University College London Institute of Neurology Detecting and tracking early neurodegeneration in familial Alzheimer’s disease A thesis submitted for the degree of Doctor of Philosophy Philip S.J. Weston 1 For Emma and Evie 2 Declaration of authorship and originality I, Philip S.J. Weston, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Philip S.J. Weston 3 Acknowledgements Above all I would like to thank the FAD family members who so kindly donated their time and energy to participate in research. Without their effort and dedication none of the studies reported in this thesis would have been possible. I am grateful to the Medical Research Council for funding my Clinical Research Training Fellowship, and to the National Institute of Health Research, which provided valuable funds for other aspects of the study. My primary supervisor, Nick Fox, has been a constant source of support, inspiration, and motivation. I am grateful to Nick for entrusting me with such a valuable cohort of special individuals, and for allowing me to oversee the conduct of the studies presented here. I also thank my secondary supervisor Jon Schott for providing additional useful advice and support throughout. Finally I would like to thank my co-workers, collaborators and colleagues. On the two imaging projects: Manja Lehman, Natalie Ryan, Marc Modat, Ivor Simpson, Nico Toussaint, and Seb Ourselin. On the serum neurofilament light project: Henrik Zetterberg, Kaj Blennow, Simon Mead, and Ron Druyeh. On the accelerated long-term forgetting study: Adam Zeman, Chris Butler, Yuying Liang, Seb Crutch, and Susie Henley. I also thank Kirsty Macpherson for undertaking the majority of the neuropsychological testing, and to Jenny Nicholas and Tess Poole provided invaluable statistical support. I am also grateful to Martin Rossor, who was always available to offer guidance relating numerous aspects of the research. I lastly thank Chris Lane, Camilla Clark, Tom Parker, Cat Slattery, Ross Paterson, Alex Faulkes and Phil Fletcher, for being a constant source of friendship, support, and amusement. 4 Abstract Alzheimer’s disease (AD) is recognized to have a long presymptomatic period, with initial deposition of extracellular amyloid and intracellular tau, followed by downstream neurodegeneration and cognitive decline. There is great interest in testing potential disease-modifying treatments for AD prior to the onset of symptoms, when minimal neuronal loss has occurred. To facilitate this, robust and sensitive methods are needed to identify at-risk individuals, stage their disease, and track progression. Familial Alzheimer’s disease (FAD) shares many features, clinically, radiologically, and neurophysiologically, with the more common sporadic form of disease. Carriers of autosomal dominantly inherited mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes have relatively predictable ages at symptom onset, based on family history. Study of FAD mutation carriers therefore provides the opportunity for the prospective study of asymptomatic individuals with known underlying AD pathology prior to the onset of clinical disease. The studies presented herein aim to improve the identification and characterization of early FAD neurodegenerative change and its earliest downstream cognitive effects. A multimodal approach is taken, with both presymptomatic and mildly symptomatic individuals included. Chapter one provides an introduction to AD and methods for measuring early neurodegeneration. Chapter two then outlines the general methodological approach across the different studies. Chapters three and four present results of magnetic resonance imaging studies of macrostructural (cortical thickness) and microstructural (diffusion-weighted imaging) cortical change. Chapter five reports results for a new blood-based biomarker of neurodegeneration – serum neurofilament- light. Chapter six investigates a novel approach to presymptomatic cognitive testing – 5 assessing accelerated long-term forgetting. In all studies, significant differences between mutation carriers and non-carrier controls are detectable during the presymptomatic period. 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. 6 Table of Contents Declaration of authorship and originality ................................................................. 3 Acknowledgements .................................................................................................... 4 Abstract ....................................................................................................................... 5 List of tables ............................................................................................................. 14 List of figures ............................................................................................................ 15 Abbreviations ............................................................................................................ 17 Introduction ......................................................................................................... 20 1.1 Alzheimer’s disease ........................................................................................ 20 1.1.1 A brief history ........................................................................................... 20 1.1.2 The size of the problem ............................................................................ 21 1.1.3 Clinical features ....................................................................................... 22 1.1.4 Neuropathological features ...................................................................... 25 1.1.5 Genetic risk factors in sporadic AD .......................................................... 34 1.1.6 Environmental risk factors in AD .............................................................. 35 1.1.7 Treatment ................................................................................................ 37 1.2 The presymptomatic phase of Alzheimer’s disease ........................................ 44 1.2.1 Theoretical models of presymptomatic disease ........................................ 44 1.2.2 The need for biomarkers of presymptomatic AD ...................................... 46 1.2.3 The limitations of studying presymptomatic sporadic AD .......................... 48 1.3 Familial Alzheimer’s disease .......................................................................... 50 1.3.1 The genetic inheritance of FAD ................................................................ 50 1.3.2 The amyloid precursor protein gene ......................................................... 51 1.3.3 The presenilin genes ................................................................................ 52 1.3.4 Clinical features ....................................................................................... 54 7 1.3.5 Genotype-phenotype interactions ............................................................ 55 1.3.6 Predicting age at onset ............................................................................ 57 1.3.7 Genetic support for the amyloid cascade hypothesis ............................... 59 1.3.8 The utility of FAD in the research of presymptomatic disease .................. 59 1.4 Evidence of presymptomatic changes in familial and sporadic AD .................. 61 1.4.1 The need for markers of early disease ..................................................... 61 1.4.2 Measuring AD molecular pathology .......................................................... 64 1.4.3 Measuring neurodegeneration with structural MRI ................................... 68 1.4.4 Measuring neurodegeneration with diffusion-weighted MRI ..................... 77 1.4.5 Measuring neurodegeneration with fluorodeoxyglucose PET imaging ...... 92 1.4.6 Measuring neurodegeneration with CSF biomarkers ................................ 93 1.4.7 Measuring neurodegeneration with blood-based biomarkers ................... 95 1.4.8 Measuring early cognitive change ............................................................ 99 1.4.9 Summary of the evidence in support of findings in FAD being applicable to sporadic disease ................................................................................................ 106 1.5 Aims of this thesis ........................................................................................ 107 1.6 Publications arising from this chapter ........................................................... 109 2 General methods ............................................................................................... 109 2.1 Study participants ......................................................................................... 109 2.1.1 Participant recruitment ........................................................................... 110 2.1.2 Family mutations .................................................................................... 111 2.1.3 Inclusion criteria ..................................................................................... 113 2.2 Consent and ethical considerations .............................................................. 113 2.3 Structure of cohort study .............................................................................