Associations between metabolic risk factors and indicators for Alzheimer's Disease pathology in a middle aged cognitively health cohort

Dementia due to Alzheimer's disease (AD) is a devastating condition characterized clinically by progressive cognitive impairment and pathologically by amyloid plaques, neurofibrillary tangles and severe atrophy. Diabetes mellitus (DM), obesity, and associated insulin resistance in middle age, are linked to a greater risk of developing dementia due to AD. Given the potential of modifying metabolic risk factors at midlife, my research explored the pathophysiological mechanisms involved in the link between insulin resistance and obesity at middle-age and AD pathology using molecular and imaging biomarkers. Specifically, my studies aimed to investigate the potential effect of metabolic risk factors on the accumulation of amyloid plaques and neurofibrillary tangles, alter brain structure and blood flow, and influence cognition in middle age.;The first study was conducted to assess the effects of insulin resistance on cognitive decline over a 4-10year period, and demonstrated that indeed, insulin resistance is associated with cognitive trajectories. The next three studies were aimed at identifying changes in AD biomarkers in CSF and brain imaging as predicted by insulin resistance, body mass index and abdominal obesity. The main findings indicate that elevated insulin resistance at midlife may affect amyloid processing as indicated by altered CSF levels, as well as acting via a tau-related mechanism, an effect that differed by APOE epsilon4 genotype. Given that tau in CSF is likely originating from axons, this finding was followed up by a neuroimaging study employing diffusion tensor imaging to examine the effects of insulin resistance and APOE epsilon4 on neural microstructure. Similar to the findings in CSF, the effects of insulin resistance on microstructure differed by APOE epsilon4 genotype. Finally, my studies of abdominal obesity suggest that this risk factor is not associated with amyloid or tau pathology as measured in CSF, nor microstructural changes, yet central obesity was associated with moderate effects on cerebral blood flow. In conclusion, the work presented in my thesis demonstrates a robust effect of insulin resistance on cognitive and biomarker outcomes in midlife, which may explain the increased risk of developing AD.