Knight, W.D.; (2010) Measures of onset, progression and intervention in Alzheimer’s disease: the familial paradigm. Doctoral thesis , UCL (University College London).

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Abstract

Familial Alzheimer’s disease (FAD) is a valuable paradigm for the study of the more common sporadic AD (SAD). The two forms of the illness share many neuropathological, clinical and radiological characteristics but it is not yet possible to predict the onset of SAD or confirm its presence without histopathological analysis. Fully penetrant amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) gene mutations permit both, and therefore lend themselves to clinical research with results which may be applied to the study of SAD. The identification of biomarkers of onset and progression are vital in the selection of research participants and in the rapid evaluation of new therapies. This thesis further characterizes FAD with a number of studies. These address the use of imaging biomarkers and help clarify the nature of the relationship between FAD and SAD. Two reports of novel pathogenic FAD mutations are included as well as other studies exploring the clinical and radiological (structural and molecular) phenotypes associated with FAD. Key findings are as follows: the novel PSEN1 p. L166del and S132A mutations are both associated with FAD; the APPV717G mutation can be associated with pure progressive amnesia reflected in an atypical structural imaging profile; APP locus duplication is a significant cause of early onset dementia in the UK and the recognised phenotype should be expanded to include early seizures and apparently sporadic disease; regional cortical thickness (CTh) decline accelerates after diagnosis in FAD mutation carriers (MC) and differences between MC and controls are detectable in presymptomatic mutation carriers more than 4 years prior to clinical diagnosis; APP and PSEN1 mutations may produce different temporal and topographical patterns of cortical change; increased 11C-PiB retention in a highly heterogeneous pattern may be detected in presymptomatic PSEN1 mutation carriers.

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