Slattery, Catherine Frances; (2019) Clinical and genetic heterogeneity in young onset sporadic Alzheimer’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Alzheimer’s disease, the commonest neurodegenerative condition, is characterised by accumulation of amyloid plaques and neurofibrillary tangles, neuronal loss, brain atrophy and cognitive impairment. Sporadic young onset Alzheimer’s disease shows marked clinical heterogeneity, with non-memory presentations including the syndromes of posterior cortical atrophy, logopenic aphasia and frontal Alzheimer’s disease, seen in around a third of individuals. This variability presents challenges for diagnosis and may confound clinical trial outcomes, but provides an opportunity to explore factors influencing differential selective vulnerability within neural networks which in turn may provide important clues to Alzheimer’s disease pathogenesis. This thesis describes the recruitment of a cohort of a deeply phenotyped patients with sporadic young onset Alzheimer’s disease (n=45) and healthy controls (n=24), and a series of genetic, clinical, neuropsychological, and structural, diffusion and functional magnetic resonance imaging experiments to explore disease heterogeneity and its associations. There are a number of key findings. APOE ε4 genotype contributes to, but does not fully explain clinical heterogeneity, with the youngest ages of onset and most atypical presentations seen in ε4-ve individuals. Heterozygosity of the rare TREM2 genetic variant for late-onset Alzheimer’s disease, p.R47H, is shown to confer risk for young onset Alzheimer’s disease, driving younger age of onset rather than clinical phenotype. Regional brain atrophy profiles in APOE ε4 genotypes are shown to broadly align with the associated neuropsychological deficits. Microstructural damage studied using diffusion tensor imaging, and – applied for the first time to Alzheimer’s disease – Neurite Orientation Dispersion and Density Imaging – provides a fine-grained profile of white matter network breakdown, revealing regional differences based on APOE ε4 genotype, and correlations with focal neuropsychological deficits. Finally, activation fMRI using a music paradigm to probe relationships between cognitive performance and brain function is shown to delineate different patterns of brain activation during memory tasks in different Alzheimer’s disease phenotypes.

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