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Interventions to delay or prevent the onset of Alzheimer’s disease (AD) would dramatically reduce the number of people living with dementia in the future. To reach this goal, it will be critical to identify individuals with preclinical AD, a clinically as ymptomatic disease stage that is characterized by accumulation of betaamyloid aggregates and neurofibrillary tangles in the brain, which are thought to contribute to neuronal injury and structural brain changes. The overarching goal of this dissertation was to better understand relationships between key pathological features of AD during this important preclinical trial and to assess the combinedpowerofbiomarkerstopredictprogressionalongtheADtrajectorypriortotheonset of clinical impairment. These experiments addressed two major questions: are early indicators of preclinical AD better associated with biomarkers that capture multi plepathologies simultaneously than with a biomarker for a single pathology measured in isolation? and do longitudinal analyses of pathology and cognitive decline within individuals provide better indications of movement along the AD trajectory compared to cross sectional models?
To address these questions, three Specific Aims assessed relationships between multiple biomarkers and both their cross sectional and longitudinal associations with brain change. Specifically, analyses were performed to investigate whether biomarkers for amyloid and neural injury predict longitudinal brain amyloid accumulation, white matter microstructural changes, and cognitive decline in late middle aged adults with elevated risk of AD due to parental family history and genetic factors. As hypothesized, measures of cooccurring amyloidosis and neural injury were more commonly associated with disease outcomes than markers of a single pathology, and longitudinal models enabled detection of early pathological and cognitive decline often not possible with cross sectional approaches. This dissertation provides important contributions to the field by assessing the preclinical trial of AD using a unique cohort of individuals who were middle-aged and cognitively healthy at study entry and who are enriched with risk factors for AD; by investigating an extensive panel of multimodal biomarkers; and by examining longitudinally measured change within individuals in terms of both biomarker levels and cognitive performance.