O'Connor, Antoinette; (2021) Familial Alzheimer’s disease: preclinical disease and pathophysiology biomarkers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

It is now well recognised that Alzheimer’s disease (AD) has a long presymptomatic period, with evidence of amyloid deposition being detected approximately 20 years before the onset of cognitive decline. This clinically silent period opens up a treatment window at a potentially more tractable stage of the disease. As we move towards AD prevention trials, there is a need for robust and sensitive methods that can detect and track disease progression, especially during this asymptomatic period. Familial Alzheimer’s disease (FAD) is an autosomal dominant condition that has many shared clinical, radiological, and neuropathological features with the more common sporadic form of disease. In addition, the age at onset in FAD is reasonably consistent between successive generations. Therefore, study of FAD mutation carriers provides an opportunity to prospectively characterise the sequence, and timings, of key pathological changes in AD. In addition, this reasonably pathologically pure form of AD provides a valuable opportunity to better understand the molecular drivers of disease onset. The studies presented in this thesis aim to facilitate the identification of biomarkers of FAD, with the overarching aim of identifying biomarkers of preclinical disease and/or key pathological processes. A multimodal approach is taken, with both presymptomatic and mildly symptomatic individuals being included. Chapter 1 introduces the background to the problems addressed in this thesis by providing an overview of early onset and familial Alzheimer’s disease and its preclinical period. Chapter 1 also outlines some of the key pathological drivers of AD onset, and specifically FAD. Chapter 2 then outlines the methodological approaches that are common to the different studies reported in this thesis. The first data chapter of this thesis (Chapter 3) performs data-driven modelling of cognitive performance in a clinically asymptomatic FAD cohort to demonstrate the sequence and timing of early cognitive change in FAD (Chapter 3). Following on from this the trajectory of a promising AD biomarker, plasma phospho-tau181 (p-tau181), 3 in FAD is explored (Chapter 4). This study, which was the first to examine the utility of plasma p-tau181 in FAD, showed that increased levels are detected in presymptomatic mutation carriers and that increases begin over a decade prior to estimated symptom onset. The ability of imaging measures of tau, specifically longitudinal tau positron emission topography (PET) scanning, to detect presymptomatic change is also examined (Chapter 5). In contrast to blood measures of p-tau181, this study did not find evidence of increased tau signal in presymptomatic mutation carriers, instead it showed tau burden in FAD increases in close temporal proximity to symptom onset. Finally, Chapter 6 investigates the influence of FAD genotype on plasma amyloid beta ratios. This study, the first to investigate inter-mutation differences in plasma amyloid beta profiles, showed evidence of marked inter-group differences as well as associations between the relative production of longer (≥ 42 amino acids length) amyloid beta peptides and the estimated timing of symptom onset in Presenilin1 mutation carriers. The thesis draws together these different approaches and discusses how they advance our understanding of the neurobiology of AD and their potential utility in both clinical assessment and presymptomatic therapeutic trials.

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