2. What are the structural and functional brain endophenotypes that are altered in relationship with early AD proteinopathies measured in CSF? 3. What is the impact of vascular factors in AD, and how can this be measured using MRI features? 4. What are the genetic pathways that determine distinct imaging features? In Chapter 2, I present the EPAD cohort through its characterization based on pathological markers of Alzheimer’s disease, and present our semi-automatic multimodal and multisite pipeline to curate, preprocess and quality control the EPAD MRI dataset, and compute image-derived phenotypes. In Chapter 3, I present alterations of brain functional and structural properties in the preclinical stages of AD, as measured by multimodal quantitative MRI techniques. Chapter 4 investigates the relevance of MRI for the understanding of possible alternative early pathological mechanisms, specifically focusing on the role of semi-quantitative and quantitative vascular markers and their association with AD pathology. Chapter 5 aims at providing evidence of the genetic bases and associated polygenic pathways promoting distinct imaging biomarkers alterations in preclinical AD. This thesis is concluded with a general discussion in Chapter 6.