| Summary: | This thesis investigates relationships between clinical, neuroimaging and neuropathological features in autosomal dominant familial Alzheimer’s disease (FAD), with the aim of studying phenotypic heterogeneity and preclinical change. Chapters 1 and 2 introduce the background to the problem to be addressed in this thesis with an emphasis on current understanding of clinical and imaging changes in AD, and specifically in FAD. The FAD phenotype can be highly variable and, although it shares many clinical features with sporadic AD, it also possesses important differences. The clinical spectrum of FAD is first investigated, through analysis of all symptomatic cases studied at our research centre over the past twenty-five years (Chapter 3). Associations between phenotypic and pathological heterogeneity are then explored, with a study investigating genetic determinants of white matter hyperintensities and cerebral amyloid angiopathy (CAA) in FAD (Chapter 4). CAA is a common but variable feature of AD that appears to be an important factor in amyloid-modifying therapy and the term ‘ARIA’ has been coined to describe amyloid-related imaging abnormalities, thought to relate to vascular amyloid, that have been observed in a variety of amyloid-modifying therapy trials. Spontaneous changes of ARIA in FAD and the genetic risk factors that may provoke them are then described (Chapter 5). The recent launch of preclinical treatment trials for FAD necessitates better understanding of the trajectory of biomarker changes early in the disease. Observations from amyloid imaging studies, of presymptomatic amyloid deposition in the thalamus and striatum, motivated the final study, which examines changes in volume and diffusivity of these subcortical structures and their connecting white matter tracts in symptomatic and presymptomatic FAD mutation carriers (Chapter 6). Together, these studies demonstrate that exploring phenotypic heterogeneity and preclinical imaging changes can illuminate aspects of the underlying disease process, informing our understanding of FAD and potential effects of treatment.
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